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Pembrolizumab Monotherapy Extended Survival in Advanced Lung Cancer

Goodwin, Peter M.

doi: 10.1097/01.COT.0000542460.00053.ff

CHICAGO—Patients whose non-small cell lung cancer (NSCLC) expressed more than 1 percent of the PD-L1 tumor proportion score (TPS) lived longer when treated with the anti-PD-1 antibody pembrolizumab than a control group of patients receiving platinum-based chemotherapy in the open-label, phase III KEYNOTE-042 study reported at the 2018 ASCO Annual Meeting plenary session (Abstract LBA4).

“Based on the primary endpoint, we did show that patients who expressed PD-L1 at 1 percent or greater had a much better overall survival than patients who got chemotherapy when they received pembrolizumab,” said principal author of the study, Gilberto Lopes MD, Associate Professor of Clinical Medicine at the University of Miami's Sylvester Comprehensive Cancer Center.

Patients treated with pembrolizumab monotherapy lived a median of 4-8 months longer than those who received chemotherapy and had fewer severe side effects than with chemotherapy (18% as compared with 41%).

Patients with TPS of 50 percent or more had a hazard ratio of 0.69 (p=0.003), which was statistically significant and a clinically important difference. “For [patients with] 1 percent and higher TPS, we had a hazard ratio of 0.81—still a 20 percent improvement in overall survival and a p value of 0.0012,” said Lopes. And the median overall survival (OS) improved between 4 and 8 months depending on the degree of PD-L1 expression, he noted.

More patients responded to immunotherapy than chemotherapy. “Duration of response was much longer for pembrolizumab than for chemotherapy. In most groups, we saw an improvement from about 8 to 9 months with chemotherapy to approximately 20 months with pembrolizumab.”

Lopes added that apart from an improvement in effectiveness the toxicity had been lower. “Pembrolizumab only had about half the severe grade 3-5 toxic effects that chemotherapy did,” he told Oncology Times. “If we look overall—even though patients in the pembrolizumab arm had a median of 9 cycles of treatment versus 6 cycles with chemotherapy—60 percent of patients had adverse events as compared to 90 percent [treated with] chemotherapy.”

Severe adverse events (AEs) were fewer. “We had a rate of about 17-18 percent for pembrolizumab versus 40-41 percent for chemotherapy,” he said.

Lopes described the double benefit of greater efficacy with less toxicity as “certainly a home run as a new treatment option for patients that have an expression of at least 1 percent and above.” And he said the treatment was a new step that brought more options and increased survival. But this had to be put in context of current studies with combinations of chemotherapy and immunotherapy. “We will have to learn how to identify which patients can do best with immunotherapy as single agent and which patients will need combinations with chemotherapy,” he explained.

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Study Details

A total of 1,274 patients were randomized (637 to each arm) to treatment with up to 35 cycles of pembrolizumab or investigator's choice of up to 6 cycles of paclitaxel plus carboplatin or pemetrexed plus carboplatin with optional pemetrexed maintenance for patients who had non-squamous histology only. Both squamous and non-squamous cancers were included but not cancers with genetic changes that could be treated with targeted therapies (EGFR and ALK inhibitors).

Primary endpoints were OS in three groups of patients: 599 who had TPS of 50 percent and above, 818 patients with TPS of at least 20 percent, and 1,274 patients who had tumors with TPS expression of 1 percent or more. The trial did not recruit patients with TPS expression below 1 percent.

After 12.8 months median follow-up, 13.7 percent of patients were still being treated with pembrolizumab and 4.9 percent were receiving pemetrexed maintenance. Pembrolizumab significantly improved OS in patients with TPS of 50 percent or more (HR 0.69). The median was 20 months with pembrolizumab compared with 12.2 months for chemotherapy.

Patients with TPS of 20 percent and above had HR of 0.77 and median OS of 17.7 months with pembrolizumab compared to 13 months with chemotherapy. And in patients with TPS of at least 1 percent the HR was 0.81. Those treated with immunotherapy lived a median of 16.7 months compared with their matched controls who lived for 12.1 months median under chemotherapy.

Grade 3-5 drug-related AEs were less frequent with pembrolizumab: 17.8 percent as compared with 41.0 percent for chemotherapy.

The study authors concluded that KEYNOTE-042 was the first study with a primary endpoint of OS to demonstrate superiority of pembrolizumab over platinum-based chemotherapy in patients with previously untreated advanced or metastatic NSCLC who did not have sensitizing EGFR or ALK alterations and did have PD-L1 TPS of at least 1 percent. And the authors stated that these data confirmed and potentially extended the role of pembrolizumab monotherapy as a standard first-line treatment for PD-L1-expressing advanced or metastatic NSCLC.

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ASCO Expert Commentary

ASCO Expert John V. Heymach MD, PhD, Professor and Chair of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, said findings represented “an important milestone to the field,” noting that for the first time the majority of patients with NSCLC who also have expression of the PD-L1 marker at greater than 1 percent (more than two-thirds of patients) and who were without driver mutations (that could be targeted by other precision therapies) received more benefit from pembrolizumab than chemotherapy.

“This says the majority of patients with non-small cell lung cancer can start with a non-chemotherapy regimen: which is really a major advance,” he shared with Oncology Times.

He noted the landscape for lung cancer therapy was now changing on a “week-by-week basis”—which he described as “breathtaking, very exciting, and obviously wonderful for patients” since the time when (from the early 1970s to the early 2000s) chemotherapy had been the only option for patients with advanced NSCLC (usually platinum doublets: platinum combined with another drug such as paclitaxel, gemcitabine, or pemetrexed). “But all of them had pretty comparable efficacy and were marginal with substantial toxicities. So the median survival was on the order of about 8 months.” Heymach acknowledged that EGFR inhibitor therapy had more recently (since early 2000s) given “wonderful benefit” for the 12-15 percent of the population who had EGFR “driver mutations” and that even more recently patients with ALK driver mutations (about 4%) were benefiting from ALK-directed therapies. But for the rest of the population chemotherapy had remained the standard.

Other studies had very recently found pembrolizumab to bring benefit in combination with chemotherapy in patients with both non-squamous and squamous NSCLC, stated Heymach. “But the KEYNOTE-042 study is an important advance because of testing immunotherapy by itself—without chemotherapy—for all the patients who had PD-L1 greater than 1 percent. And it showed that immunotherapy alone, with no chemotherapy, was superior to chemotherapy.”

Heymach emphasized the importance of the finding that pembrolizumab had been so well-tolerated. “This really is a double win for patients. Not only is survival improved, but they can receive something that is dramatically easier and better tolerated as compared to chemotherapy.”

Heymach also drew attention to the quality of responses to immunotherapy which were less transient than those seen typically to chemotherapy. “Those who receive immunotherapy—if they respond—often have very durable responses. In fact, in many cases it can go for years.”

Peter M. Goodwin is a contributing writer.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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