LUNG CANCER
V3 / N6 / DECEMBER 2018
FOR THORACIC SPECIALISTS Read online at LungCancerNews.org & Visit IASLC.org
INSIDE 6
Dr. Fred R. Hirsch Departs IASLC CEO Role, Joins Mount Sinai Hospital
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Scientific Highlights from the IASLC Latin America Conference on Lung Cancer
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Neoadjuvant Nivolumab Shows Unprecedented Pathologic Complete Response for Stage III NSCLC
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James P. Allison and Tasuku Honjo Jointly Awarded the Nobel Prize
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Prophylactic Cranial Irradiation in Locally Advanced NSCLC Falls Flat
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NCI Corner: Racial Differences in the Transcriptomes of Lung Tumors
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The Future Is Now: Pathology Is Going Digital
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Fighting the Tobacco Scourge: Implementation of TobaccoControl Measures Begets Public Health Success
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FDA Approval Processes in the Era of Targeted Therapies: A Conversation with Dr. Richard Pazdur
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The State of Lung Cancer in Egypt: Progress Is at Hand
NEWS
I N T E R N AT I O N A L A S S O C I AT I O N F O R T H E S T U D Y O F L U N G C A N C E R IMMUNOTHERAPY
Explaining IMpower132: An Interview with Dr. Vassiliki A. Papadimitrakopoulou In the following interview, Vassiliki A. Papadimitrakopoulou, MD, Jay and Lori Eisenberg Distinguished Professor of Medicine and section chief of Thoracic Medical Oncology at the University of Texas MD Anderson Cancer Center, discusses the findings and implications of IMpower132.
Q: Please explain the findings of IMpower132. A: IMpower132 was a global, randomized, open-label, phase III study of 578 patients with stage IV nonsquamous NSCLC who were chemotherapy naive. Eligibility criteria included measurable disease by Response Evaluation Criteria in Solid Tumors guidelines v1.1 and Eastern Cooperative Oncology Group Performance Status 0-1. Exclusion criteria
included tumors known to harbor EGFR driver mutations or ALK translocations, untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy. Patients were randomly assigned 1:1 to receive four or six cycles of carboplatin at a dose of AUC 6 mg/mL/min or to 75 mg/m2 of cisplatin plus 500 mg/m2 of pemetrexed every 3 weeks, followed by pemetrexed as maintenance therapy (Arm B) or to carboplatin/pemetrexed or cisplatin/pemetrexed plus 1,200 mg of atezolizumab, followed by combination pemetrexed and atezolizumab as maintenance therapy (Arm A). Results of the study showed that the atezolizumab plus platinum pemetrexed– based chemotherapy (Arm A) resulted in improved progression-free survival (PFS; median 7.6 months versus 5.2 months for the control group) and was associated with a 40% reduction in risk
for disease progression (hazard ratio [HR] 0.60, 95 CI [0.49, 072]) in all patients and Vassiliki A. across key clini- Dr. Papadimitrakopoulou cal subgroups, including Asian patients (HR 0.42, 95% CI [0.28, 0.63]), never smokers (HR 0.49; 95% CI [0.28, 0.87]), and current and former smokers (HR 0.61, 95% CI [0.50, 0.74]). Also, at the interim overall survival (OS) analysis, atezolizumab plus pemetrexed–based chemotherapy demonstrated a numerical improvement in OS of 4.5 months over pemetrexed-based chemotherapy alone (HR: 0.81, 95% CI [0.64, 1.03]; p = 0.0797).
Q: Does IMpower132 change the therapeutic playing field in any way? continued on page 6
IMMUNOTHERAPY
Targeted Therapy Plus Immune Checkpoint Inhibitors: Research Opportunities, But No Improvement in Activity to Date by targeted therapy (Table 1).1 In pre-clinical studies, oncogenic EGFR and ALK The treatment of patients with advanced signaling was reported to induce immune NSCLC harbouring an actionable oncoescape via the PD-1/PD-L1 axis.2,3 Some gene with tyrosine kinase inhibitors retrospective studies suggested an asso(TKIs) directed at its oncogenic molecuciation between EGFR-positive or ALKlar alteration represents one of the most positive NSCLC and PD-L1 expression.3 significant advances in lung cancer manHowever, other studies have reported agement. Another area of achievement in an inverse relationship between PD-L1 the treatment of advanced Table 1. Modulation of Immune Cell Function by Selected Molecular Targeted Agents1 expression and EGFR NSCLC has been the use mutations and no assoAgent Effect of immune checkpoint ciation between PD-L1 Bevacizumab Reduces regulatory T cells; increases DC maturation/priming and expression and ALK inhibitors targeting proT cell tumor infiltration grammed death receptor-1 rearrangement, as well EGFR-targeting mAb Promotes immunogenic cell death (PD-1) and programmed as an uninflamed tumor Erlotinib Upregulates NKG2D ligands death receptor ligand-1 microenvironment.5-7 Ibrutinib Promotes immunogenic cell death (PD-L1). Although EGFR Imatinib Promotes expansion of circulating natural killer cells and ALK TKIs can induce Existing Data JAK2 inhibitors Increases DC maturation, decreases STAT3, decreases tumor PD-L1 rapid responses in a large Early-phase studLapatinib Promotes tumor infiltration by cytotoxic T cells ies of combination number of patients with MAPK inhibitors Upregulates expression of MHC class I molecules advanced oncogene-driven targeted therapy and Sorafenib Reduces regulatory T cells immune checkpoint NSCLC, the duration Sunitinib Reduces regulatory T cells inhibitors in patients of response is generally Abbreviations: DC, dendritic cell; MHC, major histocompatibility complex. By Ross Soo, MB BS, PhD, FRACP
modest. In contrast, immune checkpoint inhibitors have the potential for durable disease control; however, the response rates are lower. Given this situation, research must address whether molecular targeted agents and immune checkpoint inhibitors can be combined safely to improve antitumor activity. Immune cell function can be modulated
with pretreated or treatment-naive EGFR-positive or with EML4ALK–positive NSCLC have been Dr. Ross Soo reported (Table 2, page 8). Response rates for combination EGFR TKIs or ALK TKIs plus immune checkpoint inhibitors are, at best, similar to previously reported response rates with EGFR TKIs/ALK TKIs alone, suggesting no synergistic effect. This observation has also been seen in preclinical studies of EGFR TKIs and immune checkpoint inhibitors8 as well as ALK TKIs and immune checkpoint inhibitors.9 Unfortunately, in some studies of combination EGFR/ALK TKIs plus immune checkpoint inhibitors, grade 3 to 4 treatment-related adverse events were unexpectedly higher than previously reported continued on page 8