Pembrolizumab improves survival in patients with advanced non–small cell lung cancer (NSCLC). Compared with docetaxel, the drug more than doubles survival in patients whose tumor cells express high levels of PD-L1. Although the drug had a beneficial effect in patients with nonsquamous NSCLC, it didn't significantly increase survival in patients with squamous NSCLC.

For more than a decade, docetaxel has been a standard of care for patients with advanced non–small cell lung cancer (NSCLC) who no longer respond to other therapies, such as platinum-based agents. New research shows that these patients survive longer if they receive the recently approved checkpoint inhibitor pembrolizumab (Keytruda; Merck) instead.

The number of treatment options for patients who would typically receive docetaxel is increasing rapidly. Pembrolizumab was approved in 2015 for patients whose tumors carry the PD-L1 protein, as determined by an FDA-approved companion diagnostic test. Another PD-1 pathway inhibitor, nivolumab (Opdivo; Bristol-Myers Squibb), was also approved last year for the treatment of nonsquamous and squamous NSCLC.

Roy Herbst, MD, PhD, of the Yale School of Medicine in New Haven, CT, and colleagues performed the first head-to-head comparison of pembrolizumab and docetaxel (Lancet 2015 Dec 19 [Epub ahead of print]). The 1,034 patients in the phase II/III trial had progressed after receiving two or more cycles of platinum-doublet chemotherapy but had not previously been treated with docetaxel. They were randomized to receive the drug or one of two dosages of pembrolizumab: 2 mg/kg or 10 mg/kg.

The trial differs from previous studies in several ways. For example, unlike recent nivolumab trials, it included only patients who prospectively tested positive for PD-L1, the target of pembrolizumab and nivolumab. In addition, unlike other trials of checkpoint inhibitors that block the PD-1 pathway, the new study enrolled patients who had previously received more than one line of treatment.

The lower dose of pembrolizumab increased median survival by 1.9 months over docetaxel, whereas the higher dose extended patients' lives by 4.2 months. The effect was larger in patients whose tumors expressed PD-L1 on at least 50% of their cells: Median survival for those taking docetaxel was 8.2 months, but it was 14.9 months for patients who received the lower dose of pembrolizumab and 17.3 months for those treated with the higher dose. “We now know there's a group that benefits a lot” from pembrolizumab, says Herbst.

The drug is effective for about 60% to 70% of patients with advanced NSCLC, says Herbst, and the study shows that “the biomarker [PD-L1] can help us find out which patients it will work in.”

The researchers also asked whether the drug had the same effect in nonsquamous and squamous NSCLC. Patients with nonsquamous disease benefited from pembrolizumab, but patients with squamous NSCLC who received the drug didn't live significantly longer than patients who received docetaxel. Herbst says that although mortality was lower in the treated patients, the survival difference might not have reached statistical significance because the trial included a relatively small number of people with squamous NSCLC—only 222.

The survival results are impressive, particularly for the patients with the highest levels of PD-L1 expression, says Justin Gainor, MD, of Massachusetts General Hospital in Boston, who wasn't connected to the study. “They are unprecedented for patients with advanced cancer that had been previously treated.” He adds that the study “validates PD-1 pathway inhibitors as a standard of care in patients who would have previously received chemotherapy.” –Mitch Leslie

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