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Lung cancer (NSCLC) KEYNOTE-189 Met its Dual Primary Endpoints of Overall Survival and Progression-free Survival

Patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer (NSCLC) who received pembrolizumab (Keytruda) plus chemotherapy had significantly longer overall survival (OS) and progression-free survival (PFS) compared with those who received chemotherapy alone, according to data from the phase III clinical trial KEYNOTE-189, presented at the AACR Annual Meeting 2018, April 14-18.

This study is being simultaneously published in The New England Journal of Medicine.

“The long-term survival of patients with advanced NSCLC remains poor and the standard of care for most patients is chemotherapy, which affords a survival benefit measured in months,” said Leena Gandhi, MD, PhD, associate professor in the Department of Medicine and director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health.

In May 2017, the U.S. Food and Drug Administration approved pembrolizumab plus pemetrexed and carboplatin-based chemotherapy as first-line treatment for patients with advanced nonsquamous NSCLC based on data from the phase II cohort G of the KEYNOTE-021 study, but it was not widely adopted in the absence of positive results from a phase III study, Gandhi explained. “Further, the phase II study did not initially demonstrate a survival benefit,” she said.

“Results from KEYNOTE-189 are practice-changing,” noted Gandhi. “This phase III trial demonstrated an improvement in overall response rate (ORR), PFS, and OS across all groups of patients, irrespective of PD-L1 expression, halving the risk of death, which is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations.”

KEYNOTE-189 is a randomized, double-blind, phase III study in patients with metastatic nonsquamous NSCLC who received no prior treatment for metastatic disease. Patients (616) were randomized, 2:1, to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab (test arm) or placebo (control arm). Patients were stratified based on PD-L1 tumor proportion score (<1 percent or ≥ 1 percent), among other factors.

After a median follow-up of 10.5 months, median OS was not reached in the test arm, versus 11.3 months in the control arm. Compared with patients in the control arm, those in the test arm were 51 percent less likely to die, and those in the high PD-L1 score group were 58 percent less likely to die.

Median PFS was 8.8 months for the pembrolizumab arm, versus 4.9 months for the control arm.

Patients were allowed to cross over to receive pembrolizumab if they progressed on the control arm. “Despite a 50 percent crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” Gandhi said.

“Toxicities were as expected other than an increase in the rate of acute kidney injury in the pembrolizumab arm (5.2 percent, versus 0.5 percent in control arm),” Gandhi added. Discontinuation of all treatment because of adverse events was 13.8 percent in the test arm, versus 7.9 percent in the control arm. Immune-related adverse events occurred in 22.7 percent of patients in the test arm, versus 11.9 percent of patients in the control arm.

A limitation of the study is that it was not designed to assess whether those with high PD-L1 expression benefited from pembrolizumab alone versus pembrolizumab plus chemotherapy, Gandhi noted. In addition, “The control arm did not perform as well as some historical controls, but this was a rigorous randomized study which did show a clear difference between the two arms,” she said.

This study was sponsored by Merck. Gandhi has served on scientific advisory boards for Merck, Genentech/Roche, Syndax, Ignyta, and AstraZeneca, and has obtained research funding from Merck.

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