Home Run: Chemo-Checkpoint Inhibitor Combo in Newly Diagnosed Metastatic NSCLC

Best Practices in Lung Cancer – November 2018 Vol 9 —November 29, 2018

A burning question is whether immunotherapy combinations will further improve outcomes over checkpoint inhibitor therapy alone; and if so, which combinations will rise to the top. Combining pembrolizumab with standard pemetrexed/platinum chemotherapy improved overall survival (OS) by 51% versus chemotherapy alone as first-line therapy for metastatic nonsquamous non–small cell lung cancer (NSCLC) in the phase 3 KEYNOTE-189 trial. The survival benefit for pembrolizumab/chemotherapy was independent of PD-L1 expression.

These results were published online in The New England Journal of Medicine on the day of the presentation at the AACR 2018 Annual Meeting.

“Halving the risk of death is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations,” stated lead author Leena Gandhi, MD, PhD, director of Thoracic Medical Oncology at the Perlmutter Cancer Center, NYU Langone Health, New York City.

“In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy with pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. Pembro­lizumab plus pemetrexed and platinum may be a new standard of care for first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression,” Dr Gandhi told listeners.


KEYNOTE-189 enrolled 616 patients with untreated stage IV nonsquamous NSCLC and no sensitizing EGFR or ALK alterations. Patients were stratified for PD-L1 expression (tumor proportion score [TPS] <1% or ≥1%) and randomized 2:1 to treatment with 4 cycles of pemetrexed and a platinum-based chemotherapy plus either pembrolizumab or placebo. In the experimental arm, maintenance therapy was pembrolizumab plus pemetrexed; in the placebo arm, maintenance therapy was pemetrexed. Patients were allowed to cross over to pembrolizumab if they developed progressive disease.

A significant benefit in OS was observed with pembrolizumab plus chemotherapy. Median OS was not yet reached in the experimental arm versus 11.3 months in the control arm. At 12 months, 69.2% of patients were alive in the experimental arm versus 49.4% of the control arm. The addition of pembrolizumab achieved a 51% increase in OS (P <.00001).

All subgroups benefited from the addition of pembrolizumab, but the greatest benefit was in the group with high PD-L1 expression (TPS ≥50%).

Progression-free survival (PFS) was significantly improved in the pembrolizumab combination group: median PFS was 8.8 months versus 4.9 months for controls, representing a 51% improvement. One-year PFS was 34.1% versus 17.3%, respectively (P <.00001). PFS benefit was greatest in the high PD-L1 group, but other subgroups also fared better with pembrolizumab.

Safety Analysis

The rate of adverse events was similar across both treatment arms. Almost every patient experienced at least 1 adverse event, and approximately two-thirds had a grades 3 to 5 adverse event.

Treatment discontinuations due to adverse events was 13.8% in the pembrolizumab combination arm versus 7.9% in the control arm.

More immune-mediated adverse events were observed with the pembrolizumab/chemotherapy combination: 22.7% versus 11.9%, respectively. Grades 3 to 5 acute renal injury was more frequent: 5.2% versus 0.5% in the control arm. Grade 3/4 nephritis was reported in 1.5% versus 0%.

Dr Gandhi said that although all subgroups experienced a survival benefit from pembrolizumab, PD-L1 testing is still needed.

“We would be hesitant to give up on that biomarker. PD-L1 may be part of a biomarker, perhaps added to tumor mutational burden,” Dr Gandhi stated. “In the US, we routinely get PD-L1 testing for most nonsquamous NSCLC. We also typically order next-generation sequencing, which can estimate tumor mutational burden.”

During the discussion, Roy Herbst, MD, chief, Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, stated that this new triplet combination will change the standard of care.

“The answer to the question about whether these results will change the standard of care for untreated nonsquamous NSCLC is an absolute ‘Yes’,” he emphasized. “This randomized phase 3 trial sets a new standard. The results of this trial quite frankly exceeded expectations. The study showed extraordinary rates of overall survival, progression-free survival, and objective response.”

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