Roger Dansey, MD
The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of frontline pembrolizumab (Keytruda) for the treatment of patients with metastatic non–small cell lung cancer whose tumors do not harbor EGFR
The application, which is specifically for patients with PD-L1 expression levels ≥50%, is based on data from 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
The positive opinion will now be reviewed by the European Commission. A final approval decision for use in the European Union is anticipated by March 2017.
“Lung cancer is one of the leading causes of death in the EU, so today’s news is an important step forward for many patients in Europe. If approved, patients with metastatic non–small cell lung cancer with high PD-L1 expression could receive Keytruda instead of chemotherapy as their initial treatment,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, the developer of pembrolizumab, said in a statement. “We are committed to working collaboratively with governments and other stakeholders to ensure that Keytruda will be made available to patients in Europe as quickly as possible.”
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).
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.
Pembrolizumab is currently improved in the EU for use in patients with locally advanced or metastatic PD-L1–positive NSCLC after the failure of at least 1 prior chemotherapy, as well as targeted therapy for patients with EGFR
- Reck M, Rodriguez-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.
- Reck M, Rodriguez-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.