Pemetrexed Approval for Frontline Pembrolizumab/Chemo Combo in NSCLC Gets Expansion
The FDA expanded the indication for for pemetrexed (Alimta) injection plus pembrolizumab (Keytruda) and platinum-based chemotherapy for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) without EGFR or ALK alterations.
The FDA expanded the indication for for pemetrexed (Alimta) injection plus pembrolizumab (Keytruda) and platinum-based chemotherapy for the first-line treatment of patients with metastatic nonsquamous non—small cell lung cancer (NSCLC) without EGFR or ALK alterations.1
The decision was based on data from the phase III KEYNOTE-189 trial.2,3 In the double- blind study, 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression and who were not EGFR or ALK positive, were randomized 2:1 to receive pembrolizumab plus pemetrexed and either cisplatin or carboplatin (n = 410) or chemotherapy alone (n = 206).
Pembrolizumab plus chemotherapy in the first-line setting reduced the risk of death by 51% in patients with NSCLC without EGFR or ALK mutations. 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, 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).
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 compared to 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43-0.64; P <.001).
Pembrolizumab was administered as a 200- mg fixed dose every 3 weeks, with 500 mg/m2 of pemetrexed plus 75 mg/m2 of either cisplatin or carboplatin (area under the concentration curve, 5) on day 1 every 3 weeks for 4 cycles, followed by 200 mg of pembrolizumab plus 500 mg/m2 of pemetrexed every 3 weeks. The control arm’s regimen was identical, with placebo instead of pembrolizumab.
Patient characteristics were well balanced between the 2 arms. The median age was 65 years in the pembrolizumab arm, 62.0% of the patients were men, and all but 1 of the patients had an ECOG performance status of 0 or 1. Current and former smokers made up 88.3% of the cohort, and 96.1% of patients had adenocarcinoma.
Additional results showed that the OS benefit with pembrolizumab was observed across PDL1 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 expression ≥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.
Discontinuation rates 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%; of placebo, 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 arm. Grade ≥3 AEs that occurred in ≥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 arm versus 11.9% of the control arm, including grade ≥3 AEs in 8.9% versus 4.5%, respectively. Pneumonitis led to 3 deaths in the pembrolizumab cohort.
1. FDA Expands Lilly's ALIMTA (pemetrexed) Label with Combination of KEYTRUDA (pembrolizumab) and Platinum Chemotherapy for the First-Line Treatment of Metastatic Nonsquamous Non-Small Cell Lung Cancer. Eli Lilly & Company. Published January 31, 2019. https://bit.ly/2JfuTA6. Accessed January 31, 2019.
2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
3. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378:2078-2092.