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Metastatic lung cancer: Pembrolizumab plus chemo prolongs survival

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First-line pembrolizumab should be standard

The recent phase 3 KEYNOTE-189 trial by Gandhi and her colleagues solidifies a shift in first-line standard therapy for some lung cancer patients, according to Joan H. Schiller, MD.

“This trial illustrates that PD-1 pathway inhibitors can be successfully combined with chemotherapy,” Dr. Schiller wrote in an editorial in the New England Journal of Medicine.

In the study, patients treated with carboplatin-pemetrexed-pembrolizumab therapy had longer overall and progression-free survival compared with patients treated with just chemotherapy.

“The magnitude of benefit is impressive,” Dr. Schiller wrote, “with a hazard ratio for death of 0.49 and 12-month overall survival of 69.2% in the pembrolizumab-combination group.”

However, “many unanswered questions remain,” Dr. Schiller said, particularly concerning the utility of the commonly used PD-L1 tumor proportion score, which “appears to be problematic, with some randomized trials showing benefit only with a score of 50% or more and others showing benefit at other cutoff points, including less than 1%.”

In the current study, all subgroups benefited from the addition of pembrolizumab, including patients with a score of less than 1%.

Despite the need for more research, Dr. Schiller said she believes that existing findings have revealed unprecedented benefits. “Is carboplatin-pemetrexed-pembrolizumab now the first-line standard therapy for patients with nonsquamous NSCLC lacking targetable mutations? In my opinion, the answer is yes.”

Dr. Schiller is with the Inova Schar Cancer Institute. These comments are adapted from an editorial (N Eng J Med. 2018 May 31. doi: 10.1056/NEJMe1804364 ). The author reported financial support from Merck, Lily, AstraZeneca, Genentech/Roche, OncoGenex, Halozyme, Synta, Vertex, Bristol-Myers Squibb, Clovis, Xcovery, AbbVie, Astex, Janssen, and Free to Breathe.



In patients with advanced non–small-cell lung cancer (NSCLC) without targetable mutations, the addition of pembrolizumab to first-line combination chemotherapy improves overall and progression-free survival, according to results from the phase 3 KEYNOTE-189 trial.

The researchers found that while patients in all subgroups benefited from the addition of pembrolizumab to chemotherapy, patients with a tumor proportion score of at least 50% benefited the most.

In 2017, accelerated approval was granted for pembrolizumab in combination with carboplatin and pemetrexed as first-line therapy for patients with NSCLC lacking EGFR and ALK mutations. This approval was based on response rates and progression-free survival from the KEYNOTE-024 phase 2 trial.

KEYNOTE-189 solidifies these findings, according to investigators. “Together with the results from KEYNOTE-024, the data from KEYNOTE-189 suggest that introducing immunotherapy as a first-line therapy may have a favorable long-term effect on outcomes,” wrote lead author Leena Gandhi, MD, director of the Perlmutter Cancer Center at New York University, and her colleagues. The report was published in the New England Journal of Medicine.

The double-blind, phase 3 trial assessed 616 treatment-naive patients with metastatic nonsquamous NSCLC without ALK or EGFR mutations. Patients received a platinum-based drug and pemetrexed plus placebo or 200 mg of pembrolizumab every 3 weeks for four cycles. After this, patients received placebo or pembrolizumab with pemetrexed maintenance therapy for up to 35 cycles. Primary endpoints were overall and progression-free survival, determined by a blinded radiologist.

At 12 months, the estimated overall survival was 69.2% for patients treated with pembrolizumab plus chemotherapy, compared with 49.4% for patients treated with chemotherapy alone. For patients treated with the pembrolizumab combination, median progression-free survival was 8.8 months, compared with 4.9 months for those treated with just chemotherapy. Median follow-up time was 10.5 months.

“The survival benefit associated with the pembrolizumab combination was observed in all subgroups of PD-L1 tumor proportion scores,” the authors wrote, “including patients with a score of less than 1%, a population for which single-agent PD-1 and PD-L1 inhibition have a small chance of benefit.” As with previous studies, the subgroup of patients with a tumor proportion score greater than or equal to 50% received the greatest benefit when pembrolizumab was added.

The authors noted that further research is needed to determine whether patients with high PD-L1 expression (TMS ≥ 50%) would benefit more from pembrolizumab combination therapy compared with pembrolizumab monotherapy, which is currently indicated.

SOURCE: Gandhi et al. N Engl J Med. 2018 May 31. doi: 10.1056/NEJMoa1801005.

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