Pembrolizumab Improves Survival, Reduces Toxicity Over Chemotherapy in Low PD-L1–Expressing NSCLC

Pembrolizumab Improves Survival, Reduces Toxicity Over Chemotherapy in Low PD-L1–Expressing NSCLC

Dr. Gilberto Lopes Jr.
Pembrolizumab significantly improved overall survival (OS) compared with platinum-based chemotherapy as first-line therapy for patients with advanced/metastatic non–small cell lung cancer (NSCLC), even those with low levels of PD-L1 expression, according to results of a large phase III trial (Abstract LBA4).*

“What we have seen over the last few years is that a combination of new agents, including targeted agents and immunotherapies, has helped people live a little longer, but we still have a lot of work to do,” Gilberto Lopes Jr., MD, MBA, FAMS, of the Sylvester Comprehensive Cancer Center at the University of Miami Health System, said during a press briefing held June 3.

Previous studies have established that pembrolizumab monotherapy can improve survival outcomes compared with chemotherapy in both previously treated and treatment-naive metastatic NSCLC, specifically in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). The new KEYNOTE-042 study compared pembrolizumab to chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed) in 1,274 patients with locally advanced or metastatic NSCLC and much lower PD-L1 expression (TPS ≥ 1%). The study excluded patients with sensitizing EGFR mutations and ALK translocations.

Patient characteristics were well balanced between the groups (637 patients in each group); more than 70% were men, 29.0% were enrolled in East Asia, and nearly 70% had ECOG performance status of 1. Most patients in both groups (approximately 78%) were current or former smokers. Just under half of both groups had a PD-L1 TPS ≥ 50%, followed by TPS 1%-19% in approximately 35%-36%, and TPS 20%-49% in 16%-18%.

The study met its primary endpoint, with improved OS with pembrolizumab. In the full cohort of patients with TPS ≥ 1%, the median OS was 16.7 months with pembrolizumab and 12.1 months with chemotherapy (HR 0.81, 95% CI [0.71, 0.93]; p = 0.0018). In those with TPS ≥ 20%, the median OS was 17.7 months and 13.0 months, respectively (HR 0.77, 95% CI [0.64, 0.92]; p = 0.0020]). And in the patients with TPS ≥ 50%, the median OS was 20.0 months with pembrolizumab and 12.2 months with chemotherapy (HR 0.69, 95% CI [0.56, 0.85]; p = 0.0003).

In the highest TPS group, the response rate with pembrolizumab was 39.5% compared with 32.0% with chemotherapy. In the TPS ≥ 20% group, the response rates were 33.4% and 28.9%, respectively, and in the TPS ≥ 1% group, they were 27.3% and 26.5%, respectively. The duration of response was longer with pembrolizumab; in the full TPS ≥ 1% cohort, the median duration of response was 20.2 months compared with 8.3 months with chemotherapy.

Although the median number of doses was higher with pembrolizumab than with chemotherapy (nine vs. six, respectively), more patients reported treatment-related adverse events (AEs) with chemotherapy (89.9%) than with pembrolizumab (62.7%). The same was true for grade 3-5 treatment-related AEs, reported in 41.0% of patients in the chemotherapy arm and 17.8% in the pembrolizumab arm. Grade 3-5 immune-mediated AEs and infusion reactions were more frequent with pembrolizumab (8.0%) than with chemotherapy (1.5%).

“Pembrolizumab becomes an option for patients who have advanced NSCLC who do not have EGFR mutations or ALK translocations, and who express PD-L1 at least at that 1% level,” Dr. Lopes concluded. “We do need to do a lot more work. Even though patients do better today, they still do not do well enough. The vast majority of patients with advanced lung cancer will have disease progression and will succumb to lung cancer.” He noted that there are ongoing trials involving combinations of immunotherapies or immunotherapy along with chemotherapy that could further improve the treatment landscape.          

During the press briefing, John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center, stressed that the differences in toxicity can play a dramatic role in patients’ quality of life and that these results are a “double-win,” in that the immunotherapy option improves survival while also reducing toxicity.

“The era when chemotherapy was the only option for patients with NSCLC is drawing to a close,” he said. “This study represents a true milestone for the field…the majority of patients with NSCLC can start their treatment without chemotherapy.”  

–Dave Levitan

*Data based on the press briefing.