A randomized phase III study of pembrolizumab versus pembrolizumab with carboplatin plus pemetrexed for locally advanced or metastatic nonsquamous non–small cell lung cancer with PD-L1 TPS ≥ 50%: LAPLACE-50.

8554 Background: For patients with advanced non-squamous non-small cell lung cancer (NSCLC) and high PD-L1 expression (TPS ≥50%), both pembrolizumab monotherapy and immune checkpoint inhibitor with platinum and pemetrexed combination chemotherapy are recognized as standard first-line therapies. However, direct head-to-head comparisons to determine the optimal strategy in this specific population are limited. We conducted a randomized phase III trial to compare these approaches. Methods: In this open-label, randomized phase III trial, previously untreated patients with advanced/metastatic non-squamous NSCLC and PD-L1 TPS ≥50% were randomized (1:1) to receive either pembrolizumab monotherapy (Arm A) or pembrolizumab plus carboplatin and pemetrexed (Arm B). The primary endpoint was progression-free survival (PFS) with a predefined non-inferiority margin of 1.25 for the hazard ratio (HR). Secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Due to slow accrual, the trial was terminated prematurely, and a final analysis was performed on the available cohort. Results: A total of 70 patients were randomized (Arm A, n=35; Arm B, n=35), and 69 patients were included in the full analysis set. Median PFS was 8.1 months in Arm A and 9.2 months in Arm B (HR 1.25; 90% CI, 0.77–2.04), and non-inferiority of pembrolizumab monotherapy was not demonstrated. ORR was 57.1% in Arm A and 73.5% in Arm B (odds ratio 0.49, 95% CI, 0.18–1.36; p=0.172). Median OS was 55.1 months in Arm A and 23.5 months in Arm B (HR 0.83, 95% CI, 0.42–1.63; p=0.663). Grade ≥3 hematologic toxicities were more frequent in Arm B. Serious adverse events occurred in 20.0% of patients in Arm A and 26.5% in Arm B. Conclusions: Although this trial was limited by early termination and did not statistically demonstrate the non-inferiority of pembrolizumab monotherapy in terms of PFS, the numerical OS favored the monotherapy group despite a lower ORR. These findings suggest that for patients with PD-L1 TPS ≥50%, pembrolizumab monotherapy remains a robust treatment option with a favorable safety profile, though the addition of chemotherapy may offer higher initial response rates. Clinical trial information: jRCTs031200078.