First-line Treatment with Pembrolizumab Improves Survival in Patients with Metastatic Nonsquamous Non-small Cell Lung Cancer
Published on 16th April
Results of a phase III clinical trial called KEYNOTE-189, presented at the Annual Meeting of the American Association for Cancer Research (AACR), held April 14-18., 2018, shows that patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer or NSCLC who received pembrolizumab (Keytruda®; Merck Oncology; previously known as MK-3475), a IgG4 humanized antibody used as programmed death 1 (PD-1) inhibitor or anti-PD-1 immunotherapy, in combination with chemotherapy, had significantly longer overall survival (OS) and progression-free survival (PFS) compared with those who received chemotherapy alone. 
This study, which is 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,” noted 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 the programmed death 1 (PD-1) inhibitor pembrolizumab + 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.
Despite a 50% 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
“[This protocol was was] not widely adopted in the absence of positive results from a phase III study,” Gandhi explained.
“Furthermore, the phase II study did not initially demonstrate a survival [any] benefit,” she said.
“Results from KEYNOTE-189 are practice-changing,” Gandhi said
“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,” she further explained.
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 or placebo. Patients were stratified based on PD-L1 tumor proportion score (<1% or ≥ 1%), 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% less likely to die, and those in the high PD-L1 score group were 58% less likely to die.Median PFS was 8.8 months for the pembrolizumab arm, versus 4.9 months for the control arm.
Response was assessed by RECIST v1.1 per blinded, independent central review. Patients in the placebo arm could crossover to pembrolizumab monotherapy if they progressed on the control arm.
“Despite a 50% 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 explained.
“Toxicities were as expected other than an increase in the rate of acute kidney injury in the pembrolizumab arm (5.2%, versus 0.5% in control arm),” Gandhi added.
Discontinuation of all treatment because of adverse events was 13.8% in the test arm,versus 7.9% in the control arm. Immune-related adverse events occurred in 22.7% of patients in the test arm, versus 11.9% 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.
“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 twoarms,” she concluded.
This study was sponsored by Merck.
Last Editorial Review: April 16, 2018
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