The approval of pembrolizumab has been recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use as a frontline treatment for patients with metastatic nonsquamous non–small cell lung cancer without <em>EGFR</em> or <em>ALK</em> mutations, regardless of PD-L1 expression. The recommendation is based on data from the phase III KEYNOTE-189 trial.
Roger M. Perlmutter, MD, PhD
The approval of pembrolizumab (Keytruda) has been recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as a frontline treatment for patients with metastatic nonsquamous nonsmall cell lung cancer (NSCLC) withoutEGFRorALKmutations, regardless of PD-L1 expression. The recommendation is based on data from the phase III KEYNOTE-189 trial.
The application will now be reviewed by the European Commission for a final decision on whether the pembrolizumab regimen will be approved for this indication in the European Union.
In the KEYNOTE-189 trial, patients with nonsquamous NSCLC withoutEGFRorALKmutations received frontline pembrolizumab or placebo in combination with pemetrexed (Alimta) and either cisplatin or carboplatin. At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64;P<.001).1,2
The median OS was not reached in the pembrolizumab cohort, compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. The OS benefit was observed, irrespective of PD-L1 status. The study also met the coprimary endpoint of progression-free survival (PFS), with a median PFS of 8.8 months (95% CI, 7.6-9.2) in the pembrolizumab group versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43 to 0.64;P<.001).
“There is significant need for innovative therapies that can improve the overall survival of patients suffering from metastatic nonsmall cell lung cancer, as lung cancer is the leading cause of cancer deaths in Europe,” Roger M. Perlmutter, MD, PhD, president, Merck (MSD) Research Laboratories, said in a statement.
“The KEYNOTE-189 trial demonstrated a significant survival benefit for the combination of Keytruda with chemotherapy as compared with standard-of-care chemotherapy alone. We look forward to working with European regulatory authorities to bring this important treatment regimen to patients in Europe as quickly as possible,” added Perlmutter.
The double-blind phase III KEYNOTE-189 study accrued 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients were notEGFR- orALK-positive, and had not received systemic therapy for advanced disease. The trial randomization was 2:1 in favor of the pembrolizumab arm.
In the experimental arm (n = 410), patients received pembrolizumab at a 200-mg fixed dose every 3 weeks plus 500 mg/m2of pemetrexed plus either 75 mg/m2of cisplatin or carboplatin (AUC 5) on day 1 every 3 weeks for 4 cycles, followed by 200 mg of pembrolizumab plus 500 mg/m2of pemetrexed every 3 weeks. The regimen administered to the control group (n = 206) was identical, except that pembrolizumab was replaced with placebo.
Treatment was administered until disease progression, unacceptable toxicity, physician decision, or consent withdrawal. Patients in the control arm with disease progression were allowed to cross over to receive pembrolizumab. Beyond the primary OS and PFS endpoints, secondary endpoints included overall response rate (ORR) and duration of response.
Patient characteristics were well balanced between the 2 arms. The median age was 65.0 years in the pembrolizumab arm (range, 34.0-84.0), 62.0% of the patients were male, and all but 1 of the patients had an ECOG performance status of 0 or 1. Current/former smokers comprised 88.3% of the cohort and 96.1% of patients had adenocarcinoma.
Also in the pembrolizumab group, PD-L1 expression level as measured by tumor proportion score (% of tumor cells with membranous PD-L1 staining) was <1% in 31% of patients; ≥1% in 63.4%; 1% to 49% in 31.2% of patients; ≥50% in 32.2%; and not evaluable in 5.6%.
The pembrolizumab OS benefit was observed across PD-L1 subgroups, including the <1% expression group (12-month OS rate, 61.7% vs. 52.2%; HR, 0.59; 95% CI, 0.38-0.92); the 1% to 49% cohort (12-month OS rate, 71.5% vs. 50.9%; HR, 0.55; 95% CI, 0.34-0.90), and those with a score of 50% or greater (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).
The ORR per blinded, independent central radiologic review was 47.6% (95% CI, 42.6-52.5) in the pembrolizumab arm and 18.9% (95% CI, 13.8-25.0) with chemotherapy alone (P<.001). The disease control rate was 84.6% versus 70.4%, and the median duration of response was 11.2 months versus 7.8 months in the pembrolizumab versus control arms, respectively.
The rate of discontinuation of all study drugs due to adverse events (AEs) was 13.8% in the pembrolizumab arm compared with 7.9% in the control arm. The discontinuation rate of pembrolizumab was 20.2% and placebo was 10.4%. Death related to AEs occurred in 6.7% versus 5.9% of the pembrolizumab versus control arms, respectively.
Diarrhea (30.9% vs 21.3%) and rash (20.2% vs 11.4%) were the only 2 AEs occurring in ≥10% of patients that occurred more commonly in the pembrolizumab versus the chemotherapy-alone arm. Grade ≥3 AEs occurring in at least 10% of patients in either arm were anemia (16.3% with pembrolizumab vs 15.3% in the control group) and neutropenia (15.8% vs 11.9%, respectively).
The rate of acute kidney injury was 5.2% in the pembrolizumab arm versus 0.5% in the chemotherapy-alone arm. Eight patients (2.0%) receiving the PD-1 inhibitor had grade ≥3 acute kidney injury.
Immune-mediated AEs occurred in 22.7% of the pembrolizumab group versus 11.9% of the control group, including grade ≥3 AEs in 8.9% versus 4.5%, respectively. Pneumonitis led to 3 deaths in the pembrolizumab cohort.