EC Approves Frontline Pembrolizumab for PD-L1+ Metastatic NSCLC

Roy Baynes, MD, PhD

The European Commission has expanded the indication for pembrolizumab (Keytruda) to include the frontline treatment of patients with metastatic non—small cell lung cancer (NSCLC) that expresses PD-L1 on ≥50% of cells and does not harbor an EGFR or ALK mutation.

The approval was based on data from phase III KEYNOTE-024 trial, and followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), which was granted in December 2016. In the pivotal trial, frontline pembrolizumab reduced the risk of death by 40% and improved progression-free survival (PFS) by 4.3 months compared with standard doublet chemotherapy for patients with metastatic PD-L1—positive NSCLC.^1,2

“The approval of Keytruda as a first treatment instead of chemotherapy for patients who express high levels of PD-L1 has the potential to transform the way metastatic non-small cell lung cancer is treated,” Roy Baynes, MD, PhD, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories, said in a statement. “We are committed to ensuring that patients in Europe — who are in need of new treatment options – are able to quickly gain access to Keytruda.”

In the phase III study, 305 patients were randomized to receive pembrolizumab at 200 mg intravenously every 3 weeks (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 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).

Fewer treatment-related adverse events (AEs) were seen with the PD-1 inhibitor versus chemotherapy (73.4% vs 90%). Grade 3 to 5 AEs were significantly less common with pembrolizumab (26.6%) compared with chemotherapy (53.3%). Serious AEs were similar between the 2 arms for pembrolizumab and chemotherapy, respectively (21.4% vs 20.7%). AEs led to treatment discontinuation for 7.1% of patients in the pembrolizumab arm versus 10.7% of those receiving chemotherapy.

The most common treatment-related AEs of any severity for pembrolizumab were diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%). With chemotherapy, the most common AEs of any-grade were anemia (44%), nausea (43.3%), and fatigue (28.7%). Immune-mediated AEs occurred in 29.2% of those treated with pembrolizumab versus 4.7% of those in the chemotherapy arm.

In the United States, pembrolizumab was approved as a frontline therapy for PD-L1—positive NSCLC in October 2016, this approval was also based on the KEYNOTE-024 data. The PD-1 inhibitor is also approved as a second-line therapy for PD-L1–positive patients with NSCLC, in both the United States and Europe.

References

1. ​Reck M, Rodgriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
2. Reck M, Rodgriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer [published online October 9, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1606774.