Based on data from the phase III KEYNOTE-189 trial, the FDA has expanded the approval for pemetrexed injection in combination with pembrolizumab and platinum-based chemotherapy to include the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer without <em>EGFR</em> or <em>ALK</em> alterations.
Based on data from the phase III KEYNOTE-189 trial, the FDA has expanded the approval for pemetrexed (Alimta) injection in combination with pembrolizumab (Keytruda) and platinum-based chemotherapy to include the first-line treatment of patients with metastatic nonsquamous nonsmall cell lung cancer (NSCLC) withoutEGFRorALKalterations.1
The FDA previously granted full approval to frontline pembrolizumab for use in combination with standard chemotherapy for patients with metastatic nonsquamous NSCLC.2,3
"KEYNOTE-189 demonstrated an exceptional effect of the Alimta-pembrolizumab-platinum chemotherapy combination in the first-line setting, offering significantly improved survival in patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations," said Anne White, president, Lilly Oncology. "This new indication reinforces Lilly's continued commitment to providing practice-changing treatment options that can make a meaningful difference for people living with lung cancer."
In the double-blind, phase III KEYNOTE-189 study, 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression and were notEGFR- orALK-positive, were randomized 2:1 to receive pembrolizumab plus pemetrexed and either cisplatin or carboplatin n = 410), or chemotherapy alone (n = 206). Patients also had not received systemic therapy for their advanced disease.
Results showed that the addition of pembrolizumab to chemotherapy in the first-line setting reduced the risk of death by 51% in patients with NSCLC withoutEGFRorALKmutations. The median overall survival (OS) was not reached in the pembrolizumab arm compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm versus 49.4% (95% CI, 42.1-56.2) in the control arm (HR, 0.49; 95% CI, 0.38-0.64;P<.001).
Moreover, the study 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).
In the experimental arm, pembrolizumab was administered 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 in the control arm was identical, except that pembrolizumab was replaced with placebo.
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.
Additional results showed that the OS benefit with pembrolizumab 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% (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).
The objective response rate 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.
Regarding safety, the rate of discontinuation of all study drugs due to adverse events (AEs) was 13.8% in the pembrolizumab arm versus 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.
The immunotherapy/chemotherapy regimen was initially granted an accelerated approval in June 2018 for the first-line treatment of patients with metastatic nonsquamous NSCLC, based findings from the cohort G of the phase II study KEYNOTE-021 trial, in which the 12-month PFS rate was 56% with pembrolizumab plus pemetrexed and carboplatin compared with 34% with chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.84;P= .0038).4