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First-line pembro + chemo improved survival in KEYNOTE-189

Patients with newly diagnosed metastatic NSCLC who received pembrolizumab 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 2018.

KEYNOTE-189 is a randomized, double-blind, phase III study in patients with metastatic nonsquamous NSCLC who received no prior treatment for metastatic disease. 616 patients 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 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. OS benefit in the pembro arm was observed across subgroups, including all PD-L1 TPS categories (HR [95% CI] 0.59 [0.38-0.92] for < 1%, 0.55 [0.34-0.90] for 1-49%, and 0.42 [0.26-0.68] for ≥ 50%).
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,” 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.
„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.

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.”
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.

Gandhi L et al., abstract CT075: KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC