Pembrolizumab in Metastatic Non–Small-Cell Lung Cancer

Posted by Carla Rothaus

Published May 30, 2018

When pembrolizumab is combined with chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC), are benefits limited to patients whose tumors have high levels of programmed death ligand 1 (PD-L1) expression?

The phase 3 KEYNOTE-189 trial compared the combination of pemetrexed and a platinum-based drug plus either pembrolizumab or placebo in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without sensitizing EGFR or ALK mutations and with any level of programmed death ligand 1 (PD-L1) expression. All data reported in the May 31, 2018 issue of the New England Journal of Medicine are based on the first interim analysis. Read the latest NEJM Original Article here.

Clinical Pearls

Q: What is the rationale for combining pembrolizumab with chemotherapy as first-line therapy for patients with advanced NSCLC without sensitizing EGFR or ALK mutations?

A: Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic NSCLC lacking sensitizing EGFR or ALK mutations. Pembrolizumab, nivolumab, and atezolizumab, are approved as second-line therapy. Among patients in whom the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) is 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. However, patients with a tumor proportion score of 50% or greater represent a minority of those with NSCLC. Because patients with advanced NSCLC can undergo rapid clinical deterioration during disease progression, less than one half of patients with advanced NSCLC ever receive second-line therapy. First-line combination regimens that include a PD-1 or PD-L1 inhibitor may maximize the chance of response and lead to prolonged survival.

Q: Does the addition of pembrolizumab to standard chemotherapy increase survival as compared to chemotherapy alone in patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations?

A: The KEYNOTE-189 trial showed that in patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Morning Report Questions

Q: When pembrolizumab is combined with chemotherapy in patients with advanced NSCLC, are benefits limited to patients whose tumors have high levels of PD-L1 expression?

A: In the KEYNOTE-189 trial, exploratory end points included the effect of PD-L1 expression on efficacy and patient-reported outcomes. Results for overall survival showed that the benefit of the pembrolizumab combination was observed in all subgroups that were analyzed, including those with a PD-L1 tumor proportion score of less than 1%, a score of 1 to 49%, and a score of 50% or greater. The hazard ratio for progression-free survival was less than 1.00 across all subgroups that were analyzed and across all subgroups of PD-L1 tumor proportion score, although the upper boundaries of the 95% confidence intervals crossed 1.00 for patients who were 65 years or older and those with a PD-L1 tumor proportion score of less than 1%. The response rate was higher in the pembrolizumab-combination group than in the placebo-combination group across all categories of PD-L1 tumor proportion score, with the greatest between-group difference in patients with a tumor proportion score of 50% or greater.

Q: What effect does the addition of pembrolizumab to standard chemotherapy have on the frequency of adverse events?

A: In the KEYNOTE-189 trial, the addition of pembrolizumab did not appear to increase the frequency of adverse events that are commonly associated with chemotherapy regimens involving pemetrexed and a platinum-based drug. Similarly, the incidence of most immune-mediated adverse events was not higher with pembrolizumab-combination therapy than that previously observed with pembrolizumab monotherapy. The exception may be nephritis and acute kidney injury, both of which are also associated with pemetrexed and platinum-based drug and occurred with a greater frequency in this trial than in earlier trials of pembrolizumab monotherapy.