Oncology Tribune July 2012 HK

July- August June 2012
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Pan-ErbB blocker tops standard chemo in lung cancer
NEWS Asian study unveils mechanism of HBV integration in HCC
CONFERENCE Better strategies needed for ALL in adolescents and young adults
INDUSTRY UPDATE First-line temsirolimus improves survival in poor-prognosis mRCC patients
CASE STUDY Capecitabine in advanced gastric cancer
Jul-Aug 2012
Pan-ErbB blocker tops standard chemo in lung cancer

Christina Lau
fatinib, an investigational drug that irreversibly blocks EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4), significantly extended progression-free survival (PFS) vs pemetrexed plus cisplatin in the largest phase III trial in EGFR mutation-positive advanced lung adenocarcinoma. [ASCO 2012; abstract LBA7500] The oral pan-ErbB inhibitor was particularly beneficial for patients with deletion 19 or L858R common mutations that together accounted for 89 percent of all EGFR mutations in the trial. Unlike reversible EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, afatanib blocks the entire ErbB family of receptors permanently, said lead investigator Dr. James Yang of the National Taiwan University Hospital. While gefitinib and erlotinib have demonstrated significant benefits vs first-line chemotherapy, LUXLung3 is the first trial in EGFR mutation-positive lung cancer to use pemetrexed/cisplatin as a chemotherapy comparator. The global trial included 345 treatmentnave patients from 25 countries who had stage IIIB (wet) or IV disease (median age, 61 years; ECOG performance status, 0-1; East Asians, 72 percent; never-smokers, 68 percent). Patients were randomized 2:1 to receive afatinib (40 mg) once daily or pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) q21d until progression. The trial met its primary endpoint of PFS.
After a median follow-up of 8 months, patients receiving afatinib had a significant 4.2-month improvement in PFS. Median PFS was 11.1 months with afatinib vs 6.9 months with pemetrexed/cisplatin [hazard ratio (HR), 0.58; p=0.0004], Yang reported. Twelve-month PFS rate was 47 vs 22 percent. Importantly, the PFS benefit of afatanib was consistent in all relevant subgroups, including gender, age at baseline, race (Asian or non-Asian), baseline ECOG performance status, and smoking history (never smoked, or smoked <15 pack-years and stopped >1 year). The benefit of afatinib was even greater in patients with deletion 19 or L858RV [n=308], he continued. In these patients, afatinib doubled PFS to 13.6 months vs 6.9 months with pemetrexed/cisplatin [HR, 0.47; p<0.0001]. PFS rate at 12 months was 51 vs 21 percent. Patients treated with afatinib also had a significantly higher objective response rate (56.1 vs 22.6 percent with pemetrexed/cisplatin; p<0.001), a longer duration of response (11.1 vs 5.5 months), and a higher disease control rate (90 vs 81 percent). In patients with deletion 19 or L858R, objective response rate was 60.8 vs 22.1 percent (p<0.0001). In addition, afatinib significantly prolonged the time to deterioration of cough and dyspnea, resulting in a better quality of life. Grade 3/4 adverse events that were increased with afatinib included diarrhea [14.4 vs 0 percent], rash/acne [16.2 vs 0 percent], stomatitis/mucositis [8.7 vs 0.9 per-
Jul-Aug 2012 pemetrexed/cisplatin arm. In LUX-Lung3, only 7.9 percent of patients discontinued afatinib due to treatment-related adverse events (vs 11.7 percent with pemetrexed/cisplatin), and only about 1 percent discontinued the drug due to diarrhea.
cent], paronychia [11.4 vs 0 percent], and dry skin [0.4 vs 0 percent], said Yang. These adverse events were as expected with EGFR-targeting therapies, and were manageable and reversible. It is also important to note that patients in the afatinib arm received 16 cycles of therapy, vs 6 cycles in the
PERSPECTIVES Dr. Kwok-Chi Lam
Department of Clinical Oncology, Prince of Wales Hospital
The LUX-Lung3 trial has echoed what we have seen in other randomized phase III trials, with consistent HR for progression-free survival. It is difficult to compare the treatment efficacy of different EGFR TKIs across different trials. Afatinib can be one of the treatment options for patients with EGFR mutation-positive tumors. We might know which EGFR TKI is better as results of the LUX-Lung7 trial (comparing afatinib with gefitinib in EGFR mutation-positive chemonave non-small cell lung cancer) become available in future.
Cancer drug shortages a global problem

Naomi Rodrig
he European Hematology Association (EHA), the American Society of Hematology (ASH) and the European Cancer Patient Coalition (ECPC) issued a joint call to action to address the looming crisis of cancer drug shortage. The announcement, issued at the recent 2012 EHA Congress, comes on the footsteps of the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, which also highlighted the problem. According to ASCO officials, disrupted manufacturing and quality control are the main culprits behind the shortages that have left many cancer patients without necessary treatments. Were never sure when a generic drug is suddenly going to go out of supply, said Dr. Richard Schilsky, Chair of the ASCO
Government Relations Committee. Hundreds of drugs have been in short supply in the US over the past year, including methotrexate, used frequently for leukemia; liposomal doxorubicin, which treats ovarian cancer; paclitaxel, used in a variety of cancers; mustargen, used to treat lymphoma; and 5-fluorouracil (5-FU), a key component of adjuvant therapy for colorectal and other cancers. The situation in Europe seems to be even more serious. In the US, legislation is under way that may curb drug shortages, but in Europe we do not even have a proper understanding of the scope of the problem, remarked EHA President, Dr. Ulrich Jager. The US FDA is drafting legislation requiring mandatory 6-month advance notification
Jul-Aug 2012 epirubicin and 5-FU were out of supply in HA hospitals. The solution was substitution; for example, epirubicin was used to substitute doxorubicin and vice versa. For 5-FU, we used other brands. While the supply of these drugs has been back to normal now, liposomal doxorubicin, which is commonly used in second-line treatment of recurrent ovarian cancer, has been out of supply for almost a year. We have to use topotecan, a more toxic drug, for this indication, she said. I guess the main reason for the shortages is on the manufacturing side, such as lack of raw materials. In other situations, the drug company ceased to produce the drug because it is not commonly used, such as mitotane for adrenocortical carcinoma, a very rare cancer, Kwok suggested.
by drug companies for withdra-wals or manufacturing interruption, with penalties for non-reporting. Early alerts may enable government agencies to source the same or alternative drugs from overseas manufacturers. The situation in Europe is undoubtedly more complex. We are not one country; we are 27 countries, each with its own rules and regulations, noted Dr. Anton Hagenbeek, The Netherlands, who emphasized that drug supply and pricing are subject to government policies. Asian countries have not been spared either. In my opinion, cancer drug shortage is a global problem, and Hong Kong is affected as well, commented Dr. Carol Kwok of the Department of Oncology, Princess Margaret Hospital. Just a few months ago, three commonly used cytotoxic drugs doxorubicin,
Big strides in cancer genetics research in Asia
ncreasing numbers of high-quality cancer genetics studies conducted in Asia are making it into prestigious journals, affirming the regions position as an upcoming hub of advanced oncology research. In the current issue, we report three stories of innovative research from Asia, as investigators from Hong Kong, China and Singapore are shedding new light on carcinogenesis pathways. One of the studies focused on reversal of apoptosis, which may induce oncogenic transformation in various cell types, while the others looked at specific cancers hepatocellular carcinoma and an aggressive type of lymphoma that is common in China and Korea. The expanding industry funding for basic research in Asia also reflects increasing confidence in its quality as well as a fresh enthusiasm for long-term R&D investment in the region. Although many of these studies are still at the preclinical stage, some may eventually lead to new therapeutic or diagnostic products. The global pharma industry is now willing to stay the course, which may give an even greater boost to Asian medical and life-science research. The Editor
Jul-Aug 2012
News
Asian study unveils mechanism of HBV integration in HCC

Naomi Rodrig
he Asian Cancer Research Group (ACRG) in collaboration with the Shenzhen-based genomics company BGI recently published the results of a genome-wide study unveiling the mechanism of recurrent hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC) genomes. [Nature Genetics 2012. DOI: 10.1038/ng.2295] HBV integration is thought to be one of the major causes underlying HCC development, as previous studies have shown that it may induce chromosomal instability, leading to carcinogenesis and tumor recurrence. However, this is the first whole-genome sequencing study to systematically investigate the breakpoints of HBV DNA and the human genes which are affected by such integration in a large sample of 88 pairs of HCC tumor and non-tumor liver tissue obtained from 88 patients operated at Queen Mary Hospital [QMH], said Professor Ronnie Poon, Chief of the Division of Hepatobiliary & Pancreatic Surgery at the University of Hong Kong (HKU) who was one of the study investigators. The study was initiated by Dr. John Luk, a corresponding author of the paper, when he was working at HKU. He subsequently moved to the National University of Singapore where he recruited talents in bioinformatics analysis for the project. In the study, which enrolled 81 HBV-positive and seven HBV-negative patients with HCC, HBV integration was observed more frequently in tumors than in normal tissues (86.4 vs 30.7 percent).
The researchers also identified a specific region of the viral genome that is most commonly cleaved during integration into the host genome. Approximately 40 percent of HBV breakpoints within the HBV genome were located at a 1,800-bp region where the viral enhancer, X gene and core gene are located, they wrote. In addition to the previously reported human genes TERT and MLL4, they discovered three novel genes associated with recurrent HBV integration CCNE1, SENP5 and ROCK1. All these genes are known to play an important role in cancer development and progression, and showed upregulated expression in tumor vs normal tissue. Another observation was that the number of HBV integration events was positively correlated with tumor size, and serum levels of hepatitis B surface antigen (HBsAg) and alpha-fetoprotein. The number of HBV integrations was also associated with patient survival. Patients with <3 detected HBV integrations survived longer than those with >3 integrations, suggesting that the number of integrations may be a
Jul-Aug 2012
News
integration into the human genome, he said. He stressed that such genome-wide cancer study is very demanding in terms of technology platforms and bioinformatics analysis, and would have been very difficult for a single academic institution to perform. ACRG is an independent, not-for-profit company established in 2010 by Eli Lilly, MSD and Pfizer to accelerate research on cancers that are common in Asia. Collaboration among institutes and with pharmaceutical companies is very important, and I appreciate such effort by pharmaceutical companies. HKU initiated the study, provided the samples, and performed some experiments and data analysis, especially the clinical correlation. ACRG not only provided funding support for the study, but its investigators were involved from the very early phase of study design. The mapping and sequencing analysis and several other experiments were performed by BGI. Their sequencing ability is obviously important to this study. This is really a collaborative effort and the credit should go to all parties and investigators involved, said Poon.
prognostic indicator in HCC patients. This is the first study that correlated the HBV integration patterns with clinical outcome in patients with HBV-related HCC, Poon told Oncology Tribune. Notably, a higher frequency of HBV integration was observed in HCC patients who were in their twenties or thirties, which may explain the development of the tumors in younger individuals without chronic hepatitis or cirrhosis. According to Poon, over 6 percent of the 3,500 primary HCC cases who presented to QMH between 2001 and 2010 were <40 years of age. The median survival of these young patients is much poorer compared with older patients [8.3 vs 16.1 months], and this may be explained by the increased number of viral integrations as shown in this study, he said. Poon noted that current drugs which inhibit HBV replication cannot completely eradicate the virus or prevent its re-integration into the human genome. This study provides insight into future drug development to prevent hepato-carcinogenesis by HBV, although there is no drugbeing developed yet to disrupt HBV DNA
Jul-Aug 2012
News
changes may cause new tumors to form after cancer therapy. In cancer cells that undergo reversal of apoptosis after treatment, new mutations may develop, causing the cancer to become more aggressive or metastatic. The researchers proposed naming the reversal of apoptosis as anastasis, a Greek term for rising to life. While recent research indicates that cancer stem cells [CSCs] are resistant to chemotherapy and implicated in metastasis, our observation is that anastasis occurs not only in CSCs, but also in most cancer cells, Fung told Oncology Tribune. Further study is needed on the relationship between CSCs and anastasis. Although carcinogenesis represents a harmful side effect of anastasis, anastasis may be conducive to tissue repair and formation of new genetic combinations. Our findings suggest that inhibiting anastasis may enhance the effect of chemotherapy, while promoting anastasis may facilitate tissue recovery, said principal investigator Dr. Ho-Lam Tang of CUHKs School of Life Sciences and John Hopkins University School of Medicine. For example, ongoing studies demonstrated that genistein a predominant isoflavone in soybean with well-documented anticancer effects could inhibit anastasis in cancer cells. This effect was observed at non-toxic concentrations of 2.5-25 g/mL in our work with CUHKs Center for Soybean Research, said Fung. Genistein had a synergistic anti-cancer effect in combination with chemotherapy. Further investigation will be carried out on the mechanism. However, Fung warned against improper use of herbal medicine with potential anticancer properties, as they may drive cancer progression or oncogenic transformation in normal cells.
Reversal of apoptosis may drive carcinogenesis

Christina Lau
recent study from the Chinese University of Hong Kong (CUHK) demonstrated that the process of apoptosis can be reversed even after passing the critical checkpoints of no return, which may lead to genetic changes that contribute to carcinogenesis or resistance to cancer treatments. [Mol Biol Cell 2012;23:2240-2252] Accor ding to the researchers, this unanticipated rescue mechanism observed in both normal and malignant cells may have important applications in cancer treatment. It is generally believed that apoptosis which is a protective mechanism that eliminates damaged cells through programmed cell death is irreversible once cells pass certain checkpoints, including cell shrinkage, mitochondrial fragmentation, nucleus condensation, DNA breakdown and caspase-3 activation, said Professor Ming-Chiu Fung of the Department of Biology. Our previous work showed that human cancer cells could evade the apoptotic process even after passing the presumed point of no return, and this may be one of the causes of cancer recurrence. [Br J Cancer 2009;100:118-122] In their current study, Fung and colleagues treated primary liver and heart cells, macrophages, embryonic NIH 3T3 fibroblasts, cervical cancer HeLa cells and brain cells with apoptosis inducers. Surprisingly, the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. More importantly, some cells acquired permanent genetic changes and underwent oncogenic transformation after the reversal of apoptosis, Fung pointed out. In normal cells, these genetic
Jul-Aug 2012
Conference Covera ge
American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA
Better strategies needed for ALL in adolescents and young adults

Christina Lau
dolescents and young adults with high-risk acute lymphoblastic leukemia (ALL) have poorer survival and higher toxicity from treatment than their younger counterparts, according to new data from a major phase III study which highlights the need for better treatment strategies for this group of patients. [Abstract CRA9508] Historically, ALL patients older than 16 years have an inferior outcome compared with patients aged 1 to 15 years because older patients have higher rates of relapse and toxicity, said lead author Dr. Eric Larsen of the Maine Childrens Cancer Program in Scarborough, Maine, USA. In the Childrens Oncology Group [COG] study ALL0232, we tested dexamethasone vs prednisone during induction and high-dose methotrexate vs escalating Capizzi methotrexate plus PEG asparaginase during interim maintenance 1 in a 2 x 2 factorial design. For the fist time, patients aged 21-30 years were eligible for enrollment in an ALL study. ALL0232 enrolled patients with newly-diagnosed B-precursor high-risk ALL. Of 2,571 eligible patients, 501 (20 percent) were aged 16-30 years. This represents the largest cohort of adolescent and young adult ALL patients to date in a single clinical trial, he said. At 5 years, patients aged 16-30 years had significantly poorer event-free survival (EFS) and overall survival (OS) than those <16 years
(68 vs 80.9 percent and 79.8 vs 88.4 percent, respectively; p<0.0001 for both). Relapses were significantly more frequent in adolescent and young adult patients, primarily due to a higher rate of bone marrow relapse, reported Larsen. The 5-year cumulative relapse rate was 21.3 percent in patients aged 16-30 years, vs 13.4 percent in younger patients [p=0.002]. Marrow relapse at 5 years was 15.3 vs 9 percent, respectively [p=0.0007]. Central nervous system (CNS) relapse was similar between the two groups (5 years, 5.2 vs 3.7 percent; p=0.58). According to the investigators, the treatment strategy of the
Jul-Aug 2012
compared with previous studies that showed EFS rates of 50-60 percent, remarked Larsen. However, our results suggest that we need to find novel agents that improve leukemia control with reduced toxicity. As older ALL patients dont tolerate chemotherapy as well as younger patients, their compliance is often lower and treatment protocols for them tend to be less intense in terms of the number of drugs, dosages and treatment duration. As a result of our study, the COG is considering several options to both enhance leukemia control and reduce the toxicity of treatment.
trial was to try to improve disease control in the CNS. Remission, defined as <5 percent marrow blasts at the end of induction, was also significantly lower in adolescent and young adult patients (97.2 vs 98.8 percent; p=0.0134). Mortality during post-induction remission was significantly higher among those aged 16-30 years vs those <16 years (5 years, 5.5 vs 2.1 percent; p<0.0001), although there was no significant difference in induction mortality between the two groups (2.4 vs 1.8 percent; p=0.36). Adolescent and young adult patients treated in ALL0232 had improved outcome
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Jul-Aug 2012
Continuous androgen deprivation still standard of care for prostate cancer

Yen Yen Yip
ontinuous androgen deprivation remains standard of care in hormone-sensitive metastatic prostate cancer, according to a large multinational phase III study. [Abstract 4] Some doctors recommend intermittent hormonal therapy to men with metastatic prostate cancer, believing it will reduce their risk of side effects without compromising outcome, but our findings demonstrate a clear downside to this approach for certain men, said lead investigator Dr. Maha Hussain from the University of Michigan, Ann Arbor, USA. The primary objective of the SWOG (Southwest Oncology Group) 9346 study, which spanned 17 years, was to determine if intermittent androgen deprivation was non-inferior to continuous therapy. The study included more than 1,500 patients newly diagnosed with hormone-sensitive prostate cancer, with prostate-specific antigen (PSA) levels 5 ng/mL prior to initiation of androgen deprivation therapy, and a SWOG performance status of 0 to 2. The subjects were treated with goserelin and bicalutamide for 7 months, and those who achieved PSA 4 ng/mL at the 6th or 7th month were then randomized to receive continuous or intermittent therapy. After a median follow-up of 9.2 years, the primary endpoint of overall survival (OS) was inferior in the intermittent therapy group (5.1
years vs 5.8 years with continuous therapy; HR, 1.09). Among patients with minimal disease, OS was significantly better for those who received continuous therapy (7.1 vs 5.2 years; p=0.034). However, in patients with extensive disease spread, intermittent and continuous therapies were comparable. Androgen deprivation therapy leads to significant setbacks in quality of life, and is also associated with increased fractures, decreased cognitive function, increased risk of diabetes and altered lipid profiles. In addition, many patients eventually progress to castration-resistant disease, commented Dr. William Oh from the Mount Sinai School of Medicine, New York, USA. Previous preclinical data have suggested that intermittent therapy can re-induce apoptosis and prolong time to castration resistance. [Cancer 1993;71:2782-2790] The advantages of the intermittent approach and its comparable efficacy were confirmed by at least 23 phase II trials, Oh noted. However, these studies were essentially underpowered to evaluate survival. The SWOG 9346 findings will be practice changing for many doctors who routinely use intermittent therapy, said Hussain. Neither SWOG 9346 nor any randomized trial has ever shown a superior cancer outcome with intermittent androgen deprivation therapy, said Oh. This preclinical concept [supporting intermittent therapy] must no longer be propagated.
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Jul-Aug 2012
Regorafenib offers hope for GIST patients failing TKIs

Christina Lau
he multi-kinase inhibitor regorafenib may represent the first targeted treatment option for patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who progressed despite prior use of both imatinib and sunitinib. The phase III GRID (Regorafenib in Progressive Disease) trial included 199 patients from 17 countries who failed at least imatinib and sunitinib the only two drugs approved for GIST worldwide. Patients were randomized to receive regorafenib 160 mg once daily plus best supportive care (BSC) (n=133), or placebo plus BSC (n=66), on a 3-weeks-on 1-week-off schedule. The trial was unblinded on disease progression, when placebo-treated patients were eligible for crossover to openlabel regorafenib and regorafenib-treated patients continued on their treatment. On the next progression, patients were taken off treatment. [Abstract LBA10008] The trial met its primary endpoint, with progression-free survival [PFS] being four times longer in the regorafenib arm. Median PFS was 4.8 months for regorafenib vs 0.9 months for placebo [HR, 0.27; p<0.0001], reported Dr. George Demetri, Dana Farber Cancer Institute, Massachusetts, USA. PFS rates at 3 and 6 months were 60 vs 11 percent and 38 vs 0 percent, respectively. The same PFS benefit was maintained in patients with KIT exon 11 (n=51) or exon 9
(n=15) mutation, the most common mutations in GIST (HR, 0.212 and 0.239, respectively). Disease control and objective response also favored regorafenib, at 52.6 vs 9.1 percent and 4.5 vs 1.5 percent, respectively. Although overall survival [OS] favored regorafenib [HR, 0.77], the difference between the two arms did not reach statistical significance as 85 percent of patients in the placebo arm crossed over to receive open-label regorafenib, pointed out Demetri. Regorafenib was generally well tolerated in the trial, with side effects similar to those of imatinib and sunitinib. The most common grade 3 adverse events were hand-foot skin reaction, hypertension and diarrhea. The side effects were all manageable with dose modifications, he noted. Positive results of the trial were submitted to regulatory authorities in March 2012. If approved, regorafenib will fulfill an urgent unmet need for GIST patients who have exhausted all other treatment options, he suggested. While imatinib and sunitinib have increased patient survival in metastatic GIST from 3-6 months to 5 years or more, 85-90 percent of patients ultimately develop resistance to these tyrosine kinase inhibitors [TKIs] that target KIT or PDGFRA. Regorafenib is a structurally distinct oral inhibitor of KIT, VEGFR-1, murine VEGFR-2, PDGFR-b, RET, BRAF and FGFR-1 that appears to target GIST in a possibly more powerful way, making it a potentially significant new option.
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Jul-Aug 2012
Antidepressant relieves chemo-induced neuropathic pain

Yen Yen Yip
or the first time, a randomized controlled trial has found the serotoninnorepinephrine reuptake inhibitor (SNRI) duloxetine to be effective against chronic neuropathic pain associated with taxane- or platinum-based chemotherapy. [Abstract CRA 9013] In the study, duloxetine conferred a 30 percent reduction in pain score for 33 percent of patients. In the placebo group, only 17 percent achieved a similar reduction in pain. A 30 percent decrease in pain is clinically significant and important to patients, commented lead investigator Dr. Ellen Lavoie Smith, University of Michigan School of Nursing, Ann Arbor, USA. A total of 220 patients with peripheral neuropathic pain associated with paclitaxel or oxaliplatin were randomized to receive duloxetine (30 mg daily in the first week, then 60 mg daily for 4 weeks) or placebo. Although mean pain scores fell in the placebo group as well, patients who received du-
loxetine achieved a significantly greater degree of pain relief (p=0.003). Overall, 59 percent of patients taking duloxetine achieved some degree of pain relief vs 38 percent of placebo recipients. Pain scores fell by half in 21 percent of patients on duloxetine vs 9 percent on placebo. However, a small proportion of patients felt more pain after receiving treatment; fewer patients on duloxetine experienced this effect compared with the placebo group. Not everyone responded to duloxetine, Lavoie Smith said. Duloxetine... works by increasing amounts of pain-inhibiting neurotransmitters; we think patients who respond may have some abnormalities in the way their brain processes pain and we have to identify who might respond so we can target the use of this drug. The drug was generally well tolerated. Fatigue, insomnia, nausea, somnolence and dizziness were the most common adverse events. Seven percent of recipients experienced severe adverse events and 11 percent dropped out of the study as a result of side effects.
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Jul-Aug 2012
ASCO 2012 Sa tellite Symposium
Everolimus plus exemestane improves PFS in advanced breast cancer

UpdateddatafromtheBOLERO -2trial demonstrate that everolimus (Afinitor, Novartis) in combination with exemestane more than doubled progression-free survival (PFS) in women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2-negative Prof. Smith Dr. Andr Prof. Rugo (HER2-) advanced breast cancer who are resistant to hormonal therapy. The data, presented at a Novartis-sponsored symposium held in conjunction with the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, confirm evidence from previous analyses on the survival benefits of adding everolimus to exemestane.
Overcoming endocrine resistance
Over two-thirds of breast cancers express the ER which contributes to tumor growth and progression. Patients who are ER+ benefit from endocrine therapeutic agents, such as anti-estrogens that target ERs. In postmenopausal patients, aromatase inhibitors (AIs) are the first-line treatment choice. However, up to 25 percent of all breast cancer patients do not respond to endocrine therapy (de novo resistance), whereas others will eventually relapse despite an initial response due to either intrinsic or acquired resistance. [Clin Cancer Res 2010;16:1979-1987] Molecular mechanisms of resistance are emerging. This has led to the development of targeted therapies. However, the challenge is to define which patients will most likely benefit from these therapies, and which do not need them, said Professor Ian Smith of the Royal Marsden Hospital and Institute of Cancer Research in London, UK.
Everolimus: Targeting the PI3K/ AKT/mTOR Pathway
Abnormalities in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway have been implicated in several forms of human cancer. Activation of the AKT/mTOR pathway leads to resistance to endocrine therapy and their inhibition reverses the resistance, explained Dr. Fabrice Andr of the Institute Gustave Roussy Villejuif, France. Research on endocrine-resistant cells showed that selective inhibitors of the PI3K/ AKT/mTOR pathway provide significant growth inhibition in long-term estrogendeprived breast cancer cells. [Nat Rev Drug Discov 2005;4:988-1004] Kinase activation induced by long-term estrogen deprivation and genomic alteration acquired during the natural course of the disease may lead to acquired resistance, said Andr. We still have no idea how to identify patients who are resistant to endocrine
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Jul-Aug 2012

Figure 1. BOLERO-2 18-month follow-up: PFS based on local assessment
100 80 60 40 20 0
0
Patients at risk EVE 10 mg + EXE PBO + EXE
therapy before they relapse, or patients who are more likely to respond to treatments that may reverse resistance, said Professor Hope Rugo of the University of California, San Francisco, USA. Everolimus, an oral mTOR inhibitor, has promising clinical activity in women with HER2+, HER2-, and ER+ breast cancer when combined with HER2-targeted therapy, chemotherapy, and hormonal therapy, respectively. [Pharmacotherapy 2012;32:383-396] The phase II TAMRAD trial, conducted by the Groupe dInvestigateurs Nationaux pour lEtude des Cancers Ovariens et du sein (GINECO Group, France), was designed to evaluate the efficacy and safety of everolimus in combination with tamoxifen vs tamoxifen alone in patients with hormone receptorpositive (HR+), HER2- metastatic breast cancer with prior exposure to AIs. Results showed that addition of everolimus to tamoxifen delayed disease progression compared to tamoxifen alone, with median time to disease progression of 8.6 vs 4.5 months. [Ann Oncol 2012; 23(suppl 2): ii17ii24; abstract 13O_PR]
Probability (%) of event
Median PFS: EVE + EXE: 7.8 months PBO + EXE: 3.2 months HR=0.45 Log-rank p value <0.0001
Censoring times EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Time (weeks)
485 436 366 304 257 221 185 158 124 91 239 190 132 96 67 50 39 30 21 15 66 10 50 8 35 5 24 3 22 1 13 1 10 1 8 0 2 0 1 0 0 0
EXE = exemestane; EVE = everolimus; HR = hazard ratio; PBO = placebo; PFS = progression-free survival Adapted from Piccart MJ, et al. J Clin Oncol 2012;30(suppl): abstract 559.
[Cancer Res 2011;71(24 suppl):abstract S37; N Engl J Med 2012;366:520-529] Updated results of an 18-month followup showed a median PFS of 7.8 months for patients receiving exemestane plus everolimus (n=485) (7.4 in the 12-month follow-up) vs 3.2 months for patients receiving exemestane alone (n=239). (Figure 1) An independent review showed a PFS of 11 months in the combination arm vs 4.1 months in the exemestane-only arm. Compared to 32.2 percent of patients who died in the exemestane-only arm, 25.4 percent in the combination arm died. [J Clin Oncol 2012;30(suppl): abstract 559]
100 80 60 40 20 0 Probability (%) of event
Median time to QoL deterioration EVE + EXE: 8.3 months PBO + EXE: 5.8 months Log-rank p value=0.0084 Censoring times EVE + EXE (n=485) PBO + EXE (n=239) 6 12 18 0 24 30 36 42 48 54 60 66 72 78 84 90 96
Time to deterioration in QoL (months)

176 49 145 36 119 27 99 19 71 16 52 7 43 6
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BOLERO-2 study
New subgroup analyses
BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) is an international, randomized phase III trial designed to evaluate everolimus in combination with exemestane vs exemestane alone in postmenopausal women with ER+ HER2- advanced breast cancer refractory to treatment with nonsteroidal AIs (NSAIs) such as letrozole or anastrozole. The study included 724 advanced breast cancer patients from 189 sites worldwide. Eligible patients were randomized (2:1) to exemestane (25 mg/day) with everolimus (10 mg/day) or placebo.
The clinical benefit of everolimus was observed in all subgroups in the BOLERO-2 study. It is very encouraging that there are numerically fewer deaths in the everolimus arm vs the placebo arm, and this difference has continued with the latest analysis of data, said Rugo.
Delaying bone progression
Subgroup analysis showed that everolimus delayed bone progression in patients with or without bone metastasis at baseline, said Rugo. The delay was more
0
0
EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
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Jul-Aug 2012

Time (weeks)
66 10 50 8
485 436 366 304 257 221 185 158 124 91 239 190 132 96 67 50 39 30 21 15
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significant in patients with bone metastases at baseline. [Eur J Cancer 2012;48(suppl 1): abstract LBA3] NSAIs are associated with decrease in bone mineral density and increased risk of fractures. Therefore, it is important to evaluate whether new therapies in combination with exemestane affect bone turnover. A BOLERO-2 subanalysis evaluated the effect of everolimus in combination with exemestane vs exemestane alone on markers associated with bone formation and resorption. Results showed that bone turnover markers were reduced in the combination arm vs the exemestane-alone arm during the first 12 weeks of therapy, suggesting clinical benefits on bone health.
Maintaining quality of life (QoL)
Figure 2. BOLERO-2 18-month follow-up: QoL*

100 80 60 40 20 0
0
Probability (%) of event
Median time to QoL deterioration EVE + EXE: 8.3 months PBO + EXE: 5.8 months Log-rank p value=0.0084
Censoring times EVE + EXE (n=485) PBO + EXE (n=239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time to deterioration in QoL (months)

485 239 427 201 305 116 245 83 198 62 176 49 145 36 119 27 99 19 71 16 52 7 43 6 29 3 18 1 13 0 9 0 8 0
* QoL evaluated at baseline and every 6 weeks thereafter until progression, using the EORTC-QLQ-30 (European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire) Global Health Scale with minimal important difference of 5%. EVE = everolimus; EXE = exemestane; QoL = quality of life Adapted from Beck JT, et al. ASCO 2012; abstract 539.
among Asian patients (HR=0.56; p<0.05). The PFS benefit with everolimus plus exemestane vs exemestane alone was similar in Asian patients (median, 8.48 vs 4.14 months) and nonAsian patients (median, 7.33 vs 2.83 months). [Noguchi S, et al. ASCO 2012; abstract 540]
Elderly vs younger patients
A subgroup of patients was assessed to determine whether any disruption in health-related quality of life (HRQoL) occurred with the everolimus-exemestane combination. Results demonstrate that median time to definitive deterioration in HRQoL was 8.3 months for everolimus plus exemestane vs 5.8 for exemestane alone, suggesting that adding everolimus to exemestane maintained QoL in the patients. (Figure 2) [Beck JT, et al. ASCO 2012; abstract 539]
In Asian patients
Adding everolimus to exemestane was beneficial for both elderly (65 years) and younger (<65 years) patients. At a median follow-up of 12.5 months, PFS was 6.83 months with the combination vs 4.01 months with exemestane alone in elderly patients (HR=0.56; p<0.05), compared with 8.31 and 2.92 months, respectively, in those <65 years (HR=0.37; p<0.05). [Pritchard KI, et al. ASCO 2012; abstract 551]
Conclusion
Of 143 Asian patients in the BOLERO-2 study, 98 received everolimus plus exemestane and 45 received exemestane alone. At the time of database lock, 56 percent of Asian patients in the combination arm had experienced disease progression vs 76 percent in the exemestane-alone arm. Combination therapy reduced the risk of disease progression by 44 percent vs exemestane alone
Results of the 18-month follow-up of the BOLERO-2 trial are supportive of previously presented data from the 12-month follow-up. Everolimus, when added to exemestane, significantly improves PFS in patients with ER+ HER2- advanced breast cancer. The PFS benefit was demonstrated across various subgroups of patients. This combination is a step forward that offers good QoL.
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Jul-Aug 2012
ASCO 2012 Meeting Highlights
PISCES study: mRCC patients favor pazopanib for better QoL

Pazopanib is an oral multi-kinase angiogenesis inhibitor which significantly improves progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC). It has also demonstrated a unique safety profile compared with other approved agents for mRCC. As Professor Bernard Escudier of the Institut Gustave Roussy, France, elaborated at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, drug tolerability is a major determinant of health-related quality of life (HRQoL), which in turn determines patient preference for one therapy over another.
Prof. Escudier
Pazopanib and sunitinib: Comparable efficacy, different safety
erability and HRQoL on a patients choice of treatment.
Pazopanib and sunitinib are both approved treatments for mRCC, with comparable efficacy but differences in terms of safety profile, noted Escudier. An indirect comparison suggested that PFS rates associated with pazopanib in treatment-nave subjects were not significantly different from sunitinib (hazard ratio [HR], 0.93). However, pazopanib was less toxic, with lower rates of grade 3 or 4 adverse events (44 percent) as compared with sunitinib (67 percent). [McCann L. ASCO GU 2010; abstract 413] Safety and tolerability takes on a special significance in mRCC, where patients may have to be treated for many months, or even years. While the evaluation of drug tolerability is not easy, a strong association between adverse events and HRQoL suggests that patient preference is a legitimate and useful endpoint, said Escudier. The PISCES (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer) was thus designed to assess the impact of tol-
PISCES: Are differences in drug tolerability clinically meaningful for patients?
PISCES was a double-blind, crossover study, in which 169 patients were randomized 1:1 to receive pazopanib 800 mg for 10 weeks, followed by a 2-week washout period, and then sunitinib 50 mg for 10 weeks, or vice versa (sunitinib then pazopanib). Patients were eligible if they had previously untreated mRCC, any renal cancer histology, measurable or non-measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, good or intermediate prognosis, no brain metastases, and adequate cardiac and renal function. [Abstract CRA4502] The subjects were stratified based on their ECOG performance status and the number of metastatic sites (1 vs 2). CT scans were performed before the start of the trial, during the 2-week washout period, and again at the end of the second
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90 80 70 60 50
Primary analysis population

Difference (pazopanib vs sunitinib) p value
49.3%
Percent of patients
< 0.001
70%
(n=80)
treatment period. 30 Patients who had received 1 dose in 20 Primary analysis population 90 both treatment periods completed a ques(n=9) 22% 10 80 Difference (pazopanib vs (n=25) 8%49.3% tionnaire at the end of the study, while 0 70 Pazopanib preferred sunitinib) Sunitinib preferred No preference Primary analysis population p value < 0.001 they were still blinded and before end60 70% (n=80) 50 of-study imaging results were disclosed, 70% 40 said Escudier. The primary endpoint of the 30 study was patient preference, where the 20 (n=9) 22% subjects indicated which drug they pre10 22% Primary analysis population (n=25) 8% 8% 0 ferred to continue treatment with. Two adPatients werepreferred able to select >1 reason Pazopanib preferred No preference Pazopanib preferred Sunitinib Sunitinib preferred No preference Better quality of life ditional questions were asked to determine Less fatigue Adapted from Escudier BJ, et al. ASCO 2012; abstract CRA4502. the reasons that influenced their choice, Less changes in food tastes in mouth/throat Figure 2. Reasons influencing patients choice of therapy and the single most important reason forLess soreness Less nausea/vomiting Pazopanib preferred (n=80) Less soreness in hands/feet Primary analysis population their preference. Patients were able to select >1 reason Sunitinib preferred (n=25) Less loss of appetite Other endpoints included physician prefBetter quality of life Less stomach pain Primary analysis population Less fatigue Less diarrhea Patients were able to select >1 reason Less changes in food tastes erence, safety and quality of life. Other Less soreness in mouth/throat
Figure 1. PISCES primary endpoint: Patient preference 40
Percent of patients
90 80 70 60 50 40 30 20 10 0
Percent of patients
Difference (pazopanib vs sunitinib) p value
49.3%
< 0.001
(n=80)
(n=9)
(n=25)
Patients prefer pazopanib
Results showed that patients had a strong preference in favor of pazopanib, said Escudier. In the primary endpoint analysis, 70 percent of patients said they preferred to continue treatment with pazopanib vs 22 percent for sunitinib. Only 8 percent of patients did not have any preference. These differences were statistically significant (p<0.001). (Figure 1) All pre-planned sensitivity analyses were statistically in favor of pazopanib, Escudier noted. Better quality of life, less fatigue and fewer changes in food taste were most commonly cited by patients as the reasons that influenced their preference for pazopanib. (Figure 2) Patients also preferred pazopanib because they experienced less soreness in the mouth/throat, nausea/vomiting, soreness in the hands/ feet, loss of appetite, stomach pain, diarrhea and hair color change during the treatment period.
Better quality of life Less nausea/vomiting Less hair colour change fatigue Pazopanib preferred (n=80) LessLess soreness in hands/feet 0 10 20 30 40 preferred 50 60 70 Sunitinib (n=25) Lesstastes loss of appetite Less changes in food Number of patients Less stomach pain Less soreness in mouth/throat Less diarrhea Less nausea/vomiting Other Less hair colour Pazopanib preferred (n=80) Less soreness in hands/feet change 0 10 20 30 40 50 60 preferred 70 (n=25) Sunitinib Less loss of appetite Number of patients Less stomach pain Adapted from Escudier BJ, et al. ASCO 2012; abstract CRA4502. Less diarrhea Other Less hair colour 3. change Figure Physician preference in PISCES
0 10
Number of patients Primary analysis population

Primary analysis population
20
30
40
50
60
70
90
Percent of physicians
80
90 80 70 60 50 40 30 20 10 0 61%
70 60 50 40 30 20 10
Pazopanib preferred Sunitinib preferred Sunitinib preferred NoNo Preference Preference
Pazopanib preferred
61%
22%
17%
17% Pazopanib preferred Sunitinib preferred No preference Primary analysis population
22%
0 90
No preference 80 Pazopanib preferred Sunitinib preferred Pazopanib preferred 70 Sunitinib preferred 60 No Preference 50 Adapted from Escudier BJ, et al. ASCO 2012; abstract CRA4502.
40 30 61%
Physician preference reflects patient choice 20

22%
10 17% Interestingly, physician preference was 0 Pazopanib preferred Sunitinib preferred No preference quite comparable to patient preference,said Escudier. The physician preference analysis was completed while the patients were still blinded. Results indicated that 61 percent of
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panib. In contrast, dysgeusia, mucositis, stomatitis and hand-foot syndrome occurred more frequently in the sunitinib group. In terms of biological and hematological toxicity, pazopanib was more likely to cause an increase in the levels of alanine aminotransferase (ALT) and total bilirubin. However, myelosuppression was more common with sunitinib, leading to higher rates of anemia, lymphopenia, neutropenia, leukopenia and thrombocytopenia.
physicians preferred pazopanib, compared with 22 percent who preferred sunitinib. Seventeen percent of the physicians had no preference at all. (Figure 3)
Improved quality of life and drug safety
Using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACITF) tool to evaluate fatigue, the PISCES investigators confirmed that patients were significantly less likely to experience fatigue when they received pazopanib (p=0.002), said Escudier. A supplementary questionnaire that evaluated soreness in the mouth/throat, hands and feet also established pazopanibs superiority over sunitinib (p<0.001, p=0.025, p=0.005, respectively). Fewer dose modifications were required with pazopanib, he pointed out. In the pazopanib group, 13 percent of patients required a dose reduction a lower incidence compared with sunitinib (20 percent). Patients receiving pazopanib were also less likely to discontinue therapy prematurely due to adverse events. In the first treatment period, 18 percent of patients on sunitinib discontinued therapy compared with 14 percent on pazopanib. In the second treatment period, treatment discontinuation rates for sunitinib and pazopanib were 31 percent and 15 percent, respectively. Adverse events were in line with known profiles for both drugs, said Escudier. This innovative trial clearly demonstrates the better tolerability of pazopanib over sunitinib. In a comparison of non-hematologic toxicity between the two drugs, it appeared that diarrhea was more common with pazo-
Conclusions
The PISCES study demonstrated that mRCC patients preferred pazopanib over sunitinib, as they had better HRQoL and were less fatigued during pazopanib therapy. The preference for pazopanib was reflected among physicians as well. This is an excellent method to report the way patients are feeling about the toxicity of drugs. Its an important reminder that lowgrade toxicities, which may not seem bad, have an effect on your quality of life if experienced over a long period of time, Escudier noted. How patients feel when they take a drug over many months isnt reflected in traditional adverse event reporting. However, the study design of PISCES does not allow an efficacy comparison, he highlighted. Upcoming results of the COMPARZ (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) study will provide a headto-head comparison of efficacy and safety in treatment-nave subjects with mRCC. These landmark findings, together with that of PISCES, will help clinicians decide on the most appropriate treatment option for patients, said Escudier.
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Jul-Aug 2012
Trastuzumab emtansine: A new weapon against HER2-positive mBC

Approximately 15 to 20 percent of all breast cancers involve human epidermal growth factor receptor 2-positive (HER2+) disease. Targeted therapy options for patients with HER2+ metastatic breast cancer (mBC) have been limited, with a median time to progression of <10 months. Recently, much-anticipated results of the EMILIA study demonstrated that an innovative experimental drug, trastuzumab emtansine (T-DM1, Roche), provided significant improvements Prof. in progression-free survival (PFS) over current treatments. Professor Kimberly Blackwell Blackwell of Duke University Cancer Institute, Durham, US, presented the data at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. Latest data from the CLEOPATRA trial which evaluated the addition of pertuzumab to trastuzumab based therapy in HER2+ BC were also presented at the meeting.
Trastuzumab emtansine
T-DM1 is a three-part antibody-drug conjugate comprising trastuzumab, the potent cytotoxic agent DM-1, and a stable linker that binds the antibody and the cytotoxic drug. Emtansine refers to the linker and DM-1 combination. Once T-DM1 binds to the extracellular component of the HER2 receptor and is internalized, the emtansine component separates from trastuzumab and delivers microtubule-disrupting cytotoxic activity to antigen-expressing tumor cells, explained Blackwell. [Clin Cancer Res 2011; 17:6437-6447] In a phase II trial of patients without prior HER2-directed therapy for mBC, T-DM1 achieved a statistically significant 5-month improvement in median PFS compared with a combination of trastuzumab and docetaxel (14.2 vs 9.2 months; p=0.035). [Hurvitz S. ESMO 2011]
EMILIA: A phase III study of T-DM1
EMILIA is the first randomized, phase III
trial to evaluate T-DM1 against capecitabine plus lapatinib, the only approved combination for trastuzumab-refractory HER2+ mBC. The study recruited 991 patients with HER2+ locally advanced or mBC whose disease had progressed within 6 months of initial treatment with trastuzumab and a taxane-based chemotherapy, Blackwell noted. The study was designed with two co-primary endpoints: PFS by independent review and overall survival (OS). The key secondary endpoints were PFS by investigator review, objective response rate (ORR), duration of response, and time to symptom progression. The T-DM1 and control arms had a median follow-up of 12.4 months and 12.9 months, respectively. Median dose intensity for T-DM1 was 99.9 percent; dose intensity was lower for patients on capecitabine [77.2 percent] and lapatinib [93.4 percent], she said. Dose reductions were also less frequent on T-DM1 [16.3 percent] than with capecitabine [53.4 percent] and lapatinib [27.3 percent].
Proportion progression-free Proportion progression-free
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1.0 0.8 0.6 0.4 Cap + Lap T-DM1 Median, mos No. of events 6.4 304 9.6 265
Stratified HR=0.650 p<0.0001
Superior PFS
Figure 1. EMILIA: PFS by independent review

0.2 1.0 0.0 0.8 0 2 4 6
176 236
EMILIA met its primary endpoint of improving PFS with T-DM1 treatment, delivering an absolute improvement of 3.2 months in median PFS as compared with capecitabine/lapatinib, reported Blackwell. The median PFS for the two treatment arms was 9.6 months vs 6.4 months (p<0.0001). (Figure 1) PFS results from the investigator assessment were consistent with the independent review. The treatment effect was shown to consistently favor T-DM1 in most subgroup analyses, including world region, treatment line for metastatic disease and the presence of visceral disease, and in clinically relevant subgroups such as estrogen receptor status and exact line of therapy, noted Blackwell. However, patients over 65 years of age had a hazard ratio of 1.06, indicating a less definitive PFS advantage for T-DM1 in this small patient subgroup.
Trend towards improved OS
8
129 183
10
73 130
12
53 101
No. at risk by independent review: Cap + Lap 0.6 496 404 310 T-DM1 495 419 341
Median, mos No. of events Cap 6.4 22 24 304 14 + Lap 16 18 20 26 28 T-DM1 9.6 265 Time (mos)
35 72 25 54 Stratified 14 9 HR=0.650 8 5 p<0.0001 44 30 18 9 1 3 0 1
30
0 0
0.4 0.2 0.0 0 2 4 6

176 236
8
129 183
10
73 130
12
53 101
No. at risk by independent review: Cap + Lap 496 404 310 T-DM1 495 419 341
14 16 18 Time (mos)
35 72 25 54 14 44
20
9 30
22
8 18
24
5 9
26
1 3
28
0 1
30
0 0
Unstratified HR=0.66 (p<0.0001). Cap = capecitabine; HR = hazard ratio; lap = lapatinib; PFS = progression-free survival; T-DM1 = trastuzumab emtansine Adapted from Blackwell K, et al. ASCO 2012; abstract LBA1.
Figure 2. Objective response rate and duration of response in patients with measurable disease
ORR Difference: 12.7%
p=0.0002 50 40 30.8% 43.6% 1.0 0.8 0.6 0.4 0.2 1.0 0.0
DOR
Cap + Lap T-DM1
Median, mos 6.5 12.6
Percent
30 20 10 50 0 40 120/389
ORR Difference: 12.7%

p=0.0002 173/397 43.6%
Proportion progression-free Proportion progression-free
DOR
Cap + Lap T-DM1
0 2 4 6
Median, mos 6.5 12.6

0 2 0 0 0 0 0 0 0 0 0 0 0 0
Cap + Lap
30.8%
T-DM1
No. at risk Cap + Lap0.8 120 105 77 48 32 14 9 8 3 3 1 1 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Percent
30 Cap = capecitabine; DOR = duration of response; lap = lapatinib;0.6 ORR = objective response rate; T-DM1 = trastuzumab emtansine Adapted from Blackwell K, et al. ASCO 2012; abstract LBA1. 20 10 0 0.4 0.2 0.0
Higher objective response rate

120/389 173/397
Median OS was 23.3 months for patients who received capecitabine/lapatinib, but had not been reached for the T-DM1 group. Interim analysis indicated that T-DM1 improved OS vs the comparator. Based on the pre-planned analysis, there was an absolute difference in OS of 7.7 percent at 1 year and 17.9 percent at 2 years in favor of T-DM1, said Blackwell. One-year survival rate among patients who received T-DM1 was 84.7 percent vs 77 percent for capecitabine/lapatinib. Two-year survival was 65.4 percent vs 47.5 percent. As the efficacy boundary has not been crossed and OS has not been reached in T-DM1 patients, the OS analysis has not achieved statistical significance. The final analysis is expected in 2014.
T-DM1 delivered superior results in ORR and duration of response (DOR) as well. ORR in the T-DM1 group was 43.6 percent, significantly higher than the 30.8 percent for those who received capecitabine/lapatinib (p=0.0002). (Figure 2) In patients with an objective response, there was a 6.1-month absolute improvement in median DOR with T-DM1 [12.6 vs 6.5 months], said Blackwell.
Cap + Lap T-DM1
No. at risk Cap + Lap T-DM1
2 4
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0 2 0 0 0 0 0 0 0 0 0 0 0 0
120 105 77 48 32 14 9 8 3 3 1 1 173 159 126 84 65 47 42 33 27 19 12 8
Delay in symptom progression
Time to symptom progression was measured by evaluating the patients physical and functional well-being, as well as BC-specific symptoms. T-DM1 showed a 2.5-month delay in time to symptom progression from baseline, which is clinically important, commented Blackwell. Median time to progression on T-DM1 was 7.1 months vs 4.6 months on capecitabine/lapatinib (p=0.0121).
Better safety profile
T-DM1 was associated with fewer grade
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Jul-Aug 2012

dose. Cardiac toxicity was rare in both groups.
3 adverse events than capecitabine/lapatinib (57 vs 40.8 percent). A higher proportion of patients who received capecitabine/ lapatinib discontinued their treatment due to adverse events (10.7 vs 5.9 percent). Only one toxicity-related death occurred in the T-DM1 group vs five in the comparator group. Among patients receiving T-DM1, the most common grade 3 adverse events were thrombocytopenia (12.9 vs 0.2 percent) and anemia (2.7 vs 1.6 percent). T-DM1-treated subjects also had increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, but in most cases they were normalized by the time of the next T-DM1
Conclusions
The first phase III study of T-DM1 demonstrated that its efficacy and safety profile is superior to the established capecitabine/ lapatinib regimen. Based on these findings, T-DM1 will be submitted to the EMA and the US FDA for approval as therapy for HER2+ mBC. Targeted cancer therapy has progressed another step forward with the EMILIA study, and T-DM1 should offer an important therapeutic option in the treatment of HER2+ mBC, Blackwell concluded.
CLEOPATRA study updates

CLEOPATRA is a phase III randomized, double-blind clinical trial evaluating the efficacy and safety of pertuzumab, a novel anti-HER2 monoclonal antibody, combined with trastuzumab plus docetaxel as first-line therapy for HER2+ mBC. The rationale for adding pertuzumab to trastuzumab-based therapy is to achieve a more comprehensive shutdown of the HER2 pathway, thus delaying the development of resistance. In 2011, the study had demonstrated that adding pertuzumab to trastuzumab and docetaxel improved PFS over placebo, trastuzumab and docetaxel. A poster presentation by Professor Jose Baselga, Massachusetts General Hospital, Boston, US suggested that pertuzumab combined with trastuzumab and docetaxel may also be well-tolerated in patients with HER2+ early BC. The addition of pertuzumab did not limit the dose or dose intensity of docetaxel that could be delivered. Most adverse events occurred when pertuzumab was administered concomitantly with docetaxel. Grade 3 adverse events were infrequent, but a higher rate of febrile neutropenia occurred in patients from Asia. Nonetheless, the occurrence of febrile neutropenia and most adverse events stopped with the discontinuation of docetaxel. [Poster 597] In another poster, Professor Javier Cortes, Vall dHebron University Hospital, Barcelona, Spain evaluated health-related quality of life (HRQoL) data from CLEOPATRA. Patients who received pertuzumab had similar HRQoL scores as those who received placebo, despite adverse events associated with the pertuzumab-containing regimen. This may be attributed to the fact that the addition of pertuzumab substantially delayed the time to onset of specific BC symptoms. An index score assessing physical, functional and breast well-being could have improved with discontinuation of docetaxel as well. [Poster 598]
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Jul-Aug 2012
Bevacizumab shows benefit in platinum-resistant ovarian cancer

Platinum-resistant ovarian cancer is notoriously difficult to treat as therapeutic options are limited in number and efficacy. This may change, as the phase III AURELIA trial demonstrated that bevacizumab (Avastin Roche, Roche), when added to standard chemotherapy, significantly improves progressionfree survival (PFS) in patients with platinum-resistant recurrent disease. Results were presented recently at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting by Professor Eric Pujade-Lauraine of the Group dInvestigateurs Nationaux pour lEtude des Cancers Ovariens (GINECO) and Universit Paris Descartes in France.
Prof. PujadeLauraine
Unmet need in difficult-to-treat disease
Most patients with advanced ovarian cancer will relapse. At first relapse, 25 percent of patients have platinum-resistant disease, and almost all patients with recurrent ovarian cancer will ultimately develop platinum resistance, said PujadeLauraine. However, treatment options for platinum-resistant ovarian cancer are limited. While single-agent weekly paclitaxel, pegylated liposomal doxorubicin (PLD) or topotecan is the current standard of care, combination regimens have failed to improve efficacy vs monotherapy. Median overall survival [OS] is typically less than 12 months, he pointed out. Ovarian cancer is a highly VEGF-driven disease. As bevacizumab has demonstrated single-agent activity in platinum-resistant ovarian cancer, our objective was to evaluate the efficacy and safety of adding bevacizumab to chemotherapy in this setting, he said. [J Clin Oncol 2007;25:51805186; J Clin Oncol 2008;26:1773]
AURELIA: Bevacizumab in platinumresistant recurrent disease
AURELIA is a multicenter, international trial in 361 patients with epithelial ovarian, primary peritoneal or fallopian tube cancer whose disease progressed within 6 months after 4 cycles of platinum-based therapy. Study patients had received 2 prior anticancer regimens, and had no history of bowel obstruction or abdominal fistula, or clinical or radiological evidence of recto-sigmoid involvement. [Abstract LBA5002] The patients were randomized 1:1 to receive chemotherapy based on investigator choice (n=182), or bevacizumab (15 mg/kg q3w) in combination with chemotherapy (n=179). Chemotherapy options in the trial were paclitaxel (80 mg/m2 days 1, 8, 15 and 22 q4w), topotecan (4 mg/m2 days 1, 8 and 15 q4w or 1.25 mg/m2 days 1-5 q3w), and PLD (40 mg/m2 day 1 q4w). Treatment in both arms was continued until progression or unacceptable toxicity. At disease progression, patients
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Jul-Aug 2012

OS data were not yet mature and will be released in 2013.
Safety and tolerability
in the chemotherapy-alone arm were allowed to cross over to bevacizumab monotherapy, while those in the bevacizumab/ chemotherapy arm continued with their chemotherapy without bevacizumab. The chemotherapy drugs used in the trial are equally effective for resistant ovarian cancer, differing only in their toxicities. Investigators selected the chemotherapy based on each patients previous experience with the drugs, said PujadeLauraine. Baseline characteristics were well balanced between the two treatment arms.
Significant improvements in PFS and response
The trial met its primary endpoint of PFS. PFS nearly doubled, with bevacizumab/chemotherapy reducing the risk of progression by 52 percent vs chemotherapy alone. The difference was highly significant, PujadeLauraine reported. The PFS benefit was consistent in all patient subgroups regardless of age, platinum-free interval, tumor size, presence of ascites, or assigned chemotherapy. (Figures 1 and 2) Overall response rates (ORR) were also significantly higher with bevacizumab/chemotherapy vs chemotherapy alone. (Figure 3) The responses in the chemotherapy arm are in line with whats expected in platinumresistant patients, he noted.
Figure 1. PFS: Overall population
1.01.01.0
BEV + CT CT CT CT BEV +BEV CT + CT (n=182) (n=179) (n=179) (n=182) (n=182) (n=179) Events, n (%) 166 (91%) 135 (75%) Events, n (%) n (%) 166 (91%) 135 (75%) Events, 166 (91%) 135 (75%) Median PFS, months 3.4 6.7 Median PFS, months Median PFS, months 3.4 3.4 0.48 6.7 6.7 (unadjusted) HR HR (unadjusted) 0.48 0.48 HR (unadjusted) Log-rank p-value <0.001 Log-rank p-value <0.001 Log-rank p-value <0.001 (2-sided, unadjusted) (2-sided, unadjusted) (2-sided, unadjusted)
The safety profile of bevacizumab was consistent with findings of pivotal trials of bevacizumab across various tumor types. Grade 3 adverse events that were higher in the bevacizumab/chemotherapy arm included hypertension (7.3 vs 1.1 percent with chemotherapy alone), proteinuria (20.1 vs 6.6 percent), gastrointestinal perforation (1.7 vs 0 percent), and fistula or abscess (1.1 vs 0 percent). Other grade 3 adverse events, including bleeding, thromboembolic event, hematologic toxicity, wound-healing complication, reversible posterior leukoencephalopathy syndrome and cardiac disorders, were not significantly different between the two arms. The rates of gastrointestinal perforation, fistula or abscess were very low with bevacizumab/chemotherapy in the AURELIA trial, noted Pujade-Lauraine. Excluding patients at high risk of gastrointestinal perforation helped limit the incidence of these adverse events. In the trial, fatigue, abdominal pain, vomiting and dyspnea were less common with bevacizumab/chemotherapy vs chemotherapy alone. Although peripheral sensory neuropathy and hand-foot syndrome were increased
Figure 3. Summary of best overall response rates
5050 50 BEV + CTCT CT BEV + CTCT 4545 45 BEV + CT p<0.001 4040 40 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 31.8 p=0.001 3535 35 30.9 31.8 p=0.001 31.8 30.9 30.9 p=0.001 27.3 3030 30 27.3 27.3 25 25 25 20 20 20 15 12.6 11.6 11.8 15 15 12.6 11.6 11.6 11.8 11.8 12.6 10 10 10 5 5 5 0 0 0 Responders RECIST CA-125 Responders RECIST CA-125 Responders RECIST CA-125 (RECIST and/or responders responders (RECIST and/or responders (RECIST responders responders responders CA-125)and/or (n=287) (n=297) CA-125) (n=287) (n=297) CA-125) (n=287) (n=297) (n=350) (n=350) (n=350)
Figure 2. Subgroup analysis of PFS

Median PFS, months Median PFS, months Median PFS, months BEV + CT of BEV +BEV CT CT CT CT No.No. of No. BEV + CT a ofCT CT BEV better+ CT better patients Subgroup HRa + BEV CT patients Subgroup CT + HR CT HRa better better better better patients Subgroup All patients 361 3.4 6.7 0.48 All patients 361 361 3.4 3.4 6.7 6.7 0.48 0.48 All patients Age, years <65 228 3.4 6.0 0.49 Age, years 228 228 3.4 3.4 6.0 6.0 0.49 0.49 Age, years <65 <65 65 133 3.5 7.8 0.47 65 65 133 133 3.5 3.5 7.8 7.8 0.47 0.47 b <3 96 2.1 5.4 0.53 PFI, months b 96 96 2.1 2.1 5.4 5.4 0.53 0.53 PFI, months PFI, monthsb <3 <3 36 257 3.6 7.8 0.46 36 36 257 257 3.6 3.6 7.8 7.8 0.46 0.46 Measurable No (<1) 74 3.7 7.5 0.46 Measurable No (<1) 74 74 3.7 3.7 7.5 7.5 0.46 0.46 Measurable No (<1) disease, cm Yes (1<5) 126 3.3 7.5 0.50 disease, cm disease, cm Yes (1<5) Yes (1<5) 126 126 3.3 3.3 7.5 7.5 0.50 0.50 Yes (5) 161 3.3 6.0 0.47 Yes (5) 161 161 3.3 3.3 6.0 6.0 0.47 0.47 Yes (5) Ascites Yes 113 2.5 5.6 0.40 Ascites Yes Yes 113 113 2.5 2.5 5.6 5.6 0.40 0.40 Ascites No 248 3.5 7.6 0.48 No No 248 248 3.5 3.5 7.6 7.6 0.48 0.48 Chemotherapy Paclitaxel 115 3.9 10.4 0.46 Chemotherapy Paclitaxel 115 115 3.9 3.9 10.4 10.40.46 0.46 Chemotherapy Paclitaxel PLD 126 3.5 5.4 0.57 PLD PLD 126 126 3.5 3.5 5.4 5.4 0.57 0.57 Topotecan 120 2.1 5.8 0.32 Topotecan Topotecan 120 120 2.1 2.1 5.8 5.8 0.32 0.32 0.2 0.3 0.5 1 2 3 45 0.2 0.3 0.5 1 2 0.2 0.3 0.5 1 3 4 253 4 5 a unadjusted; bmissing n=8; PFS = progression-free survival; BEV = bevacizumab; CT = chemotherapy; HR = hazard ratio; PFI = platinum-free interval; PLD = pegylated liposomal doxorubucin Adapted from Pujade-Lauraine E, et al. ASCO 2012; abstract LBA5002.
Estimated probability Estimated probability Estimated probability
0.80.80.8 0.60.60.6 0.40.40.4 0.20.20.2

3.4 6.7 3.4 3.4 6.7 6.7 0 0 0 0 0 0 6 6 6
TimeTime (months) No. at risk: (months) No. at risk: CT No. at risk: 93 1 0 182 37 8 1 0 20 CT 93 1 0 182 182 37 8 1 0 20 CT 140 93 88 37 49 20 18 8 4 1 1 0 1 1 0 0 BEV + CT 179 140 4 179 88 18 49 BEV + CT 140 4 1 1 0 88 18 11 0 49 BEV + CT 179
12 12 12
Time (months)
18 18 18
24 24 24
30 30 30
PFS = progression-free survival; BEV = bevacizumab; CT = chemotherapy; HR = hazard ratio Adapted from Pujade-Lauraine E, et al. ASCO 2012; abstract LBA5002.
Patients (%) Patients (%) Patients (%)
BEV = bevacizumab; CT = chemotherapy; RECIST = Response Evaluation Criteria in Solid Tumors Adapted from Pujade-Lauraine E, et al. ASCO 2012; abstract LBA5002.
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between bevacizumab/chemotherapy and chemotherapy alone.
with bevacizumab/chemotherapy, PujadeLauraine pointed out that patients treated with bevacizumab/chemotherapy had higher exposure to chemotherapy than those treated with chemotherapy alone. Bevacizumab delayed disease progression, allowing patients to be treated for a longer period of time, which led to increased cumulative toxicities of chemotherapy, he explained. The other hypothesis that bevacizumab could potentiate the toxicity of chemotherapy was unproven, because the time courses of cumulative hand-foot syndrome and cumulative neuropathy were similar
Conclusions
AURELIA is the first randomized phase III trial in platinum-resistant ovarian cancer to demonstrate a significant benefit with biologic therapy, and a significant benefit with a combination regimen vs mono-th-erapy, commented Pujade-Lauraine. In view of these significant benefits, bevacizumab in combination with chemotherapy should be considered a new standard option in platinum-resistant ovarian cancer. atin/pacltaxel plus concurrent and maintenance bevacizumab, vs 17.4 months with carboplatin/paclitaxel alone. [N Engl J Med 2011;365:2484-2496] These results formed the basis of the approval of bevacizumab for treatment of ovarian cancer in Europe in December 2011.
Previously-treated, recurrent disease
Phase III trials on bevacizumab in ovarian cancer
Bevacizumab-based therapy has demonstrated significant improvements in PFS in four phase III trials totaling nearly 4,000 patients with newly-diagnosed or recurrent ovarian cancer. Adverse events related to bevacizumab were as expected, with no new safety signals identified.
First-line therapy in advanced disease
In the GOG-0218 (Gynecologic Oncology Group-0218) trial of patients with newly-diagnosed stage III (incompletely resectable) or IV disease who had undergone debulking surgery, median PFS was 14.1 months with carboplatin/paclitaxel plus concurrent and maintenance bevacizumab, vs 11.2 months with carboplatin/paclitaxel plus concurrent bevacizumab and 10.3 months with carboplatin/paclitaxel plus placebo. [N Engl J Med 2011;365:2473-2483] In the ICON-7 (International Collaboration on Ovarian Neoplasms-7) trial (stage IIIC or IV disease, 70 percent), median PFS was 19.8 months with carbopl-
The OCEANS and AURELIA trials demonstrated significant PFS improvements with bevacizumab-based therapies in patients with previously-treated, recurrent ovarian cancer. In the OCEANS trial of patients with platinum-sensitive disease, bevacizumab plus carboplatin/gemcitabine followed by single-agent bevacizumab significantly increased PFS by 21 percent vs carboplatin/gemcitabine alone. [J Clin Oncol 2011;29(June 20 suppl): abstract LBA5007] Results of AURELIA offer hope for patients with platinum-resistant disease, with bevacizumab/chemotherapy significantly extending PFS vs chemotherapy alone.
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Bevacizumab beyond progression extends survival in mCRC

Results from a large phase III study confirm that continuing bevacizumab (BEV) (Avastin Roche, Roche) beyond first progression significantly extends survival in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus chemotherapy. The findings were presented recently at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting by Professor Dirk Arnold of the University Cancer Center Hamburg, Germany. Prof. Arnold
ML18147 study
BEV in combination with fluoropyrimidine-based chemotherapy is a standard of care for mCRC in first-line and, in BEV-nave patients, second-line settings. In nonrandomized observational studies of mCRC patients, continuing BEV plus chemotherapy beyond first progression was associated with prolonged survival vs stopping BEV, said Arnold. [J Clin Oncol 2008;26:53265334; J Clin Oncol 2010;28(15 suppl): abstract 3596] However, the efficacy and safety of continuing BEV after first progression had not been investigated in a randomized clinical trial.
Design
The ML18147 study is the first randomized phase III trial that prospectively investigated the impact of continued VEGF inhibition with BEV in mCRC patients who progressed after first-line BEV plus standard chemotherapy (oxaliplatin- or irinotecan-based at physicians discretion). The study included 820 patients who were randomized 1:1 to receive
oxaliplatin- or irinotecan-based chemotherapy with or without BEV (2.5 mg/kg/week) until further disease progression. Patients who received oxaliplatin-based chemotherapy in the first-line setting were switched to irinotecan-based chemotherapy, and vice versa. [Abstract CRA3503] The study started as a national academic trial from the AIO Group [Working Group for Medical Oncology of the German Cancer Society] in Germany with progression-free survival [PFS] as primary endpoint. Subsequently, with growing interest throughout Europe, more patients were enrolled, and the primary endpoint was changed to overall survival [OS], said Arnold. To be eligible for participation, patients had to be 18 years old with histologically confirmed mCRC, with disease progression 4 weeks prior to starting the study treatment. Those with progressive disease diagnosed >3 months after the last BEV administration, first-line PFS <3 months, and those receiving <3 consecutive months of first-
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Figure 1. OS: ITT population
1.0 1.0 0.8 0.8
line BEV were excluded. Patients were stratified by first-line chemotherapy, PFS in first-line setting [9 or >9 months], time from last BEV dose [42 or >42 days], and ECOG [Eastern Cooperative Oncology Group] performance status at baseline [0/1 or 2], added Arnold.
Baseline characteristics
CT (n=410) CT (n=410) BEV + CT (n=409) BEV + CT (n=409)

Unstratifieda HR: 0.81 Unstratifieda HR: 0.81 p=0.0062 p=0.0062 0.83 Stratifiedb HR: b Stratified HR: 0.83 p=0.0211 p=0.0211
OS estimate OS estimate
0.6 0.6 0.4 0.4 0.2 0.2 0
24 30 36 42 48 24 30 36 42 48 Time (months) No. at risk Time (months) CTNo. at risk 410 293 162 51 24 7 3 2 0 CT 410 328 293 162 BEV + CT 409 188 64 51 29 24 13 7 4 3 1 2 0 0 BEV + CT 409 328 188 64 29 13 4 1 0 a Primary analysis method; b stratified by first-line CT, first-line PFS, time from last dose of BEV, ECOG performance status at baseline; BEV = bevacizumab; CT = chemotherapy; ITT = intention-to-treat; OS = overall survival Adapted from Arnold D, et al. ASCO 2012; abstract CRA3503.
0 0
9.8 mo 11.2 mo 9.8 mo 11.2 mo 6 12 18 6 12 18
Figure 2. Subgroup analysis of OS: ITT population

Category AllCategory All populationa Patient Patient populationa Gender Gender Age Age ECOG performance status ECOG performance status First-line PFS First-line PFS First-line CT First-line CT Time from last BEV Time from last BEV Liver metastasis only Liver metastasis only No. of organs No. of organs with metastasis with metastasis Subgroup Subgroup All AIOAll AIO ML18147 ML18147 Female Female Male Male <65 years <65 years 65 years 65 0 years 0 1 1 9 months 9 months >9 months >9 months Oxaliplatin-based Oxaliplatin-based Irinotecan-based Irinotecan-based 42 days 42 days >42 days >42 No days No Yes 1 Yes >1 1 >1 n 819 n 819 260 260 559 559 294 294 525 525 458 458 361 361 357 357 458 458 449 449 369 369 343 343 476 476 630 630 189 189 592 592 226 226 307 307 511 511 HR 0 HR 0 HR HR 0.81 0.81 0.86 0.86 0.78 0.78 0.99 0.99 0.73 0.73 0.79 0.79 0.83 0.83 0.74 0.74 0.87 0.87 0.89 0.89 0.73 0.73 0.79 0.79 0.82 0.82 0.82 0.82 0.76 0.76 0.81 0.81 0.79 0.79 0.83 0.83 0.77 0.77 2 2
Baseline characteristics were well balanced between the BEV/chemotherapy (n=409) and chemotherapy-alone (n=411) arms. In the first-line setting, more than half of the patients in each arm had a PFS of 9 months (54 vs 56 percent) and received irinotecan-based chemotherapy (59 vs 58 percent). The duration between the last BEV dose and randomization was 42 days for 77 percent of patients in each arm. Use of second-line chemotherapy was well balanced during the study. The proportions of patients receiving irinotecan- and oxaliplatin-based chemotherapy were 42 and 58 percent, respectively, in the BEV/chemotherapy arm, vs 43 and 57 percent in the chemotherapy-alone arm.
Continuing BEV into second-line increases OS
Patient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when study was transferred to Roche, all patients listed under AIO were included in primary analysis; AIO = Working Group for Medical Oncology of the German Cancer Society; BEV = bevacizumab; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; ITT = intention-to-treat; OS = overall survival; PFS = progression-free survival
a

1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4
Adapted from Arnold D, et al. ASCO 2012; abstract CRA3503.
The trial met its primary endpoint, with OS significantly increased in patients who continued BEV beyond progression after first-line BEV/chemotherapy. After a median follow-up of 11.1 months for the BEV/ chemotherapy arm and 9.6 months for the chemotherapy-alone arm, median OS was 11.2 vs 9.8 months. (Figure 1)
The OS benefit was consistent in all prespecified subgroups, said Arnold. While there appeared to be a difference in treatment effect according to gender, we found no real interaction between BEV benefit and gender as the treatment-gender interaction test was not statistically significant. (Figure 2) In the study, 68.6 percent of patients in the BEV/chemotherapy arm and 67.7 percent in the chemotherapy-alone arm received 1 line of subsequent therapy, which included BEV [11.5 vs 12.2 percent], anti-EGFR therapy [39.2 vs 41.3 percent], and other therapies [54.9 vs 50.4 percent]. The balance in further lines of treatment indicates the robustness of the OS effect seen with continuing BEV into the second-line setting after first progression, suggested Arnold.
PFS estimate PFS estimate
Unstratifieda HR: 0.68 p<0.0001 Unstratifieda HR: 0.68 p<0.0001 b HR: 0.67 Stratified No. at risk CTNo. at risk BEV + CT CT BEV + CT p<0.0001 Stratifiedb HR: 0.67 0.2 p<0.0001 0.2 4.1 mo 5.7 mo 0 4.1 mo 5.7 mo 0 6 12 18 24 30 0 0 6 12 Time 18 24 30 (months) 410 409 410 409 119 189 119 189 20 45 20 45 6 12 6 12 36 42
CT (n=410) CT BEV +(n=410) CT (n=409) BEV + CT (n=409)
36
42
Time (months)
4 5 4 5
0 2 0 2
0 2 0 2
0 0 0 0
First-line PFS First-line CT Time from last BEV
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Liver metastasis only No. of organs with metastasis HR 0 1 2
9 months >9 months Oxaliplatin-based Irinotecan-based 42 days >42 days No Yes 1 >1
449 369 343 476 630 189 592 226 307 511
0.89 0.73 0.79 0.82 0.82 0.76 0.81 0.79 0.83 0.77
Secondary endpoints
Figure 3. PFS: ITT population

1.0 0.8
PFS was significantly prolonged with BEV/ chemotherapy vs chemotherapy alone (5.7 vs 4.1 months). (Figure 3) Overall response rates were similar in both arms (5.4 percent for BEV/chemotherapy vs 3.9 percent for chemotherapy alone). However, disease control rate was significantly higher with BEV/chemotherapy (68 vs 54 percent; p<0.0001) as a result of a higher number of patients who achieved stable disease (63 vs 50 percent).
Safety
CT (n=410) BEV + CT (n=409)
PFS estimate
0.6 0.4 0.2 0 4.1 mo 0 5.7 mo 6 119 189 12 20 45 18 6 12 24 4 5 30 0 2 36 0 2 42 0 0 Unstratifieda HR: 0.68 p<0.0001 Stratifiedb HR: 0.67 p<0.0001
No. at risk CT BEV + CT

a
Time (months)
410 409
Primary analysis method; b stratified by first-line CT, first-line PFS, time from last dose of BEV, ECOG performance status at baseline; BEV = bevacizumab; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; ITT = intention-to-treat; PFS = progression-free survival Adapted from Arnold D, et al. ASCO 2012; abstract CRA3503.
Conclusions
The ML18147 study confirms that continuing BEV beyond first progression while modifying chemotherapy provides significant OS and PFS benefits for mCRC patients. This represents a new second-line treatment option for patients previously treated with BEV in combination with standard chemotherapy in a first-line setting, suggested Arnold. In these patients, extended BEVbased therapy provides meaningful benefits while maintaining an acceptable safety profile. The findings also provide an important new insight about the biology of advanced CRC, he added. If the disease develops resistance to chemotherapy, it does not necessarily mean that tumors become resistant to antiangiogenic therapy. By simply switching chemotherapy drugs when the cancer progresses and continuing with BEV, we can make second-line treatment even more powerful, he said. Findings of ML18147 indicate a potential new model for treatment approaches through multiple lines, and this is currently being investigated in other tumor types.
As a result of the extended PFS, treatment duration was longer in the BEV/ chemotherapy arm than in the chemotherapy-alone arm (4.2 vs 3.2 months). However, grade 3-5 adverse events were not significantly different between the two regimens (64 vs 58 percent). There was no sign that continuing BEV beyond first progression had any impact on the rate of grade 3-5 adverse events from chemotherapy. The rates were generally low and similar in the two arms, pointed out Arnold. Compared with historical data on firstand second-line use of BEV in mCRC, BEVrelated adverse events were not increased when the agent was continued beyond first progression, he added. Although bleeding/ hemorrhage of all grades was slightly increased with BEV/chemotherapy [26 vs 9 percent], there was no real difference if you look at grade 3-5 only [2 vs <1 percent].
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Case Stud y
Use of capecitabine in advanced metastatic breast cancer

Dr. Foon-Yiu Cheung Clinical Oncologist
Presentation and treatment
A 47-year-old Chinese woman presented in 2002 with a mass in her right breast. She underwent modified radical mastectomy in August 2002. Pathology revealed a 1.7-cm invasive ductal carcinoma with grade 3 disease. Nine out of 23 resected axillary lymph nodes were involved by tumor. Resected margin was clear (5 mm). Estrogen receptor (ER) and progesterone receptor (PR) were positive while human epidermal growth factor receptor 2 (HER2) was negative. Metastatic workup was negative. The patient received adjuvant chemotherapy with the Milan scheme (four cycles of 3-weekly adriamycin and eight cycles of cyclophosphamide, methotrexate and 5-fluorouracil [5-FU]), followed by locoregional radiotherapy (RT). She received tamoxifen from June 2003 until June 2008. In June 2009, she presented with an incidental finding of lung masses on chest X-ray (CXR). Transbronchial biopsy confirmed metastatic carcinoma. ER and PR were strongly positive, while HER2 and thyroid transcription factor-1 (TTF-1) were negative. Paclitaxel and carboplatin were given for six cycles, completed in October 2009. CXR showed partial response. She underwent ovarian ablation with irradiation in October 2009 and was started on letrozole in March 2010. A few months later, the patient was found to have a secondary brain tumor at the left
Figure. PET-CT scans before (top) and after (bottom) capecitabine treatment
(A) Brain metastasis (B) Liver metastasis (C) Right hilar metastasis
parieto-occipital region by CT scan while on investigation for dizziness. Palliative whole-brain irradiation was given in June 2010 with 30 Gy in 10 fractions. Follow-up CXR in November 2011 revealed interval increase in size of the secondary lung tumor. A PET-CT in March 2012 revealed bilobar liver metastases, multiple hypermetabolic mediastinal lymph nodes and bilateral lung metastases. The left parieto-occipital brain metastasis remained hypermetabolic. Palliative capecitabine (2500 mg/m2 daily for 2 weeks in each 3-weekly cycle) was started in March 2012. Treatment was well tolerated. Repeat PET-CT in May 2012 after the third cycle revealed: Metabolic remission of bilobar liver metastases Significant metabolic improvement of hypermetabolic media-stinal lymph nodes Significant metabolic improvement of hypermetabolic intrapulmonary and left
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Case Stud y
breast cancer, and the median duration of response is about 4.5-9 months. The most commonly reported side effects are hand-foot syndrome (2-21 percent); diarrhea (3-10 percent) and nausea (3-8 percent).3 Whether it should be used in combination with other agents or as monotherapy after anthracyclin and taxane failure remains inconclusive. Combination with IV or oral vinorelbine is common. Although there is no phase III randomized trial for this scheme, the response rate reported in a phase II trial was 33-70 percent.4 This case illustrates that capcitabine is an effective agent for advanced breast cancer patients after anthracycline and taxane failure, which concurs with current published evidence. The treatment is well tolerated and, in this case, demonstrated activity against brain metastasis as well.
parieto-occipital brain metastases No new hypermetabolic meta-static lesions These findings suggest a partial treatment response. The patient plans to continue the present treatment.
Discussion
Breast cancer is the most common cancer among females in Hong Kong; in 2009, it was the third cause of cancer mortality.1 This patient first presented at a time when third-generation adjuvant chemotherapy with taxanes was either unavailable or very expensive. Adjuvant chemotherapy using the Milan scheme was the most potent option we could offer at that time. After relapse, she received subsequent systemic therapy in line with the consensus, using a taxane first. The choice of paclitaxel rather than docetaxel was solely a financial consideration, as paclitaxel is free. The subsequent use of capecitabine after progression is also in line with international recommendations, such as the NICE guideline.2 Single-agent capecitabine has a response rate of 14-28 percent in pretreated metastatic
References: 1. Top 10 cancers in 2009. http://www.ha.org.hk/cancereg. 2. NICE pathways: Advanced breast cancer, chemotherapy and biological therapy. http://pathways.nice.org.uk/pathways/advancedbreast-cancer#path=view%3A/pathways/advanced-breast-cancer/ advanced-breast-cancer-chemotherapy-and-biological-therapy. xml&content=close. 3. National Collaborating Center for Cancer. Advanced Breast Cancer: Diagnosis and treatment. Evidence Review. NICE 2009. 4. Clinical Breast Cancer 2012;12:30-39.
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Case Stud y
Figure. PET scan (A) Before chemotherapy
Capecitabine in advanced gastric cancer

Dr. Wai-Tong Ng Department of Clinical Oncology Pamela Youde Nethersole Eastern Hospital Hong Kong
Presentation
A 58-year-old Chinese man presented to Pamela Youde Nethersole Eastern hospital, Hong Kong, in February 2011 with a 2-month history of dysphagia. Upon admission, he could only tolerate fluid diet.
Investigations and diagnosis
Esophago-gastroduodenoscopy showed a circumferential tumor growth at the lower esophagus with extension to the gastric cardia. Biopsy revealed adenocarcinoma, HER2 immunohistochemistry (IHC) 3+. Computed tomography (CT) showed an irregular growth at the cardia extending to the gastroesophageal junction, and multiple slightly enlarged lymph nodes over the gastroesophageal, gastro-hepatic and upper para-aortic regions. Positron emission tomography (PET) scan revealed a primary tumor involving the distal esophagus, gastric cardia and proximal lesser curvature, and a hypermetabolic focus in the liver, which was compatible with a liver metastasis. (Figure A)
The arrow indicates the site of liver metastasis.
(B) Before chemotherapy
Treatment
The patient was given palliative chemotherapy using cisplatin, 5-fluorouracil (5-FU) and trastuzumab. After 2 cycles of treatment, there was a significant improvement in symptoms and the patient could resume normal solid diet. However, impaired renal function was noted due to the use of cisplatin. He was thus switched to oxaliplatin, capecitabine
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Case Stud y
was compared for the 664 patients treated with 5-FU combinations vs the 654 patients treated with capecitabine combinations. The median OS was 285 days for patients treated with 5-FU and 322 days for patients who received capecitabine, with an unadjusted hazard ratio (HR) of 0.87 in favor of capecitabine (p=0.027). This meta-analysis is practice changing as capecitabine is not only better than 5-FU in terms of survival, but also far more convenient as patients can avoid unnecessary hospitalization or central line insertion for the 5-FU infusion. Another important advance in the management of mGC is the integration of targeted agents into the chemotherapy backbone. Trastuzumab is currently the most widely used targeted therapy for patients with HER2-positive tumors. In the ToGA trial, median OS was 14 months among patients assigned to trastuzumab plus chemotherapy vs 11 months for those assigned to chemotherapy alone (p=0.0046).4 A subgroup analysis indicated that trastuzumab was most effective in prolonging survival in patients with HER2 IHC 3+ or IHC 2+ and FISH (fluorescence in situ hybridization)-positive tumors (HR=0.65). In these HER2-positive patients, the median OS was 16.0 months in the trastuzumab arm, compared with 11.8 months in the chemotherapy-alone arm. Currently, approximately 20 percent of mGC patients are HER2-positive, and trastuzumab plus chemotherapy represent the standard of care for this group of patients.
and transtuzumab; 8 cycles of treatment were given in total. A follow-up PET scan showed good response and the liver metastasis became hypometabolic. (Figure B) Total radical gastrectomy and distal esophagectomy were performed in November 2011 with clear margins. The liver lesion was not identifiable during the operation. Repeat PET scan after the operation showed no gross FDG-avid lesion. In early February 2012, he was given stereotactic body irradiation (55 Gy over 10 fractions) to the liver lesion (tumor location based on the pre-treatment PET scan). Trastuzumab was continued for up to 1 year and treatment was completed in April 2012. He was stable and doing well at the time of last follow-up, with no deterioration in cardiac function.
The combination of 5-FU and cisplatin is a widely accepted standard regimen for metastatic gastric cancer (mGC). However, the need for several days of hospital stay with 5-FU infusion and the potential renal toxicity associated with cisplatin have prompted the evaluation of alternative treatment regimens. Two important studies ML17032 and REAL-2 have evaluated the replacement of these agents by capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum analogue with less renal toxicity).1,2 Similar antitumor activity has been confirmed in these studies. In addition, a more interesting observation was noted in a recent combined analysis of these two studies.3 In this meta-analysis, a total of 1,318 patients who were randomized within REAL-2 (n=1,002) and ML17032 (n=316) were included. Overall survival (OS)
Discussion
References 1. Ann Oncol 2009;20:666-673. 2. N Engl J Med 2008;358:36-46. 3. Ann Oncol 2009;20:1529-1534. 4. Lancet 2010;376:687-697.
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News
New evidence linking H. pylori with colon cancer

Naomi Rodrig
hile the association between Helicobacter pylori (H. pylori) infection and an increased risk of gastric adenocarcinoma has been well established, evidence regarding its role in the development of colorectal cancer (CRC) remains controversial. Recently, a large epidemiological study reported at the 2012 Digestive Disease Week in San Diego, USA has shown an increased risk of colon neoplasms in patients with H. pylori infection. The investigators reviewed the records of nearly 157,000 patients who had undergone both colonoscopy and esophago-gastroduodenoscopy between 2008 and 2011. Overall, 16,759 patients, or 11 percent, had H. pylori infection confirmed by immunohistochemistry, reported lead author, Dr. Amnon Sonnenberg of Oregon Health and Science University and the Portland VA Medical Center, US. The prevalence of H. pylori gastritis was 9 percent among patients without colonic polyps, 11 percent in patients with hyperplastic polyps, 12 percent in those with adenoma, 14 percent in patients with advanced adenoma and 18 percent in those with adenocarcinoma. The prevalence was similar regardless of the site of the colonic lesion. Furthermore, there was a trend of increased prevalence of H. pylori infection with increasing number and size of adenomatous polyps. The data suggest a link between the prevalence of infection and lesion severity. H. pylori confers an increased risk for all types of colonic neoplasms, and the risk appears to increase with advancing stage of the neoplasm, from hyperplastic and adenomatous polyps to tubulovil-
lous adenoma, adenoma with high-grade dysplasia and adenocarcinoma, he concluded. Another report published earlier this year suggested that H. pylori infection may be associated with an increased risk of CRC in specific colorectal sites. [Am J Epidemiol 2012. DOI: 10.1093/aje/kwr331] The authors assessed the association of H. pylori seroprevalence with risk of CRC in a large population-based case-control study conducted in Germany between 2003 and 2007. Serum antibodies to H. pylori in general and the cytotoxin-associated gene A protein (CagA) were measured in 1,712 incident CRC patients and 1,669 controls. CagA-positive strains of H. pylori are considered more toxic or carcinogenic. The association between H. pylori prevalence and CRC risk was adjusted for potential confounders and stratified by age group, gender, anatomic subsites, and cancer stage. Overall, H. pylori seroprevalence was higher in CRC patients than in controls (46.1 vs 40.1 percent, respectively). Age- and genderadjusted odds ratios (OR) were 1.3 and 1.14, respectively. Stratified analyses showed that the risk elevation was essentially confined to left-sided CRC, with an OR of 1.22. H. pylori infection may be associated with a small yet relevant risk increase in the left colorectum, the authors concluded. The results of both recent studies are in contrast with previously published data. For example, a nested case-control study of men in the ATBC (Alpha-Tocopherol, Beta-Carotene) cancer prevention clinical trial in Finland, which analyzed data from nearly 30,000 subjects, found no evidence of H. pylori being a risk factor for CRC development. [Ann Epidemiol 1994;4:1-10]
Minimum Product Information Herceptin (trastuzumab) Powder for Concentrate for infusion 150 mg single dose vial & 440 mg multidose vial (with solvent) Indications: HER2 positive patients with: (i) metastatic breast cancer (MBC), either as monotherapy following at least 2 chemotherapy (CT) regimens; or in combination with paclitaxel for patients who have not received CT; or in combination with docetaxel for patients who have not received CT; or in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, or (ii) early breast cancer (EBC) following surgery, CT (neo/adjuvant) and radiotherapy (if applicable); or following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel; or in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin, or (iii) metastatic gastric cancer (MGC) in combination with capecitabine or 5-FU and cisplatin. Dosage & administration: Please refer to Herceptin PI for full guidance. HER2 testing is mandatory prior initiation of therapy. EBC/MBC/MGC 3-weekly: loading dose - 8mg/kg; subsequent doses 6mg/kg repeated at 3-weekly intervals. BC weekly: loading dose - 4mg/kg; subsequent doses: 2mg/kg weekly. Administer as IV infusions over approx. 90 min. Infusion time reduced to 30 min for subsequent doses if initial loading dose was well tolerated. Do not administer as an IV push or bolus. Observe for infusion-related symptoms. In MBC or MGC, treat until disease progression. Patients with EBC should be treated for 1 year or until disease recurrence. Contraindications: Known hypersensitivity to trastuzumab or any product excipients. Warnings & Precautions: Discontinue Herceptin infusion in case of serious adverse reactions. Patients experiencing dyspnoea at rest may be at risk of fatal infusion reactions or severe pulmonary reactions. Interstitial lung disease may occur as part of an infusion-related reaction or with a delayed onset especially in patients with prior or concomitant therapy with other anti-neoplastic therapies, these patient should not be treated with Herceptin. Heart failure has been observed. Caution in patients with symptomatic heart failure, history of hypertension or documented coronary artery disease and in EBC, in those patients with an LVEF <55%. Candidate patients should undergo baseline cardiac assessment and risk-benefit assessment. Monitor cardiac function during treatment. Consider discontinuing treatment in patients whose LVEF has not improved, or declined further, or in patients who develop clinically significant heart failure unless benefits outweigh risks. Safety of continuation or resumption in patients experiencing cardiotoxicity has not been studied. Benzyl alcohol contained in the solvent for 440mg vial. Caution for use in pregnancy as oligohydramnios have been reported. Avoid breast-feeding during therapy. Not recommended for children < 18 years old. Undesirable effects: For full listings please refer to the Herceptin PI. Very common adverse reactions (>10%): nasopharyngitis, anaemia, thrombocytopenia, weight changes, decreased appetite, insomnia, Nervous system disorders (including dizziness, headache, paraesthesia, hypoaesthesia), lacrimation increased, conjunctivitis, lymphoedema, Respiratory, thoracic and mediastinal disorders (including dyspnoea, epistaxis, oropharyngeal pain, cough, rhinorrhoea), Gastrointestinal disorders (including diarrhoea, vomiting nausea, abdominal pain, dyspepsia, constipation, stomatitis), erythema, rash, alopesia, arthralgia, myalgia, General disorders and administration site conditions (including asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion related reaction, pain, pyrexia, peripheral oedema, mucosal inflammation) & nail toxicity. Post Marketing refer to package insert. Date of preparation: December 2011 Full prescribing information should be viewed prior to prescribing.
36
Jul-Aug 2012
News
Overcoming treatment resistance in pancreatic cancer

Christina Lau
esearchers in the US have discovered how pancreatic cancer becomes resistant to chemotherapy and identified ways to improve treatment based on their findings. The studies, presented recently at the American Association for Cancer Researchs (AACR) first-ever conference on pancreatic cancer, represent progress in a disease that is notoriously difficult to treat, with 90 percent of patients likely to die within 1 year from diagnosis. Pancreatic cancer cells are largely resistant to cell death induced by chemotherapy and radiation. Fortunately, our data show that this seemingly unconquerable disease has an Achilles heel its toxin exhaust system, said Professor Sanjay Awasthi of the City of Hope Comprehensive Cancer Center in Duarte, USA. The weak point Awasthi and colleagues identified is the RLIP76 protein, which pumps out toxic chemicals accumulating in pancreatic cancer cells as a result of chemotherapy or radiotherapy before they can cause cell death. We found a higher level of RLIP76 in human pancreatic cancer cells than in normal human pancreatic cells. Depletion of RLIP76 levels killed human pancreatic cancer cells in culture and shrank established human pancreatic tumors in mice, he reported. Moreover, blocking or depleting levels of this protein dramatically enhanced the ability of radiation and doxorubicin to destroy human pancreatic cancer cells in culture. An added benefit to depleting RLIP76 levels
in mice with established tumors was a decrease in blood glucose, cholesterol and triglycerides, added Awasthi, who is founder of a company that makes recombinant RLIP76 protein for treatment of radiation poisoning. Another approach already being tested in the clinic is inhibition of the Hedgehog signaling pathway, said Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor, USA. Early results look promising. The Hedgehog pathway is normally silent in the adult pancreas but activated in patients with pancreatic cancer, contributing to the desmoplastic stroma that is characteristic of the disease. This dense stroma is believed to contribute to resistance to chemotherapy by presenting a physical barrier to chemotherapy delivery, said Kim. In addition, Hedgehog levels are increased in pancreatic cancer stem cells, which drive tumor growth by generating bulk tumor cells and are particularly resistant to chemotherapy and radiation. Kim and colleagues have achieved some success in a small number of patients with the Hedgehog pathway inhibitor GDC-0449 (vismodegib), an oral agent approved for use in basal cell carcinoma. In 20 treatment-nave patients with advanced pancreatic cancer, use of GDC-0449 (as monotherapy for 3 weeks and then in combination with gemcitabine) led to a partial response in five patients and stable disease in five patients. Progression-free survival at 3 months was 50 percent.
37
Jul-Aug 2012
News
the cancer stem cells might lead to improved outcomes. We believe that GDC-0449 has the potential to change the approach to treatment of pancreatic cancer, he continued. Data from biopsy specimens will help identify predictive markers to determine which patients would benefit from combination treatment with GDC-0449 and gemcitabine.
Treating pancreatic cancer patients with GDC-0449 first as monotherapy and then in combination with the standard chemotherapeutic drug gemcitabine might disrupt the desmoplastic stroma and improve the efficacy of the chemotherapy, Kim explained. Also, as pancreatic cancer stem cells have higher Hedgehog levels than bulk cancer cells, suppressing Hedgehog activity within
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39
Jul-Aug 2012
News
Arthritis drug to be tested in lymphoma

Christina Lau
ingaporean researchers are planning to test a Janus kinase 3 (JAK3) inhibitor in patients with natural killer (NK)/Tcell lymphoma a very aggressive form of lymphoma frequently found to harbor JAK3 mutations. NK/T-cell lymphoma is particularly prevalent in Asia, accounting for almost half of all T-cell lymphomas in some parts of the region, said Professor Bin-Tean Teh of the National Cancer Center SingaporeVan Andel Research Institute Translational Research Laboratory and DukeNational University of Singapore Graduate Medical School. Very little was known about the genetic and molecular defects causing the aggressive disease before we started our study, he continued. With no effective treatment, the prognosis of patients with NK/T-cell lymphoma is extremely poor. In their study, Teh and colleagues conducted whole-exome sequencing of NK/Tcell lymphoma cells from four patients, and identified JAK3 somatic-activating mutations in two of them. Further validation was conducted in another 61 patients with Sanger sequencing and high-resolution melt (HRM) analysis. In total, 23 of 65 cases (35.4 percent) harbored JAK3 mutations. [Cancer Discov 2012, e-pub 15 Jun] The mutations enabled NK/T-cell lymphoma cell lines to grow in culture without the normally essential growth factor, interleukin-2 (IL-2). This means that JAK3 mutations cause dysregulated activation of JAK3, suggesting that JAK3 may be a good drug target. There is a JAK3 inhibitor [CP-690550
(tofacitinib)] currently in phase III trials for treatment of rheumatoid arthritis. In our study, use of CP-690550 in the JAK3-mutant NK/T-cell lymphoma cell lines led to inhibition of STAT5 [signal transducer and activator of transcription-5] phosphorylation, along with reduced cell viability, reported Teh. We are in the process of planning a clinical trial to test the agent as a treatment for NK/T-cell lymphoma with JAK3 mutations. It is tremendously rewarding to have identified genetic mutations that appear to have an important role in driving NK/T-cell lymphoma in a considerable proportion of cases, he continued. Although relatively rare in the USA, this form of lymphoma is responsible for the deaths of a large number of people in Asia, especially in China and Korea.
41
Jul-Aug 2012
Meeting Highlights
Everolimus plus exemestane improves PFS in advanced breast cancer

At a sponsored satellite symposium in conjunction with the Asian Oncology Summit held recently in Singapore, Professor Patrick Schffski, Head of the Department of General Medical Oncology and the Laboratory of Experimental Oncology at the University Hospitals Leuven, Catholic University Leuven, Belgium, reviewed the current treatment options for metastatic renal cell carcinoma (mRCC). In particular, he highlighted the latest data focusing on the angiogenesis inhibitor pazopanib.
Prof. Schffski
Unmet needs in mRCC
The treatment options for mRCC have been revolutionized over a short period of time. Since 2005, seven targeted agents have been approved for use in the treatment of mRCC, either as first- or second-line. This has resulted in improved clinical outcomes for patients with mRCC. However, the more treatment options we have, the more difficult and complicated it becomes to make treatment decisions, said Schffski. The incidence of RCC worldwide continues to increase by 1 to 2 percent per year, which may be partly attributed to improved diagnosis. There is still an unmet medical need in mRCC, Schffski said. The drugs that we have today are not curing our patients. We are delaying tumor growth and shrinking metastasis in a large proportion of patients, but complete responses are rare. Refractoriness to treatment develops in the majority of cases. Other challenges in targeted therapy for mRCC include identification of the most effective sequence
or combination of available targeted agents to reduce adverse events and prevent or overcome the development of drug resistance. Many patients suffer from adverse events associated with some tyrosine kinase inhibitors (TKIs). Mucositis, fatigue, hand-foot syndrome and gastrointestinal complaints such as diarrhea all require adequate assessment and prompt management. In a retrospective study involving approximately 700 patients with mRCC, a variety of adverse events were reported with the targeted agents sunitinib, sorafenib or bevacizumab. In general, the adverse event profiles of these drugs varied considerably. [Levy A, et al. European Multidisciplinary Cancer Congress 2011. Abstract 7.152] For sunitinib, the main problem that we all encounter, and Im seeing it daily in my own patients as well, is fatigue/asthenia, apart from other side effects. For sorafenib, the dominant problem from my personal experience is hand-foot
42
Jul-Aug 2012
Meeting Highlights
causes less inhibition of Fit-3, a mediator of hematopoiesis. (Figure 1) A phase III trial has demonstrated that pazopanib improves progression-free survival (PFS) and response rates in both treatment-nave and cytokine-pretreated patients. In this study, patients were randomized to either pazopanib (n=290) or matching placebo (n=145). The study allowed for early cross-over from placebo to active treatment with pazopanib, without any impact on PFS. In the overall study population, PFS was significantly longer with pazopanib than with placebo (9.2 months vs 4.2 months, p<0.001). A 54 percent reduction in the risk of progression or death was also observed with pazopanib. (Figure 2) The benefits of pazopanib were even more pronounced in treatment-nave patients, with PFS reaching 11.1 months and a response rate of 32 percent. (Figure 3) In cytokine-pretreated patients, the PFS and response rates were 7.4 months and 29 percent, respectively. Median duration of response was more than 1 year. [J Clin Oncol 2010;28:1061-1068] These data have established pazopanibs role as a new option in the treatment of advanced or metastatic RCC. Of note, this drug has less hematologic toxicity compared with other targeted therapies. The most common adverse events reported were diarrhea, hypertension, hair color changes and elevation of liver enzymes, said Schffski. I see a major advantage here for pazopanib. Increases in alanine aminotransferase [ALT] and bilirubin levels are also associated with other anti-VEGF agents, with varying in-
syndrome and also fatigue/asthenia. For bevacizumab, which is usually combined with interferon-alfa, the rate of fatigue/ asthenia has reached 44.4 percent and this has led to treatment discontinuation in a considerable number of patients, he reported. Fatigue/asthenia is a repeating theme among patients treated with these targeted agents. In general, treatmentrelated adverse events have a negative impact on the well-being of patients, and the actual dosing and scheduling of drugs. Drugs are used according to labeled instructions, but many patients do not tolerate full doses. Any variation to the prescribed regimens has an effect on treatment outcomes, Schffski warned. In the study, treatment modifications occurred quite often. Between 12 to 25 percent of patients had to discontinue treatment due to adverse events.
Pazopanib in mRCC: Efficacy and safety
The treatment strategy for mRCC continues to evolve. Pazopanib a potent inhibitor of VEGFR-2, the primary mediator of angiogenesis is a welcome addition to the mRCC treatment portfolio. The drug has a favorable overall risk:benefit profile and works by inhibiting the intracellular tyrosine kinase of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In vitro studies demonstrated that pazopanib has >6 times greater affinity for VEGFR-2 and is overall more selective than sunitinib. Unlike sunitinib, pazopanib also
43
Jul-Aug 2012
Meeting Highlights
sions. Comorbidities, lifestyle and individual patient expectations should be carefully considered when making treatment decisions.
Figure 1. Pazopanib is a potent inhibitor of VEGFR-2: Preclincal studies of pazopanib and sunitinib
229 229 230 230
Proportion progression-free progression-free Proportion Proportion progression-free
cidence and severity. Arterial hypertension is an uncommon event, but there are clear guidelines on how to deal with it. (Figure 4) Fatigue is also less prominent with pazopanib than with other drugs Ive prescribed before for my patients. Fatigue can be bothersome for patients and translates into poorer outcomes, he remarked. Schffski noted that the ongoing COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial, which involves a head-to-head comparison of the two TKIs, is expected to provide more data to facilitate treatment selection for individual patients.
100 Pazopanib 100 Pazopanib Sunitinib 9090 Sunitinib 8080 229 7070 100 Pazopanib 6060 229 229 90 Sunitinib 5050 80 4040 70 229 1515 229 229 229 3030 60 229 2020 1515 1515 50 1515 1515 1010 229 2.4 229 2.4 40 0.5 0.5 00 229 15 229 30 1 -1 2 -2 3 -3 it Kit KR R R R R R R R RFR F FG15 FGF FGF F FG15 FG C-C G G G 20 G G E E E E E E D D VV V V 15 V V 15 PD PP PD 10 229 2.4 0.5 0 2009;101:1717-1723; 2) N Engl J Med 2008;358:2039-2049. Adapted from 1) Br J Cancer it -1 -2 -3 - - R R R R R F F F F F C-K G G VEG VEG VEG PD PD Kiapp (nM) Kiapp (nM) Kiapp (nM)
230
229 229
3t-3 -i FitF
229
Fit-
Figure 2. Pazopanib vs placebo: PFS in the overall population

1.0 1.0 0.8 0.8 1.0 0.6 0.6 0.8 0.4 0.4 0.6 0.2 0.2 5 5 159 159 3838 5 159 38 1010 1515 2929 2 2 15 29 2 Median PFS Median PFS Pazopanib (n=290): 9.2 months Pazopanib (n=290): 9.2 months Placebo (n=145): 4.2 months Placebo (n=145): 4.2 months
p<0.0001 p<0.0001 Median PFS Pazopanib (n=290): 9.2 months Placebo (n=145): 4.2 months p<0.0001
less hematologic toxicity compared with other targeted therapies
Figure 3. Pazopanib vs placebo: PFS in the treatment-nave Pazopanib (n=155): 11.1 months population Pazopanib (n=155): 11.1 months 0.8 60% 0.8 60% Placebo (n=78): 2.8 months
Placebo (n=78): 2.8 months 1.0 0.6 0.6 0.8 0.4 0.4 0.6 0.2 0.2 5 5 8484 2222 5 84 22 1010 1515 Median PFS p<0.001 p<0.001 Pazopanib (n=155): 11.1 months Placebo (n=78): 2.8 months
p<0.001
Proportion progression-free progression-free Proportion Proportion progression-free
This drug has
PFS = progression-free survival
0 0 0.4 0 0 Number risk 0.2 Number at at risk Pazopanib 290 290 Pazopanib Placebo 145 Placebo 0 145 0 Number at risk Pazopanib Placebo
Time (months) Time (months)

7676 1414 10
2020 6 6
reduction reduction in in risk risk of of progression progression death with oror death with 54% pazopanib pazopanib vsvs reduction in placebo placebo risk of progression or death with pazopanib vs placebo
54% 54%
Time (months)
76 14
Adapted from J Clin Oncol 2010;28:1061-1068.
20 6
290 145
1.0 1.0
Median PFS Median PFS
Conclusions
0 0 0.4 0 0 Number risk 0.2 Number at at risk Pazopanib 155 155 Pazopanib Placebo 78 Placebo 0 78 0 Number at risk Pazopanib Placebo 155 78
Time (months) Time (months)

3939 7 7 10 39 7
2020 1 1 20 1
reduction reduction in in risk risk of of progression progression death with oror death with 60% pazopanib pazopanib vsvs reduction in placebo placebo risk of progression or death with pazopanib vs placebo
Time (months)
1111 2 2 15 11 2
Pazopanib is the third TKI and the sixth targeted therapy approved for the treatment of advanced or metastatic RCC. Its safety profile is different from other agents. The drug is clearly manageable, but it is important to assess and manage relevant adverse events such as hypertension, liver enzyme elevation and diarrhea. Guidelines are available to help physicians make sound therapeutic deci-
PFS = progression-free survival
Adapted from J Clin Oncol 2010;28:1061-1068.
Figure 4. How to manage hypertension in patients taking pazopanib

Monitor blood pressure Monitor regularly (at least during every visit at outpatient clinic) Hypertension Persistent hypertension Continue pazopanib treatment and intensify existing antihypertensive drug therapy
Continue pazopanib treatment and initiate antihypertensive drug therapy
Reduce pazopanib dose and continue antihypersensitive drug Discontinue pazopanib if arterial hypertension is severe and persists despite antihypersensitive therapy and pazopanib dose reduction
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Jul-Aug 2012
Expert Opinion
Cetuximab rechallenge: Extending clinical benefits in mCRC

While the benefits of first-line chemotherapy plus cetuximab (Erbitux, Merck Serono) in patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) are well established, subsequent lines of treatment are eventually required following disease progression. A recent phase II trial demonstrated that rechallenge with cetuximab-based therapy may provide clinical benefit for patients who responded to previous treatment with the same regimen. Dr. Hui Pun, Edwin, Specialist in Medical Oncology and Director of the Comprehensive Cancer Trials Unit, Chinese University of Hong Kong, reviewed the therapeutic options for mCRC and discussed the practical implications of the study.
Dr. Hui
Treatment of mCRC
The currently available options in mCRC include three cytotoxic chemotherapy drugs 5-flurouracil [5-FU], oxaliplatin and irinotecan, and two targeted agents cetuximab and bevacizumab, said Hui. For first-line therapy we usually select two cytotoxic drugs and one targeted agent. For second line, we would try the ones we havent used before. However, for thirdline treatment, options are limited since we had probably used all the available choices and nothing is left. For selecting first-line treatment, KRAS mutation status is determined before initiating therapy, as KRAS WT tumors are likely to respond to anti-epidermal growth factor receptor (EGFR) therapy such as cetuximab. Conversely, patients with KRAS mutations would benefit from chemotherapy alone or non-EGFR targeted therapies. Although the benefit of cetuximab in KRAS WT tumors is significant, it is not covered by the public healthcare system. Therefore, we would start treatment
with chemotherapy, adding cetuximab for KRAS WT patients who can afford it or get funding from other sources, he explained. KRAS mutation testing is reimbursed, so we test everybody in case they can get funding later. At present, the Community Care Fund covers cetuximab only for mCRC patients with liver-limited metastases. According to Hui, it is recommended to use cetuximab in first-line therapy rather than reserving it for subsequent treatment lines. Some patients may deteriorate fast unless they receive powerful firstline therapy, so they may not get another chance to use the targeted therapy later. In our experience, patients who have a chance to receive all five drugs live longer than those who use fewer drugs. Hence, we tend to prescribe a targeted therapy upfront with the first chemotherapy course, he said. The standard treatment regimen of cetuximab plus FOLFOX or FOLFIRI consists of 12 biweekly cycles for a total of 6
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Jul-Aug 2012
Expert Opinion
sponses. Disease stabilization was reported in 14 patients and 4 patients had progressive disease. (Table) Table. Tumor response rates Response CR PR ORR (CR+PR) SD CCR (CR+PR+SD) PD Number of patients 2 19 21 14 35 4 % 5.1 48.7 53.8 35.9 98.9 10.2
months. While longer treatment might further arrest disease progression, its at the cost of cumulative toxicities from chemotherapy, Hui remarked.
Cetuximab rechallenge study
The phase II study investigated whether patients with KRAS WT mCRC who responded and then progressed during cetuximab-based therapy would gain a clinical benefit, after a new line of therapy, from retreatment with the same cetuximab-based regimen. [Ann Oncol 2012. DOI:10.1093/annonc/mdr623] The study was based on the hypothesis that KRAS status remains the same despite the treatments received. KRAS mutation is an early pathogenic step in CRC development and it seems to remain the same during tumor progression, the authors noted. [Oncologist 2008;13:1270-1275; Ann Surg Oncol 2010;17:1429-1434] The investigators enrolled 39 KRAS WT mCRC patients who had had a clinical benefit after cetuximab plus irinotecan-based therapy and then a progression of disease during therapy, for which they received a new line of chemotherapy with or without bevacizumab. Finally, after another progression, they were retreated with the initial cetuximab plus irinotecan-based therapy. Patients were treated until disease progression or unacceptable toxic effects. The primary endpoint was overall response rate (ORR). Tumor response was evaluated every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST). The ORR was 53.8 percent, including 19 partial responses and 2 complete re-
CR = complete response; PR = partial response; ORR = overall response rate; SD = stable disease; CCR = clinical control rate; PD = progressive disease Adapted from Ann Oncol 2012. DOI:10.1093/annonc/ mdr623.
Median progression-free survival was 6.6 months. Previous responses during the first cetuximab-based therapy (stable disease lasting >6 months or partrial response) were found to predict clinical benefit after cetuximab-based retreatment. In addition, a significant correlation between skin toxicity during the first cetuximabbased therapy and during rechallenge was observed.
Clinical implications
According to Hui, this is the first published report that clearly demonstrates the clinical benefit of rechallenge with the initial cetuximab-based therapy after progression on several treatment lines. Although there have been case reports, and we have occasionally used this approach for select-
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Jul-Aug 2012
Expert Opinion
Therefore, it is important to identify those who might benefit from this strategy with minimal toxicity.
ed patients, this is the first prospective trial to provide solid evidence, he commented. Hui noted that the multicenter design of the study further confirms the validity and applicability of the results, which may have practice-changing implications. Based on these findings, Im now much more confident to recommend retreatment with the same therapy to patients who responded previously to cetuximabbased therapy, he said. Patient selection is crucial, however, as many patients cannot tolerate several lines of chemotherapy.
Conclusions
The study is the first demonstration that rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit in mCRC, further delaying disease progression and improving the therapeutic options. Based on these data, this approach may be more widely applied in clinical practice.
Case report: Repeat rechallenge with cetuximab-based therapy

A 67-year-old man was diagnosed with adenocarcinoma of the rectum with multiple liver metastases in 6/2007. The primary tumor was asymptomatic and was not resected. 6/2007 - 2/2008: FOLFOX/XELOX; 12 cycles with good response. However, the residual liver metastases were not amenable to resection or radiofrequency ablation. 10/2008 - 3/2009: Irinotecan + cetuximab x 12 cycles (1st course). Cetuximab was started from the second cycle after confirmation of KRAS WT status. Reduction of liver metastases was documented after 5 months (Figure a), with disease progression 9 months after therapy end. 1/2010 - 3/2010: Bevacizumab + oxaliplatin x 4 cycles with poor response. 4/2010 - 11/2010: Irinotecan + cetuximab x 12 cycles (2nd course; rechallenge #1). Reduction of liver metastases was documented after 3 months (Figure b), with disease progression 3 months after therapy end. 1/2011 - 8/2011: Irinotecan + cetuximab x 12 cycles (3rd course; rechallenge #2). Reduction of liver metastases was documented after 4 months (Figure c). The patient tolerated three courses of 12-cycle cetuximab-based treatment well, and achieved good radiological response and symptom control. However, he decided to take a treatment break after the last course, and passed away a few months later following disease progression. As seen in this case, repeat rechallenge with cetuximab-based therapy can be successfully applied to achieve tumor response and prolong survival. Nevertheless, the progression-free intervals after successful response become successively shorter, with fewer therapeutic options remaining after each treatment course, commented Hui.
47
Jul-Aug 2012
Expert Opinion
Figure. CT scans: Liver metastases

(a) First course of cetuximab + irinotecan
Before
After 5 months
(b) Second course of cetuximab + irinotecan (rechallenge #1)
Before After 3 months (c) Third course of cetuximab + irinotecan (rechallenge #2)
Before
After 4 months
8 4 0 Jul-Aug 2012 Industr y Upda te 48
First-line temsirolimus improves survival in poor-prognosis mRCC patients

In a randomized phase III study, temsirolimus (Torisel, Pfizer) monotherapy demonstrated significant improvements over interferon alfa (IFN) as firstline treatment for metastatic renal cell carcinoma (mRCC) patients with poor prognosis. Dr. Thomas Yau, Clinical Assistant Professor, Department of Medicine, University of Hong Kong discussed the management options for RCC and the findings of the pivotal trial that compared temsirolimus, interferon alfa (IFN) and a combination of both.
Dr. Yau
Management of mRCC
In Hong Kong, RCC is treated in accordance with the US National Comprehensive Cancer Network (NCCN) guidelines, said Yau. Early-stage RCC patients are routinely referred for surgical tumour excision to reduce disease burden and preserve renal function. The treatment for patients with advanced or metastatic RCC when the diseased tissue cannot be completely eradicated with surgery alone is not as straightforward, explained Yau. The choice of first-line treatment for mRCC is largely dependent on the patients histological finding and prognosis, based on the Memorial Sloan-Kettering Cancer Center risk stratification system. [J Clin Oncol 2005;23:832-841] Patients with clear cell histology are mostly treated upfront with multi-targeted receptor tyrosine kinase inhibitors (TKIs) such as sunitinib or pazopanib. However, patients with non-clear cell histology, or those with poor prognosis [regardless of
histology], are treated with temsirolimus a mammalian target of rapamycin (mTOR) kinase inhibitor, he said.
Temsirolimus in poor-prognosis mRCC patients
The phase III, multicenter, randomized, open-label study evaluated the efficacy and safety of temsirolimus against IFN or combined temsirolimus/IFN therapy in 626 treatment-nave patients. Patients enrolled in this study had poor-prognosis, said Yau. Usually, those patients only survive for about 3 to 6 months. Study subjects had at least three of the following disease parameters, which predicts short survival: serum lactate dehydrogenase >1.5 upper limit of normal; hemoglobin below normal levels; corrected serum calcium level >10 mg/dL; time from initial diagnosis of RCC to randomization <1 year; Karnofsky performance score of 60 or 70; and multiple organ metastases.

Patients in the temsirolimus-only arm received a dose of 25 mg IV weekly; patients in the IFN-only arm received 3-18 million IU subcutaneously (SC) 3 times weekly; patients in the combined therapy arm received temsirolimus 15 mg IV weekly plus IFN 3-6 million IU SC 3 times weekly. [N Engl J Med 2007;356:2271-2281]
Efficacy and safety
Figure. Kaplan-Meier estimates of overall survival (A) and progressionfree survival (B)
A (A) Probability of survival
1.00 0.75 0.50 0.25 0.00 0

Number at risk Interferon alfa Temsirolimus Combination
B
Temsirolimus Combination Interferon alfa
Compared with IFN monotherapy, patients on temsirolimus monotherapy had a 49 percent increase in median overall survival 1.00 the primary endpoint (10.9 A vs 7.3 months; p=0.0078). Median Temsirolimus progresCombination 0.75 Interferon alfa sion-free survival (PFS) was 5.5 months 0.50 for patients receiving temsirolimus vs 3.1 months for 0.25 those on IFN (p=0.0001), translating into a 77 percent increase in 0.00 5 10 15 20 25 30 PFS. (Figure) 0 Months Objective response rate was nearly doubled in the temsirolimus monotherapy arm vs the IFN monotherapy arm (8.6 vs 4.8 percent). Interestingly, patients receiving combination therapy did not achieve improved outcomes vs temsirolimus monotherapy, remarked Yau. Severe adverse events were less common in patients receiving temsirolimus monotherapy, resulting in fewer dose delays, dose reductions and treatment discontinuation vs IFN monotherapy. Temsirolimus-related adverse events included mild-to-moderate rash, peripheral edema, stomatitis, hyperglycemia, hypercholesterolemia and hyperlipidemia. In my experience with six poor-prognosis patients at our hospital, four had
Probability of survival
Number at risk Interferon alfa Temsirolimus Combination 207 209 210 126 159 135 80 110 93 42 56 50 15 19 17 3 3 7 0 0 2
10
15
20
25
30
Months
207 209 210 126 159 135 80 110 93 42 56 50 15 19 17 3 3 7 0 0 2
Num Inter Tems Comb
B Probability of progressionfree survival
1.00 0.75 0.50 0.25 0.00 0

Number at risk Interferon alfa Temsirolimus Combination
(B)
Temsirolimus Combination Interferon alfa
10
15
20
25
30
Months
207 209 210 55 91 89 24 38 32 10 14 16 5 7 4 1 1 1 0 0 1
Adapted from N Engl J Med 2007;356:2271-2281.
good response to temsirolimus monotherapy. Adverse events such as mucositis and hyperglycemia were easily managed, said Yau.
Conclusion
Temsirolimus monotherapy is an effective therapeutic option for managing mRCC in patients with poor prognosis. Compared with IFN-based therapy, it has a significantly improved efficacy and an acceptable toxicity profile, concluded Yau.

Case report A 39-year-old Han Chinese woman was referred for management of mRCC in 2008. Her past health had been good except for a cholecystectomy in 1996. Apart from her uncle, who had liver cancer and colorectal cancer, her family history was unremarkable. In 2007, she was incidentally found to have a right kidney mass on a routine check-up. A subsequent CT scan showed an 8.6-cm 8.1-cm RCC. There were no retroperitoneal lesions or lymph node involvement. Right radical nephrectomy was performed in October 2007. The histological diagnosis was RCC, not further classifiable, possibly of papillary type, with clear margins. No adjuvant treatment was indicated. PET-CT after 9 months showed a mildly enlarged retrocaval lymph node medial to the second portion of the duodenum, as well as multiple hepatic nodules. Liver biopsy confirmed mRCC. Baseline blood tests results were: hemoglobin, 12.5 g/dL (normal); calcium, 2.35 mmol/L (normal); lactate dehydrogenase (LDH), 145 U/L (normal); slightly raised alanine transaminase (ALT) and aspartate transaminase (AST), 69 U/L and 54 U/L, respectively. Her Karnosfsky performance status was 100 percent. The patient was therefore classified as good risk according to the Memorial Sloan-Kettering Cancer Center risk stratification system. The patient was treated with sunitinib 50 mg daily since August, 2008. However, computer tomography (CT) reassessment after 2 months showed enlarged retrocaval and hepatic metastases, as well as a new caudate nodule, indicating progressive disease. The patient was then enrolled in a clinical trial and randomized to receive sorafenib 400 mg bid. The treatment was discontinued after 6 weeks due to progressive disease, as indicated by a slight increase in size of the segment II and segment VI hepatic lesions and the right retrocaval lymph node. Treatment was changed to intravenous bevacizumab (10 mg/kg) every 2 weeks and subcutaneous interferon (9 mIU) three times weekly. However, CT examination after 6 cycles showed worsening of all lesions. (Figure 1) Weekly intravenous temsirolimus (25 mg) was started in April, 2009. CT examination after 6 cycles showed shrinkage of the liver metastases and retrocaval lymph node. CT examinations at the 20th and 28th cycles both showed stable liver metastases. (Figure 2) Reassessment CT at the 38th course showed a mixed response in terms of sizes of the hepatic metastases, but most became necrotic. IV bevacizumab 10 mg/kg every 2 weeks was added to maximize treatment efficacy.
Figure 1. CT abdomen after 6 cycles of IV bevacizumab and interferon
Figure 2. CT abdomen after 20 cycles of temsirolimus, showing shrinkage of retrocaval lymph node
CT at the 61st course of temsirolimus and 12th course of bevacizumab showed stable disease. Subsequent MRI showed further shrinkage of the liver metastases. There were no major side effects, except for transient Grade 3 ALT elevation and Grade 2 hypertension requiring amlodipine. The patient also complained of mild stomatitis, dry skin, malaise associated with temsirolimus, and mild headache and proteinuria associated with bevacizumab. The patient eventually proceeded to left lateral segmentectomy of the liver, open radiofrequency ablation of rightlobe tumors and resection of inferior vena cava lymph node. The pathology of the resected specimen showed metastatic, poorly differentiated carcinoma. The immunohistochemical staining was positive for phosphorylated (p)-mTOR; p-4EBP1, p-Akt, p-S6. After liver metastasectomy the patient continued on temsirolimus plus bevacizumab. Her disease remained stable for 9 months.
51
Jul-Aug 2012
Calendar
ASCO 2012 Breast Cancer Symposium
13/9/2012 to 15/9/2012 San Francisco, USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: membermail@asco.org http://breastcasymposium.org/Home.aspx
3rd Oncology Forum of Hong Kong

21/7/2012 Hong Kong Info: PC Tours and Travel Tel: +852 2734 3312 / +852 2734 3315 Fax: +852 2367 3375 E-mail: veronica@pctourshk.com http://www.hkcr.org/
5th Latin American Conference on Lung Cancer

25/7/2012 to 27/7/2012 Rio De Janeiro, Brazil Info: International Conference Services Ltd. (ICS) Grit Schoenherr Tel: +1 604 681 2153 Fax: +1 604 481 1049 E-mail: lalca2012@icsevents.com http://www.lalca2012.org/index.html
International Liver Cancer Association 6th Annual Conference

14/9/2012 to 16/9/2012 Berlin, Germany Tel: +32 (0) 789 2345 Fax: +32 (0) 743 1550 E-mail: info@ilca-online.org http://www.ilca2012.org/
10th Annual Meeting of the Japanese Society of Medical Oncology

26/7/2012 to 28/7/2012 Osaka, Japan Tel: +81 3 6809 1250 Fax: +81 3 6809 1138 E-mail: jsmo2012@sunpla-mcv.com http://jsmo2012.umin.jp/en/
32nd Congress of the European Society of Surgical Oncology (ESSO)

19/9/2012 to 21/9/2012 Valencia, Spain Info: European Cancer Organization Tel: +32 2 775 02 01 Fax: +32 2 775 02 00 E-mail: esso32@ecco-org.eu http://www.ecco-org.eu/Conferences/Conferences/ ESSO-32.aspx
2012 American Association for Cancer Research (AACR)/ASCO Workshop: Methods in Clinical Cancer Research
28/7/2012 to 3/8/2012 Vail, USA Info: AACR Tel: +215 440 9300 Fax: +215 599 0111 E-mail: programs@aacr.org http://www.vailworkshop.org/index.html
European Conference of Oncology Pharmacy (ECOP)

27/9/2012 to 29/9/2012 Budapest, Hungary Info: European Cancer Organization Tel: +32 2 775 02 01 Fax: +32 2 775 02 00 E-mail: ecop2012@ecco-org.eu http://www.ecco-org.eu
2012 World Cancer Congress

27/8/2012 to 30/8/2012 Montreal, Canada Info: International Union for Cancer Control Tel: +41 22 809 1811 E-mail: congress@uicc.org http://www.worldcancercongress.org
International CardiOncology Society Annual Meeting

28/9/2012 to 29/9/2012 Milan, Italy Tel: +39 02 36753900 Fax: +39 02 43911650 / +39 02 49542900 E-mail: congress@cq-travel.com http://www.cq-travel.com/index.php?id_page=1
ASCO 2012 Multidisciplinary Symposium in Thoracic Oncology

6/9/2012 to 8/9/2012 Chicago, USA Tel: +706 502 1550 Fax: +703 502 7852 http://www.thoracicsymposium.org/
37th ESMO Congress

28/9/2012 to 2/10/2012 Vienna, Austria Tel: +41 (0)91 973 19 39 Fax: +41 (0)91 973 19 18 E-mail: registration@esmo.org http://www.esmo.org/events/vienna-2012-congress.html
52
Jul-Aug 2012
Calendar
44th Congress of the International Society of Pediatric Oncology

5/10/2012 to 8/10/2012 London, UK Info: European Cancer Organization Tel: +32 (0) 2 775 02 01 Fax: +32 (0) 2 775 02 00 E-mail: info@siop2012.org http://www.siop2012.org
Markers in Cancer Joint Meeting by ASCO, EORTC, and NCI

11/10/2012 to 13/10/2012 Hollywood, Florida, USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: membermail@asco.org http://molecularcameeting.org/Home.aspx
24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

6/11/2012 to 9/11/2012 Dublin, Ireland Info: European Cancer Organization Tel: +32 (0) 2 775 02 01 Fax: +32 (0) 2 775 02 00 E-mail: ena2012@ecco-org.eu http://www.ecco-org.eu/Conferences/Conferences/ EORTC_NCI_AACR-2012.aspx
ASCOs Quality Care Symposium

30/11/2012 to 1/12/2012 San Diego, USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: qualitysymposium@asco.org http://www.asco.org/ASCOv2/Meetings/ ASCO%27s+Quality+Care+Symposium
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July- August June 2012

w w w.oncolo g ytribu ne.co m

Pan-ErbB blocker tops standard chemo in lung cancer

NEWS Asian study unveils mechanism of HBV integration in HCC

INDUSTRY UPDATE First-line temsirolimus improves survival in poor-prognosis mRCC patients

CASE STUDY Capecitabine in advanced gastric cancer

Pan-ErbB blocker tops standard chemo in lung cancer

PERSPECTIVES Dr. Kwok-Chi Lam

Department of Clinical Oncology, Prince of Wales Hospital

Cancer drug shortages a global problem

Big strides in cancer genetics research in Asia

Asian study unveils mechanism of HBV integration in HCC

Reversal of apoptosis may drive carcinogenesis

Better strategies needed for ALL in adolescents and young adults

Continuous androgen deprivation still standard of care for prostate cancer

Regorafenib offers hope for GIST patients failing TKIs

Antidepressant relieves chemo-induced neuropathic pain

ASCO 2012 Sa tellite Symposium

Everolimus plus exemestane improves PFS in advanced breast cancer

Overcoming endocrine resistance

Everolimus: Targeting the PI3K/ AKT/mTOR Pathway

ASCO 2012 Sa tellite Symposium

Probability (%) of event

Time to deterioration in QoL (months)

New subgroup analyses

ASCO 2012 Sa tellite Symposium

Figure 2. BOLERO-2 18-month follow-up: QoL*

Probability (%) of event

Censoring times EVE + EXE (n=485) PBO + EXE (n=239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time to deterioration in QoL (months)

ASCO 2012 Meeting Highlights

PISCES study: mRCC patients favor pazopanib for better QoL

Pazopanib and sunitinib: Comparable efficacy, different safety

erability and HRQoL on a patients choice of treatment.

PISCES: Are differences in drug tolerability clinically meaningful for patients?

ASCO 2012 Meeting Highlights

Primary analysis population

Difference (pazopanib vs sunitinib) p value

Patients prefer pazopanib

Number of patients Primary analysis population

Pazopanib preferred Sunitinib preferred Sunitinib preferred NoNo Preference Preference

17% Pazopanib preferred Sunitinib preferred No preference Primary analysis population

Physician preference reflects patient choice 20

ASCO 2012 Meeting Highlights

ASCO 2012 Meeting Highlights

Trastuzumab emtansine: A new weapon against HER2-positive mBC

EMILIA: A phase III study of T-DM1

EMILIA is the first randomized, phase III

Proportion progression-free Proportion progression-free

ASCO 2012 Meeting Highlights

Figure 1. EMILIA: PFS by independent review

0.4 0.2 0.0 0 2 4 6

Median, mos 6.5 12.6

ORR Difference: 12.7%

Proportion progression-free Proportion progression-free

Median, mos 6.5 12.6

Higher objective response rate

120 105 77 48 32 14 9 8 3 3 1 1 173 159 126 84 65 47 42 33 27 19 12 8

Delay in symptom progression

T-DM1 was associated with fewer grade

ASCO 2012 Meeting Highlights

CLEOPATRA study updates

ASCO 2012 Meeting Highlights

Bevacizumab shows benefit in platinum-resistant ovarian cancer