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FDA Approves Pembrolizumab for Frontline PD-L1+ NSCLC

Jason M. Broderick @jasoncology
Published: Monday, Oct 24, 2016

Roy Herbst, MD, PhD

Roy Herbst, MD, PhD

The FDA has approved pembrolizumab (Keytruda) for the frontline treatment of patients with metastatic non­–small cell lung cancer (NSCLC) whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

The approval is based on data from the phase III KEYNOTE-024 trial, in which single-agent pembrolizumab reduced the risk of death by 40% and improved progression-free survival (PFS) by 4.3 months compared with doublet chemotherapy for untreated patients with advanced NSCLC with PD-L1 expression on ≥50% of cells.1,2

Along with the frontline approval, the FDA also authorized an update to pembrolizumab’s label to include data from the KEYNOTE-010 trial,3 which examined the PD-1 inhibitor in the second-line setting and beyond for patients with NSCLC and PD-L1 expression levels of ≥1% who have progressed on platinum-based chemotherapy and EGFR- or ALK-targeted therapy for individuals harboring those aberrations. The action converts the accelerated approval pembrolizumab previously received in this setting to a full approval.

“With this new indication, Keytruda can now be a first treatment option instead of chemotherapy for patients with metastatic non­–small cell lung cancer whose tumors express high levels of PD-L1,” Roy S. Herbst, MD, PhD, professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven, said in a statement. “These data reaffirm the importance of testing for PD-L1 expression in non­–small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with Keytruda.”

KEYNOTE-024 screened 1934 patients with NSCLC for eligibility, of which 1653 yielded appropriate tissue for testing. Overall, 30.2% of samples expressed PD-L1 on ≥50% of cells by immunohistochemistry. Patients with EGFR- or ALK-positive tumors were excluded. Of those who met the PD-L1 expression requirements, 305 were randomized to receive pembrolizumab (n = 154) or chemotherapy (n = 151), which most commonly included carboplatin plus pemetrexed (n = 67). In the chemotherapy arm, 46 patients went on to receive maintenance therapy with pemetrexed and an additional 66 patients (43.7%) crossed over to the pembrolizumab arm following progression.

Patient characteristics were well balanced between arms, except for smoking status and the incidence of brain metastases. Overall, there were more patients in the chemotherapy arm who had never smoked (12.6%) versus the pembrolizumab arm (3.2%). Additionally, more patients in the pembrolizumab arm had brain metastases (11.7%) compared with the chemotherapy group (6.6%). However, these differences were not deemed statistically significant.

The median age of patients in the pembrolizumab arm was 64.5 years and the majority were males (59.7%). Twenty-two percent were current smokers and 64.3% had an ECOG performance status of 1. The most common histology was nonsquamous (81.2%).

Pembrolizumab was administered at a fixed 200 mg IV infusion every 3 weeks. In the chemotherapy arm, patients could receive paclitaxel plus carboplatin, pemetrexed plus carboplatin, pemetrexed plus cisplatin, gemcitabine plus carboplatin, or gemcitabine plus cisplatin. Maintenance pemetrexed was allowed for patients with nonsquamous NSCLC.

The estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; P = .005). The median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR, 0.50; 95% CI, 0.37-0.68; P <.001).

The 6-month PFS rate was 62.1% in the pembrolizumab arm versus 50.3% with chemotherapy. This benefit remained consistent across subgroups. At the time of the analysis, median OS had not yet been reached. The objective response rate with pembrolizumab was 44.8% compared with 27.8% with chemotherapy. The duration of response was not reached in the immunotherapy arm versus 6.3 months with chemotherapy.

In those with squamous histology (n = 56), there was a 65% reduction in the risk of progression or death with pembrolizumab versus chemotherapy (HR, 0.35; 95% CI, 0.17-0.71). In the nonsquamous group (n = 249), the risk of disease progression or death was reduced by 45% with the immunotherapy (HR, 0.55; 95% CI; 0.39-0.76).

The pembrolizumab benefit was less pronounced when compared with platinum-based chemotherapy regimens that contained pemetrexed (HR, 0.63; 95% CI, 0.44-0.91). When pemetrexed was omitted, there was a 71% reduction in the risk of progression or death with pembrolizumab (HR, 0.29; 95% CI, 0.17-0.50).


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