The PD-1 inhibitor pembrolizumab in combination with chemotherapy may be an effective therapy for patients with newly diagnosed advanced non-squamous non–small cell lung cancer. In a clinical trial, patients who received the combination had an estimated 12-month overall survival rate of 69.2%, compared with 49.4% in patients who received chemotherapy alone.

The PD-1 inhibitor pembrolizumab (Keytruda; Merck) in combination with chemotherapy may be a better treatment option than chemotherapy alone for patients with newly diagnosed advanced non-squamous non–small cell lung cancer (NSCLC). In a phase III clinical trial—results of which were presented yesterday at the American Association for Cancer Research 2018 Annual Meeting in Chicago, IL—patients who received pembrolizumab plus pemetrexed and a platinum-based chemotherapy had better overall survival (OS) and progression-free survival (PFS) than patients who received a placebo plus the chemotherapy drugs, regardless of PD-L1 status.

The findings were published concurrently in The New England Journal of Medicine.

Pembrolizumab is FDA-approved as a monotherapy for certain forms of advanced non–small cell lung cancer, and in May 2017 it was approved in combination with pemetrexed and carboplatin for patients with metastatic NSCLC regardless of PD–L1 status, based on results from the phase II KEYNOTE-021 trial.

However, according to Leena Gandhi, MD, PhD, of Perlmutter Cancer Center at NYU Langone Health in New York, NY, who was part of the phase II trial and led the present study, the pembrolizumab–chemotherapy combination has not been widely adopted, in part due to a lack of phase III trial results.

Now, in the multicenter phase III KEYNOTE-189 trial, she and her colleagues enrolled 616 patients with newly diagnosed metastatic NSCLC. Patients were randomized 2:1 to receive pembrolizumab plus pemetrexed (Alimta; Eli Lilly) and a platinum-based chemotherapy (either cisplatin or carboplatin), or a placebo plus the chemotherapy drugs.

After a median follow-up of 10.5 months, patients in the pembrolizumab group had a 12-month estimated OS rate of 69.2%, compared with an estimated OS rate of 49.4% in the placebo group. An improvement in OS rate was seen in the pembrolizumab group regardless of PD-L1 expression levels, but it was most pronounced in patients with PD-L1 levels of 50% or greater, compared with OS for the placebo group (73% versus 48.1%). Median PFS was 8.8 months in the pembrolizumab group and 4.9 months in the placebo group, a benefit also seen across PD-L1 levels.

Based on results from KEYNOTE-189, Gandhi said pembrolizumab plus chemotherapy “really may represent a new standard of care for first-line treatment of this group irrespective of PD-L1 expression.”

Julie Brahmer, MD, of Johns Hopkins University in Baltimore, MD, who was not involved in the study, thought that the results could be practice-changing, especially for patients with PD-L1 levels less than 50%, for whom combination chemotherapy is the current standard of care. “This gives us confidence that adding pembrolizumab does improve survival for those patients,” she said.

Brahmer added that although pembrolizumab plus chemotherapy improved survival for patients with a score above 50%, for her, the biggest question still remains: “Do those patients with high PD-L1 benefit from the three-drug combination versus just single-agent pembrolizumab?”

Bryan J. Schneider, MD, of the University of Michigan in Ann Arbor, who was also not involved in the work, said clinicians in his region began adopting pembrolizumab plus chemotherapy following the 2017 FDA approval.

“It's good that the phase III data reinforce the phase II results, but I don't think it's going to change practice that much, at least not here in the Midwest, because pretty much everyone is already doing it,” he explained. He noted that because the study enrolled only patients with a good performance status, he would be reluctant to use the combination for patients who are significantly symptomatic, and, like Brahmer, he wondered whether pembrolizumab alone is a better option for patients with high PD-L1.

“I think the triple combination is going to be an important option for patients with non–squamous cell metastatic lung cancer with a good performance status who have less than 50% PD-L1 expression, but I think we have to be judicious about who is going to tolerate this, and really adhere to the eligibility criteria,” he said. –Catherine Caruso

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.