FDA Grants Full Approval for Keytruda Combination in Lung Cancer

The Food and Drug Administration (FDA) has granted a full approval to frontline Keytruda (pembrolizumab) for use in combination with standard chemotherapy for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC), based on findings from the phase 3 KEYNOTE-189 trial.

The addition of Keytruda to Alimta (pemetrexed) and either cisplatin or carboplatin in the first-line setting reduced the risk of death by 51 percent in patients with NSCLC without EGFR or ALK mutations. The median overall survival (OS) was not reached with Keytruda cohort compared with 11.3 months in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2 percent in the Keytruda arm compared with 49.4 percent in the control group.

The study also met the coprimary endpoint of progression-free survival (PFS), with a median PFS of 8.8 months in the Keytruda group versus 4.9 months in the control arm.

The approval was granted ahead of expectations, under a new FDA approval pathway for supplemental applications. Under the program, called Real-Time Oncology Review, the agency reviews pivotal clinical trial data as soon as it becomes available, prior to the formal submission of an application.

"Today’s approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of this product," the agency noted in a statement. "This is the second FDA approval using the Real Time Oncology Review pilot program."

The prior accelerated approval for Keytruda in this setting was based on cohort G in the KEYNOTE-021 trial, in which the 12-month PFS rate was 56 percent with Keytruda combined with Alimta and carboplatin compared with 34 percent with chemotherapy alone.

The double-blind phase 3 KEYNOTE-189 study accrued 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients were not EGFR- or ALK-positive, and had not received systemic therapy for advanced disease. The trial randomization was 2 to 1 in favor of the Keytruda arm.

In the experimental arm (410 patients), patients received Keytruda at a 200-mg fixed dose every three weeks plus 500 mg/m2 of Alimta plus either 75 mg/m2 of cisplatin or carboplatin (AUC 5) on day 1 every three weeks for four cycles, followed by 200 mg of Keytruda plus 500 mg/m2 of Alimta every three weeks. The regimen administered to the control group (206 patients) was identical, except that Keytruda was replaced with placebo.

Patient characteristics were well balanced between the two arms. The median age was 65 years in the Keytruda arm (range, 34.0-84.0), 62 percent of the patients were male, and all but one of the patients had an ECOG performance status of 0 or 1. Current/former smokers comprised 88.3 percent of the cohort and 96.1 percent of patients had adenocarcinoma.

The Keytruda OS benefit was observed across PD-L1 subgroups, including the less than 1 percent expression group (12-month OS rate, 61.7 percent vs. 52.2 percent); the 1 percent to 49 percent cohort (12-month OS rate, 71.5 percent vs. 50.9 percent), and those with a score of 50 percent or greater (12-month OS rate, 73.0 percent vs. 48.1 percent).

The objective response rate per blinded, independent central radiologic review was 47.6 percent in the Keytruda arm and 18.9 percent with chemotherapy alone. The disease control rate was 84.6 percent versus 70.4 percent, and the median duration of response was 11.2 months versus 7.8 months in the Keytruda versus control arms, respectively.

The rate of discontinuation of all study drugs due to adverse events (AEs) was 13.8 percent in the Keytruda arm compared with 7.9 percent in the control arm. The discontinuation rate of Keytruda was 20.2 percent and placebo was 10.4 percent. Death related to AEs occurred in 6.7 percent versus 5.9 percent of the Keytruda versus control arms, respectively.

Diarrhea (30.9 percent vs 21.3 percent) and rash (20.2 percent vs 11.4 percent) were the only 2 AEs occurring in at least 10 percent of patients that occurred more commonly in the Keytruda versus the chemotherapy-alone arm. Grade 3 or higher AEs occurring in at least 10 percent of patients in either arm were anemia (16.3 percent with Keytruda vs 15.3 percent in the control group) and neutropenia (15.8 percent vs 11.9 percent, respectively).

The rate of acute kidney injury was 5.2 percent in the Keytruda arm versus 0.5 percent in the chemotherapy-alone arm. Eight patients (2.0 percent) receiving the PD-1 inhibitor had grade 3 or higher acute kidney injury.

Immune-mediated AEs occurred in 22.7 percent of the Keytruda group versus 11.9 percent of the control group, including grade 3 or higher AEs in 8.9 percent versus 4.5 percent, respectively. Pneumonitis led to 3 deaths in the Keytruda cohort.