Luis Paz-Ares, MD
The European Commission (EC) has approved pembrolizumab (Keytruda) as a treatment for patients with locally advanced or metastatic PD-L1–positive non–small cell lung cancer (NSCLC) following at least 1 chemotherapy regimen, according to Merck, the manufacturer of the PD-1 inhibitor.
The approval stipulates that patients whose tumors are EGFR
positive should first receive an EFGR or ALK inhibitor, respectively, prior to treatment with pembrolizumab. The approved dose for the anti–PD-1 agent is 2 mg/kg every 3 weeks.
The EC’s decision, which was primarily based on data from the KEYNOTE-0101
trial, follows a previously issued recommendation from the Committee for Medicinal Products for Human Use. Under the approval, pembrolizumab can now be marketed for this indication across 28 European Union member states.
“The survival benefit for Keytruda observed in previously-treated patients who express PD-L1 is promising,” Luis Paz-Ares, MD, chair of the Medical Oncology Department, Hospital Universitario, in Madrid, Spain, said in a statement. “There is a significant unmet need for lung cancer patients, and with this approval, we now have a new personalized treatment option which uses biomarker testing to predict which patients are most likely to benefit from treatment.”
In the KEYNOTE-010 study, 1034 patients with PD-L1 expression on at least 1% of tumor cells were randomized in a 1:1:1 ratio to receive either docetaxel at 75 mg/m2
(n = 343) or pembrolizumab at 2 mg/kg (n = 345) or a larger experimental dose of 10 mg/kg (n = 346). All treatments were administered every 3 weeks.
All patients enrolled in the study had progression on at least 2 cycles of a prior platinum-containing chemotherapy, and had an ECOG performance status between 0 and 1. The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS) in the full population and those with PD-L1 expression on greater than 50% of tumor cells. PD-L1 was confirmed by immunohistochemistry using the companion diagnostic test PD-L1 IHC 22C3 PharmDx.
The median OS was 10.4 months with the 2-mg/kg dose of pembrolizumab compared with 8.5 months with docetaxel in those with >1% PD-L1 expressing NSCLC (HR, 0.71; 95% CI, 0.58-0.88; P
= .001). With the larger dose of pembrolizumab (10 mg/kg), median OS was 12.7 months, representing a 39% reduction in the risk of death versus docetaxel (HR, 0.61; 95% CI, 0.49-0.75; P
After a median follow-up of 13.1 months, the estimated 1-year OS rates were 43.2% and 52.3% for the 2-mg/kg and 10-mg/kg doses, respectively. The 1-year OS rate with docetaxel was 34.6%.
In those with ≥50% PD-L1 expression, the median OS with the 2 mg/kg dose of pembrolizumab was 14.9 months versus 8.2 months with docetaxel (HR, 0.54; 95% CI, 0.38-0.77; P
= .001). In the 10-mg/kg arm, the median OS was 17.3 months, representing a 50% improvement over docetaxel (HR, 0.50; 95% CI, 0.36-0.70; P
Median PFS was not significantly improved with pembrolizumab in those with >1% PD-L1 expression, possibly due to pseudoprogression. In this group, median PFS was 3.9 months with the 2-mg/kg dose of pembrolizumab versus 4.0 months with docetaxel (HR, 0.88; 95% CI, 0.73-1.04; P
= .07). For the 10-mg/kg dose of pembrolizumab, median PFS was 4.0 months (HR vs docetaxel, 0.79; 95% CI, 0.66-0.94; P
= .004). The P
value for significance was set as <.001.
In those with ≥50% PD-L1 expression, media PFS was 5.2 months with both the 2-mg/kg and 10-mg/kg doses of pembrolizumab, and 4.1 months with docetaxel. Overall, there was a statistically significant 42% reduction in the risk of progression or death for both doses of pembrolizumab over chemotherapy (HR, 0.58; 95% CI, 0.43-0.77; P
The safety profile for pembrolizumab considered by the EC consisted of data from 2799 patients with advanced NSCLC or melanoma who received pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in either the KEYNOTE-001, KEYNOTE-002, or KEYNOTE-010 trial.
Across the population, the most common adverse events (AEs) were were fatigue (24%), rash (19%), pruritus (18%), diarrhea (12%), nausea (11%), and arthralgia (10%). Most of these AEs were grade 1 or 2. Immune-related adverse reactions and severe infusion-related reactions were the most serious AEs.
“This approval provides an important new treatment regimen for patients in Europe with advanced lung cancer, one of the most common and challenging cancers,” Roger Dansey, MD, senior vice president and therapeutic area head, Oncology Late-Stage Development at Merck Research Laboratories, said in a statement. “In the KEYNOTE-010 trial, patients with advanced lung cancer who had failed prior regimens experienced improved overall survival when treated with Keytruda as compared with those treated with traditional chemotherapy.”
1. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550.