Low-dose pembrolizumab with chemotherapy in advanced NSCLC: A phase 3 randomized trial.

LBA1510 Background: Pembrolizumab plus Platinum doublet chemotherapy is the standard of care for advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs). Access to Pembrolizumab & other immune checkpoint inhibitors (ICIs) is limited due to their cost. There is evidence to suggest that ICIs are efficacious at lower doses. The efficacy of low-dose Pembrolizumab & Nivolumab has been demonstrated in phase 3 trials in other settings. There is no randomised data for low-dose Pembrolizumab in advanced NSCLC. We conducted this study to evaluate the efficacy of low-dose Pembrolizumab in this setting. Methods: This is a phase 3 open-label randomised trial with a superiority design that included patients with advanced NSCLC without AGAs. Participants aged ≥18 years & ECOG PS ≤2 were randomised 1:1 to receive Platinum-doublet chemotherapy (Arm A) or Platinum-doublet chemotherapy with low-dose Pembrolizumab (Arm B). Chemotherapy included Pemetrexed/Paclitaxel plus Carboplatin/Cisplatin for 4-6 cycles. Pembrolizumab 50 mg was administered every 3 weeks for the first 4 doses & then every 6-weeks. Treatment was continued until disease progression or intolerable side effects. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), safety, & QoL. The Kaplan-Meier method & the Cox proportional hazards model were used for analysis. Results: 380 participants were randomised,187 to Arm A &193 to Arm B. Participants were predominantly male (76.1%), with a median age of 57 yrs; 61.1% had ECOG PS 0-1, 38.9% had ECOG PS 2, 54.5% were former/current smokers. The most common histological subtype was adenocarcinoma (68.4%). Brain metastases were present in 27.1%. The median follow-up was 13 mos (95% CI 12.2-14.1). The median OS was 10.47 mos (95% CI 8.38-12.56) in Arm A and 13.46 mos (95% CI 11.71-15.22) in Arm B; HR 0.72 (95% CI 0.54-0.95) (p=0.020). The 1-year OS was 44.4% (95% CI 37.2-53) in Arm A and 57.32% (95% CI 44.93-65.79) in Arm B. The median PFS was 4.70 mos (95% CI 4.06-5.34) in Arm A and 6.73 mos (95% CI 5.51-7.96) in Arm B, HR 0.70 (95% CI 0.56-0.89), p=0.003. The 1-year PFS was 18.79% (95% CI 13.59 - 25.99) in Arm A and 26.72% (95% CI 20.23 - 35.29) in Arm B. Grade 3 or higher neutropenia was significantly higher in Arm B (28%) compared to Arm A (17.6%), p=0.02. There was no difference in the incidence of grade 3 or higher anemia or thrombocytopenia. Grade 3 or higher immune-related pneumonitis was seen in 3.1% in Arm B. Conclusion: The addition of low-dose Pembrolizumab to chemotherapy significantly improved overall survival and progression-free survival in patients with advanced NSCLC. There were no new safety signals. This regimen will improve access to ICIs in resource-limited settings. Clinical trial information: CTRI/2023/08/056715.