Published OnlineFirst April 20, 2015; DOI: 10.1158/2159-8290.CD-NB2015-057


Pembrolizumab Shows Promise for NSCLC Yale Rosen, CC-BY-SA 2.0

Results from the phase I KEYNOTE-001 trial indicate that the checkpoint inhibitor pembrolizumab (Keytruda; Merck) improves clinical outcomes for patients with advanced non–small cell lung cancer (NSCLC), particularly those whose tumors express high levels of PD-L1. The trial’s results were reported by Edward Garon, MD, an associate professor of medicine at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22. The results were published simultaneously in The New England Journal of Medicine (N Engl J Med 2015 Apr 19 [Epub ahead of print]). By blocking the PD-1 receptor and keeping its ligands PD-L1 and PD-L2 from binding to it, pembrolizumab prevents tumor cells from using this pathway to escape immune surveillance. Based on preliminary data from this study, pembrolizumab has received the FDA’s Breakthrough Therapy designation for patients with EGFR– and ALK– wild-type NSCLC who have progressed on or following platinum chemotherapy. The drug was initially approved for the treatment of melanoma. “For me, the most exciting moment in the development of anti–PD-1 drugs was the realization that lung cancer could respond to this form of immunotherapy,” said Suzanne Topalian, MD, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. Topalian moderated the press conference at which the findings were presented. KEYNOTE-001 enrolled 495 patients with advanced NSCLC. In the initial cohort of 182 patients, PD-L1 expression in at least 50% of tumor cells—determined by immunohistochemistry with the antibody 22C3— distinguished patients most likely to respond to pembrolizumab. That finding was confirmed in a validation cohort of 313 patients, of which


Macrophages and leukocytes infiltrate poorly differentiated non–small cell lung cancer, leading to apparent tumor cell destruction. The arrows point to tumor cells.

approximately one quarter had PD-L1 expression in at least half their tumor cells; 45.2% of them responded to pembrolizumab, with a median progressionfree survival (PFS) of 6.3 months. Because so many patients in this group are still alive, their median overall survival (OS) time has not been reached. In contrast, the respective response rates for patients with less than half of their tumor cells expressing PD-L1 or virtually none of their cells expressing it were 16.5% and 10.7%; median PFS was 3.3 and 2.3 months respectively. The median OS for both groups was 8.8 months. “This was the largest study of lung cancer patients treated with a checkpoint inhibitor, and the first confirmation that PD-L1 is clearly a marker of response,” Garon said. “I think we can now confidently say that in patients who have PD-L1 in at least half their tumor cells, pembrolizumab is associated with clinical outcomes superior to what would be anticipated with cytotoxic chemotherapy.” Garon also noted that pembrolizumab was generally well tolerated; fewer than 10% of study participants experienced serious (grade 3 or higher) side effects. Fatigue was the most common drug-related side effect, while the main immune-related adverse events were pneumonitis, infusion reactions, and hypothyroidism. “We’re talking about a patient population that’s very difficult to treat, where second- and third-line agents are generally not expected to prolong survival,” Topalian remarked, “so the results with pembrolizumab are especially impressive in this setting.” ■

• Eli Lilly and Company received FDA approval for ramucirumab (Cyramza) in combination with FOLFIRI chemotherapy for the treatment of patients with metastatic colorectal cancer whose disease progresses on or after therapy with bevacizumab (Avastin; Genentech/ Roche), oxaliplatin, and a fluoropyrimidine. Ramucirumab blocks VEGFR2. • Summit, NJ–based Celgene inked a $450 million deal with AstraZeneca to develop the PD-L1 inhibitor MEDI4736 for nonHodgkin lymphoma, multiple myeloma, and other related malignancies. AstraZeneca will also pay $250 million to France’s Innate Pharma to license the immunotherapeutic IPH2201 both as a monotherapy and in combination with MEDI4736. • In a survey of 7,000 people, 98% said that they want to be informed if researchers using their genetic data stumble upon indicators of a life-threatening disease that could be prevented or treated. Fewer people were interested in knowing about less serious conditions or genetic data of “uncertain clinical significance” (Eur J Hum Genet 2015 Apr 29 [Epub ahead of print]). • Roche signed a deal worth up to $555 million with India’s Curadev Pharma to develop cancer immunotherapies that target IDO1 and TDO. Roche will pay Curadev $25 million initially, with an additional $530 million if Curadev meets certain milestones. • A Canadian study indicates that vaccinating 12-year-old boys against human papillomavirus (HPV) may be a costeffective strategy for preventing oropharyngeal squamous cell cancer, potentially saving up to C$28 million over the boys’ lifetimes. Many countries have established HPV vaccination programs for girls but not for boys (Cancer 2015 Apr 13 [Epub ahead of print]). • In a study of 396 patients, men with castration-resistant prostate cancer who received enzalutamide (Xtandi) experienced a statistically significant increase in progression-free survival compared with those who received bicalutamide, Astellas Pharma announced. Median PFS was 19.4 months in the enzalutamide group compared with 5.7 months in the bicalutamide group.

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Published OnlineFirst April 20, 2015; DOI: 10.1158/2159-8290.CD-NB2015-057

Pembrolizumab Shows Promise for NSCLC Cancer Discovery 2015;5:572. Published OnlineFirst April 20, 2015.

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Pembrolizumab Shows Promise for NSCLC.

Data from the KEYNOTE-001 trial show that pembrolizumab improves clinical outcomes for patients with advanced non-small cell lung cancer, and is well ...
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