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Durvalumab After Chemotherapy in Stage III

Non-Small-Cell Lung Cancer
Antonia, Scott J., MD, Ph.D et al.New England Journal of Medicine. November 16, 2017
Case Presentation and Commentary By Dennis Slater, MD

Case Presentation: negative for malignant cells. Molecular studies showed

The patient is a 76-year-old white male, former no mutations for KRAS, EGFR, ALK1, ROS1, and
smoker 2 PPD for 40 years with longstanding essential BRAF. The patient was treated with radiotherapy to
hypertension, chronic low back pain secondary to the primary right upper lobe tumor and mediastinum,
lumbar spine degenerative arthritis, gout, COPD, and concurrent weekly low-dose Carboplatin and
and coronary artery disease. He worked at Electric Taxol (Belani regimen) to a total 6600R over 6 weeks.
Boat between 1959-1967 with unprotected exposure Chest CT scan 08/18/14 post concurrent chemo-
to asbestos and then for the State of Connecticut, radiation showed residual right upper lobe mass
Department of Transportation. measuring 2.8 cm and no regional lymphadenopathy;
diffuse pleural calcifications and diffuse coronary artery
A cervical spine x-ray for evaluation of neck pain in calcifications. He enlisted on the PACIFIC trial and
March 2014 noted a right upper lobe lesion. A non- was treated with durvalumab vs placebo q.2 weeks
contrast chest CT scan 03/28/14 showed a 3.6 cm between 08/20/14 – 08/05/15. Subsequent body CT
mass in the right upper lobe with spiculated margins scans showed cavitation of the right upper lobe lung
extending to the pleural surface; small nodular mass and surrounding radiation fibrosis. A pacer/
densities in the bilateral apices representing calcified defibrillator was inserted on 03/10/15 for symptomatic
pleural plaques; and small right hilar and mediastinal bradyarrhythmia and the patient was hospitalized for
nodes. FDG-PET scan 05/09/14 showed abnormal pneumonia and acute exacerbation of COPD and
uptake in the right upper lobe mass (SUV 19.6) and hypoxic respiratory failure in March 2015 and April
hypermetabolic right hilar node (SUV 16.6) and AP 2017. His cardiopulmonary status stabilized and his
window node (SUV 16.9); no other sites of abnormal performance status improved. The most recent body
FDG activity; and pleural calcifications. Brain MR CT scan 11/07/17 showed a stable cavitary lesion in
scan showed mild atrophy consistent with age. PFTs the left upper lobe, bilateral perihilar radiation fibrosis
05/13/14 showed moderate obstruction and mildly and background emphysema. g
reduced DLCO. Bronchoscopy with navigational
guided brushings and washings and biopsy of the Commentary:
right upper lobe mass, and left VATS procedure Approximately one-third of patients with non-small cell
with partial decortication and mediastinal lymph lung cancer have stage III disease on presentation. This is
nodes biopsies and pleural biopsy, was performed defined as involvement of the ipsilateral mediastinal nodes
on 06/02/14. There were no endobronchial lesions (N2 disease) or contralateral mediastinal nodes (N3 disease),
and no narrowing of the right upper lobe bronchus. or a primary tumor involving local anatomic structures (T4
Right upper lobe brushings and washings and biopsy disease). The standard treatment of stage III non-small cell
showed a few atypical squamous cells and degenerative lung carcinoma is concurrent chemo-radiation. The most
clusters and no definitive carcinoma. Biopsy of the commonly employed chemotherapy regimens are cisplatinum/
aortopulmonary window node showed metastatic etoposide, carboplatin/taxol, and cisplatinum/pemetrexed.
squamous cell carcinoma and biopsy of the left parietal Survival rates are poor; the median survival is 8-14 months
pleura showed sclerotic tissue with calcification, and the 2-year and 5-year overall survivals are 26% and
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15%, respectively. Dose-intense thoracic radiotherapy, consolidative chemotherapy, and surgical resection of residual disease have not
improved survival in randomized trials.

The PACIFIC trial was a phase III prospective randomized blinded placebo-controlled trial evaluating durvalumab, a PD-L1
blocking IgG1 monoclonal antibody as adjuvant therapy. 713 patients were treated on 2:1 randomization every 2 weeks for one
year post standard chemo-radiation. Durvalumab is one of several immune checkpoint inhibitors, targeting the PD-1/PD-L1
interaction between tumor cells (expressing PD-1) and cytotoxic T-lymphocytes (expressing PD-L1). The interaction abrogates
T-cell cytotoxicity and immune checkpoint inhibitors can reactivate T-cell cytotoxicity. Pembrolizumab, nivolumab, and atezolizumab
have already been approved for treatment of metastatic nonsmall cell lung cancer as first-line therapy (pembrolizumab, restricted
to high PD-1 tumor expression) and second-line therapy (pembrolizumab for any level of PD-L1 expression or nivolumab and
atezolizumab independent of PD-L1 expression). These immune checkpoint inhibitors have shown improved response rates,
progression-free survival and overall survival compared to standard chemotherapy. The PACIFIC trial targeted a previously
unstudied population of patients with stage III nonsmall cell carcinoma (median age 64, 70% male, 53% stage IIIA and 45%
stage IIIB, 45% squamous cell and 54% non-squamous cell, 91% previous or active smokers). The results showed a statistically
significant benefit for treated patients in progression-free survival (16.8 months vs 5.6 months), 12-month progression-free survival
(55.9% vs 35.2%), 18 month progression-free survival (44.2% vs 27.0%), median time-to-death or distant metastases (23.2
months vs 14 months). High-grade toxicity occurred in 30% of patients treated with durvalumab compared with 26% placebo, the
incidence of pneumonitis was low in treated patients (3.4% vs 2.4%), and there were no treatment-related toxic deaths. All subgroups
of patients derived benefit on forest plot analysis and the benefit was independent of PD-L1 expression or histology. Interestingly, the
small group of nonsmokers (64 patients) derived the greatest benefit (HR 0.29), contrary to the theory that tumors in smokers with a
higher number of neoantigens are more immunogenic and therefore more responsive to immune checkpoint inhibitors.

The accompanying editorial by Drs. Naiyer Rizvi and Solange Peters noted that the progression-free survival of nearly 17 months in
treated patients, one year longer than placebo, is unprecedented and that the overall survival benefit should be positive on subsequent
analysis. Since chemotherapy and radiotherapy promote immunogenic cell death of tumor cells by activating dendritic cells and
enhancing androgen presentation, the editorialists speculate that the sequencing of chemo-radiation before blockade of the PD-1/
PD-L1 pathway may have more general applicability across cancer therapy.

The PACIFIC trial highlights the success of clinical research performed at the ECHO center and The William W. Backus
Hospital. Most of the participating cancer centers were large academic institutions worldwide. 14 patients were screened and 5
patients were enlisted on the PACIFIC trial at the ECHO center, ranking ECHO as the fourth highest accruer in the U.S. The
ECHO center was acknowledged in the supplementary author section of the NEJM.

Clinical research will distinguish the William W. Backus Hospital as an institution promoting
cutting-edge clinical research inaddition to excellent clinical care, and should be encouraged
throughout the spectrum of clinical care.
-Dennis Slater, MD

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