Clinical Pearls & Morning Reports
Published May 30, 2018
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.
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.
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.
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.