Precision Diagnosis and

Treatment for Advanced

Non Small Cell Lung Cancer
Dr. dr. Noni Novisari Soeroso, M.Ked(Paru), Sp.P(K)
Departemen Pulmonologi dan Kedokteran Respirasi
FK USU – RS. USU
 INDONESIA

Global Cancer Observatory 2018; https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets

 Current Guidelines
• Indonesian Society of Respirology (ISR)
• Indonesian Association for the Study of
Thoracic Oncology (IASTO) (a
multidisciplinary working group for lung
cancer)
• Lung Cancer Guidelines 2017
Guidelines for Advanced Stage NSCLC (2018)
Indonesian Society of Respirology
Indonesian Association for the Study of Thoracic Oncology

Indonesian Society of Respirology

Indonesian Association for the Study of Thoracic Oncology
30-40% of Asian metastatic NSCLC population are EGFR mutation
positive1

AKT, protein kinase B; ALK, anaplastic lymphoma kinase; Amp, amplified; BRAF, v-Raf murine sarcoma viral oncogene homolog B; DDR2, discoidin domain receptor tyrosine
kinase 2; FGFR, fibroblast growth factor receptor; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MAP2K1, mitogen-
activated protein kinase kinase 1; NRAS, neuroblastoma RAS; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; RET, rearranged during
transfection; ROS1, proto-oncogene receptor tyrosine kinase.

Li T, King H-J, Mack DC, et al. J Clin Oncol. 2013;31:1039-1049.

 ADENOCARCINOMA

EGFR

EGFR mutation (+) EGFR mutation (-)

EGFR mutation (+) EGFR mutation (+) IHC ALK OR PDL-1

EGFR mutation EGFR mutation IHC ALK IHC ALK PDL-1 (+)
Exon 18, 19, 21 Exon 20 (T790M) (+) (-) > 50%

EGFR – TKI EGFR – TKI

Erlotinib ->1st Critozinib Kemoterapi Pembrolizumab
Osimertinib  3rd
Gefitinib -> 1st Generation
Afatinib -> 2nd
 Wild type
Mut Exon 18
7,14%
Mut Exon 19

Mut Exon 21
Mut Exon 20

Mut Exon 18+21

Mut Exon 19+20

Propotion EGFR Gene Mutation in Lung Adenocarcinoma Patients in Adam

Malik General Hospital, January 2013 – Mei 2017 (n = 260)

*Deparment of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas of North Sumatera – Adam Malik Hospita (unpublished)
 Persentase ekson 18 dengan tipe G719A dan G719S sebesar
5,9%, ekson 19 (Ins/Delekson 19)sebesar 38,2%, ekson 21
dengan tipe L858R (32,4%), tipe L861Q (14,7%), dan doubel
ekson (ekson 19 dan 21) sebesar 2,9%.
*Deparment of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas of North Sumatera – Adam Malik Hospita (unpublished)
EGFR Testing is recommended by international guideline to
determined the treatment

NCCN. NSCLC Ver 3 2019

GEFITINIB is recommended by international guideline as first line
therapy for NSCLC with EGFRm

NCCN. NSCLC Ver 3 2019

GEFITINIB Proven Efficacy:
Shows consistent PFS regardless mutation type

11.9
months

PFS
Prolongs PFS in patients with mutation
at exon 19 or exon 21
until 11.9 months

Ref:
1. Yao, et al. 2017. The Oncologist (22): 1075-1083
2. Wei, et al. Factors associated with improvement in symptoms and quality of life for first-line EGFR-tyrosine kinase inhibitor treatment in patients with EGFR-mutated non-small-cell lung cancer: A multicenter prospective SMILE Study. 2017.
GEFITINIB Proven Efficacy:
Prolongs Overall Survival regardless mutation types and location of metastases1-2

Ref:
1. Yao, et al. 2017. The Oncologist (22): 1075-1083
2. Wei, et al. Factors associated with improvement in symptoms and quality of life for first-line EGFR-tyrosine kinase inhibitor treatment in patients with EGFR-mutated non-small-cell lung cancer: A
multicenter prospective SMILE Study. 2017.
GEFITINIB Proven Safety Profile:
Shows better tolerability compared with other TKI

Ref :
1. Togashi Y et al. Lung Cancer (74);2011;98-102
GEFITINIB Improves Quality of Life:
Shows higher improvement from baseline in FACT-L and TOI

Treatment with IRESSA® improves Quality of Life, based on change in TOI and
FACT-L from baseline

Ref :
1. Togashi Y et al. Lung Cancer (74);2011;98-102
GEFITINIB Improves Quality of Life:
Clinically valuable Improvement of Quality of Life1
p < 0.0005

Around 68% patients treated with

IRESSA® who have performance
status of 3 - 4 at baseline will
experience clinically valuable
improvement to PS 0-1 (p < 0.0005)
Chemotherapy-naïve patients with poor PS (patients 20 to 74 years of age with ECOG
PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and 80 years of age with PS 1 to 4) who
had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid
polymerase chain reaction clamp method were enrolled and received gefitinib (250 mg/d)
alone.

Ref :
1. Inoue A et al. J Clin Oncol 2009;27:1-8.
Resistance Via Acquired Mutation Is the Most Common
Mechanism of Disease Progression1
Drug
Acquired resistance
Vessel Lung cancer cell with
sensitizing EGFR mutation
Brain
EGFRm NSCLC T790M may exist as a EGFR T790M mutant clone
minor clone in EGFRm Small Disease progression in CNS
tumor due to poor Small cell transformation
tumors prior to treatment1,2 metabolites
penetration of drug

Emergence of Indolent progression on TKI discontinued;

Initial response
EGFR T790M EGFR-TKI therapy re-growth of
to TKI
mutant clone sensitive clones
Tumor heterogeneity
(subpopulations of cancer cells
with unique genomes) may
exist within one patient3

Emergence of alternative
Primary resistance: no resistance mutation Rapid progression
response to TKI (eg, small cell transformation)

Most patients with metastatic EGFRm NSCLC

will progress on a first-line TKI within 8–14 months2
CNS, central nervous system; EGFR, epidermal growth factor receptor; EGFRm, EGFR mutation-positive; TKI, tyrosine kinase inhibitor.
1. Sacher AG, et al. Cancer. 2014;120(15):2289-2298. 2. Cortot AB, et al. Eur Respir Rev. 2014;23:356-366. 3. Bedard PL, et al. Nature. 2013;501(7467):355-364.
 PROPORSI MUTASI EGFR DARI CTDNA

Dengan responden 100 orang Unpublished study; Soeroso et al, 2018

 PROPORSI MUTASI EGFR DARI TISSUE

Dengan responden 100 orang Unpublished study; Soeroso et al, 2018

The EGFR T790M Mutation is the Most Common
Mechanism of Acquired Resistance to EGFR TKI Therapy1
Nearly two-thirds of patients with metastatic EGFRm NSCLC
who have progressed on an EGFR TKI have an
acquired EGFR T790M mutation

1. Sacher AG, Jӓnne PA, Oxnard GR. Cancer. 2014;120:2289-2298 . 2. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19:2240-2247.
OSIMERTINIB is recommended for therapy of NSCLC with EGFR
T790M after progressed with EGFR-TKI

Plasma-based testing should be considered at progression on EGFR TKIs for the T790M mutation. If plasma-based testing is negative, tissue-based testing with rebiopsy
material is strongly recommended. Practitioners may want to consider scheduling the biopsy concurrently with plasma testing referral

NCCN. NSCLC Ver 3 2019

AURA3 : Osimertinib vs. Platinum-Pemetrexed1,2

Study design : phase Ill, randomised, international, open-label study comparing TAGRISSO with platinum-pemetrexed in 419
patients with EGFR T790M mutation-positive NSCLC who had progressed on first-line TKI therapy.1
Primary endpoint: PFS (by investigator assessment)
Secondary endpoints: ORR, DCR, and safety

Disease progression
following 1st-line
treatment with an
EGFR TKI in patients Follow-up
with documented 80 RECIST v1.1 overall
EGFRm NSCLC mg CROSSOVER
N=419 assessments § survival
R 2:1
every 6 Optional: (OS)
+
weeks until
objective patients on
progressionǂ platinum- every
Platinum- pemetrexed
Central confirmation of pemetrexed 6 weeks
every 3 weeks could begin
tumour for up to 6 post-
EGFR T790M mutation* cycles† progression
open-label
TAGRISSO

† Platinum-pemetrexed (every 3 weeks for up to 6 cycles of pemetrexed 500 mg/m 2 plus either carboplatin AUC5 or cisplatin 75 mg/m 2). Patients whose disease had not
progressed after 4 cycles of platinum-pemetrexed could continue maintenance pemetrexed according to the approved label.
‡ Patients could receive study treatment beyond RECIST-defined progression as long as they experienced clinical benefit, as judged by the investigator.
§ In the platinum-pemetrexed group, 60% (n=82) of patients crossed over to receive TAGRISSO. Patients on platinum-pemetrexed could cross over to TAGRISSO after
BICR-confirmed progression.2

1. BPOM. 2017. Tagrisso (Osimertinib) Product Information. AstraZeneca Indonesia. . 2. Mok TS, Wu YL, Ahn MJ, et al.
N Engl J Med. 2017;376:629-640.
10
AURA3 : Baseline Demographics
TAGRISSO
(n=279)
pemetrexed (n=140)
Platinum-

• All patients had World Health Organization performance status of 0 or 1

• Asian countries who are involved in this study are: South Korea, Japan, China, Taiwan and Hongkong

• 96% of patients in each treatment group had received 1 prior regimen; the rest had received >1 prior regimen

Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.

12
AURA3 : Progression Free Survival
Osimertinib shows double PFS vs Chemotherapy
Median PFS was more than twice as long as with platinum-pemetrexed
(by investigator assessment)
PFS
ORR -
DCR
Safety

Overall Survival (OS) data were not mature at the time of this initial analysis (25% mature for TAGRISSO; 29% mature for platinum-pemetrexed
[HR=0.72; 95% CI: 0.48, 1.09; P=0.121]).

BPOM. 2017. Tagrisso (Osimertinib) Product Information. AstraZeneca Indonesia. .

13
AURA 3 : Efficacy in Patients with CNS Metastases
PFS of Patients with Osimertinib is DOUBLE than Platinum-Pemetrexed
Median PFS of OSIMERTINIB vs. platinum-pemetrexed in patients
with CNS metastases (investigator assessment)
PFS
ORR -
DCR
Safety

* Median PFS in patients without CNS metastases was 10.8 months (n=186; 95% Cl: 8.3, 12.5) with TAGRISSO vs. 5.6 months (n=89; 95% Cl: 4.2, 6.8) with
platinum-pemetrexed.2

1. BPOM. 2017. Tagrisso (Osimertinib) Product Information. AstraZeneca Indonesia. . 2. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.

15
AURA 3: Osimertinib has Tolerable Safety Profile
TAGRISSO overall frequency (n=279) Platinum-pemetrexed overall
frequency (n=136)
All causality adverse events Any grade (%) Grade ≥3 (%) Any grade (%) Grade ≥3 (%)
Respiratory, thoracic and mediastinal disorders
Interstitial Lung Disease*† 3.6 0.4 0.7 0.7
PFS

Eye disorders
Keratitis* 1.1 0 0.7 0
Gastrointestinal disorders
Diarrhoea 41 1.1 11 1.5
Stomatitis 15 0 15 1.5
Skin and subcutaneous tissue disorders
ORR -

Rash* 34 0.7 5.9 0

DCR

Dry skin* 23 0 4.4 0

Paronychia* 22 0 1.5 0
Pruritus* 13 0 5.1 0
Investigations
QTc interval prolongation‡ 1.4 0 0.7 0
Findings based on test results presented as CTCAE grade shifts
Safety

Platelet count decreased 46 0.7 48 7.4

Leukocytes decreased 61 1.1 75 5.3
Neutrophils decreased 27 2.2 49 12

* Grouped term. If a patient has multiple preferred-term level events within a specific grouped term adverse event, then the maximum CTCAE grade across
those events is counted.
†One fatal ILD event was reported that was deemed to be possibly causally related to TAGRISSO.
‡No QTc-related arrhythmias were reported in the AURA studies.

BPOM. 2017. Tagrisso (Osimertinib) Product Information. AstraZeneca Indonesia. .

19
 AURA 3: Rapid and Durable Response were seen with
Osimertinib vs platinum-pemetrexed
Percent of responders demonstrating response at ≤6 weeks (first scan)*1

Median Duration of Response (DoR)†2

* One-week window was allowed at approximately 6 weeks.

† At data cutoff, 59% (n=166) of patients receiving TAGRISSO and 12% (n=16) of those receiving platinum-pemetrexed were still receiving randomised study treatment.1

1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640. 2. 1. BPOM. 2017. Tagrisso (Osimertinib) Product Information. AstraZeneca Indonesia.
 The importance
of MDT
Radiologist
Clinician
- Conduct and interpret
imaging data - Identify clinical sign and
- Monitor radiological symptoms
response to treatment - Biopsy
- Identify the radiological - Define treatment
signs of disease - Monitor Clinical Response
progression

Pathologist
- Perform histological testing
(molecular and biomarker)
to confirm initial diagnosis
upon progression

Reference:
Powell & Baldwin. 2014. Eur Respir J 43: 1776-1786
Summary

1. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19:2240-2247. 2. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640
3. NCCN. 2017. NSCLC Guideline Ver 3 2018. 4. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up 5. Yang, et al.19
2017. Osimertinib in Pretreated T790M Positive NSCLC. Aura II Extension
Thank You