Gilberto Lopes, MD
Results from the phase III KEYNOTE-042 trial demonstrated an improvement in overall survival (OS) with single-agent pembrolizumab (Keytruda) versus chemotherapy as a frontline treatment for patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and a PD-L1 expression level ≥1%, emphasizing immunotherapy’s role in the treatment armamentarium.
“This trial is very important because it included both patients with squamous and nonsquamous NSCLC,” said lead author Gilberto Lopes, MD. “This a broader population, and the trial shows the benefit of pembrolizumab and immunotherapy in general in this patient population.”
In KEYNOTE-042, the median OS was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and a PD-L1 tumor proportion score (TPS) ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P
= .0018). Across all patients with a PD-L1 TPS of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).
The OS benefit for pembrolizumab correlated with greater levels of PD-L1 expression: TPS ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; P
= .0003); TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92; P
= .002); and TPS ≥1% (16.7 vs 12.1 months; HR, 0.81; 95% CI, 0.71-0.93; P
Based on these results, the FDA granted a priority review designation to a supplemental biologics license application for the PD-1 inhibitor in September 2018. If approved, pembrolizumab’s label would be expanded to include frontline treatment for patients with NSCLC and a tumor proportion score (TPS) ≥1% whose tumors do not harbor EGFR
genomic aberrations. The FDA is scheduled to decide on the application by January 11, 2019.
In an interview with OncLive®
, Lopes, a medical oncologist at Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the KEYNOTE-042 results and ongoing developments with immunotherapy in NSCLC.
OncLive: What was the rationale and background of the KEYNOTE-042 trial?
: The way we treat lung cancer has changed markedly over the last few years. Some days, it feels like it's changing hour to hour. We have developed new targeted agents for patients with EGFR
mutations and ALK
translocations, as well as for those with other genetic changes. Immunotherapies have become part of our standard armamentarium. Pembrolizumab, in particular, is a PD-1 inhibitor that has been tested in a number of different clinical scenarios.
In KEYNOTE-010, it was shown to be better than chemotherapy with docetaxel for patients who had failed first-line chemotherapy. It was also better than chemotherapy as a single agent for patients with a PD-L1 expression of 50% and above. In combination, it was also shown to be better than chemotherapy for patients with any level of PD-1 expression and without any PD-L1 expression.
KEYNOTE-042 was a study that was set up a number of years ago to assess the efficacy of pembrolizumab versus standard chemotherapy for patients with PD-L1 expression with a TPS of ≥1%. This was a trial designed for patients with nonsquamous and squamous histology. Patients had to have a good performance status of 0 or 1, and they could not have EGFR
mutations or ALK
translocations. Our primary endpoint was OS. OS was to be tested sequentially in patients with a TPS ≥50%, ≥20%, and ≥1%.
The primary endpoint was positive. OS was better for all patients in the trial, including patients with a TPS ≥1%. For that specific patient population, we had an HR of 0.81 and a P
value of .0018. In addition, we also tested for progression-free survival (PFS) as a key secondary endpoint. That was also supposed to be tested for the ≥50% population first. Even though it did fine with a HR of around 0.8, the P
value of .0019 was not low enough for the interim analysis, especially for it to be crossed. As such, the PFS was not positive in the interim analysis. Because of that, we did not have statistical testing for PFS for the other subgroups.
The results for response rates were quite similar between pembrolizumab and chemotherapy. [Pembrolizumab was favored in that] the durations of responses were much longer. The duration of response with pembrolizumab was 20 months and ranged between 8 and 9 months with chemotherapy.
Moreover, patients who received pembrolizumab had fewer adverse events (AEs). Seventeen to 18% of patients had treatment-related AEs that were graded 3 to 5 with pembrolizumab. Approximately 41% of patients had the same type of AEs with chemotherapy. Of course, immune-mediated AEs were more common with pembrolizumab than with chemotherapy.