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Pembrolizumab Improves Survival for Some Patients with Advanced Non-Small Cell Lung Cancer

Results of a randomized phase III study of patients with advanced non-small cell lung cancer (NSCLC) showed that the immune checkpoint inhibitor pembrolizumab (Keytruda®) extended the length of time patients lived before their disease worsened (progression-free survival) compared with chemotherapy. The immune therapy also extended overall survival. 

Based on these trial results, the U.S. Food and Drug Administration (FDA) approved pembrolizumab to treat metastatic NSCLC with PD-L1 protein present on at least half of tumor cells, as determined by an FDA-approved test called the PD-L1 IHC 22C3 pharmDx assay. PD-L1 on tumor cells binds to PD-1 protein on immune cells called T cells, suppressing the immune response to the cancer. Pembrolizumab blocks PD-1 from binding to PD-L1, allowing T cells to recognize and attack tumor cells. 

Findings from the trial, dubbed KEYNOTE-024, were reported at the 2016 European Society for Medical Oncology (ESMO) meeting in Copenhagen, Denmark, and published simultaneously in the New England Journal of Medicine (NEJM).

Martin Reck, M.D., Ph.D., of the German Center for Lung Research, Grosshansdorf, and his colleagues randomly assigned 305 patients who had previously untreated advanced NSCLC and expression of PD-L1 on at least half of their tumor cells to receive either 200 mg of pembrolizumab every 3 weeks or platinum-based chemotherapy.

Patients who received pembrolizumab had longer median progression-free survival than patients who received chemotherapy, 10.3 months versus 6.0 months. At 6 months, 80.2% of people in the pembrolizumab group were still alive compared with 72.4% of people in the chemotherapy group. 

Adverse events of any grade were less frequent in the pembrolizumab group (73.4%) than the chemotherapy group (90.0%). Serious adverse events (grades 3 through 5) were also less frequent with pembrolizumab (26.6%) than with chemotherapy (53.3%). However, immune-mediated adverse events were more common with pembrolizumab (29.2%) than with chemotherapy (4.7%). The only grade 3 or 4 immune-mediated events reported in two or more patients occurred in the pembrolizumab group: severe skin reactions (in 3.9%) and inflammation of the lungs (2.6%) and colon (1.3%). There were no immune-mediated deaths.

"The trial results are compelling," said Shakun Malik, M.D., of NCI's Division of Cancer Treatment and Diagnosis. She noted, however, that the results of another phase III trial, called CheckMate 026, that compared the efficacy of nivolumab (Opdivo®) with platinum-based doublet chemotherapy as a first-line treatment for patients with advanced NSCLC and PD-L1 positive tumors (defined as present in 1% or more of tumor cells), were "surprisingly disappointing." The study, she explained, failed to reach its primary endpoint: an improvement in progression-free survival.

Combination immunotherapies are another option that looks promising, Dr. Malik added. The phase III CheckMate 227 trial is comparing nivolumab plus ipilimumab (Yervoy®) in the first-line setting with standard chemotherapy, after the drug combination showed promise in an earlier phase trial called CheckMate 012. "The addition of ipilimumab to nivolumab in that trial resulted in markedly higher progression-free survival, as well as higher 1-year overall survival rates," said Dr. Malik.

In an accompanying editorial in NEJM, Bruce E. Johnson, M.D., of Dana-Farber Cancer Institute, noted that earlier studies showed that previously treated patients who received the checkpoint inhibitors pembrolizumab or nivolumab had a survival advantage over those who were treated with chemotherapy. "In the [earlier] study favoring pembrolizumab, patients needed to have PD-L1 expression on at least 1% of tumor cells, whereas in the studies favoring nivolumab, patients were not selected on the basis of PD-L1 expression," he wrote.

A key issue that is facing clinicians now, according to Dr. Malik, is determining the cutoff point for PD-L1 as a predictive biomarker. Earlier trials have shown that expression of the protein on at least 50% of tumor cells seems to be a reasonable cutoff, because those patients who had lower proportions of PD-L1-expressing tumor cells in earlier trials showed response rates substantially lower than those who expressed PD-L1 in 50% or more of cells. But different tests for PD-L1 expression are currently available or are in development, and researchers have yet to settle on the best test and cutoff level to define who is most likely to respond.

Researchers also are still discussing how to treat patients whose tumors have mutations, such as those in the EGFR gene, that make them candidates for targeted therapies but that also express PD-L1. The question, Dr. Malik said, is whether such patients should be treated with a targeted therapy combined with a checkpoint inhibitor or just one of the two drugs.

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