Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study

Abstract

Purpose: The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma.

Methods: Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2-negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators' choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response.

Results: Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%.

Conclusion: Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1.

FIG 1.

CONSORT diagram. ITT, intention-to-treat.

FIG 2.

PFS in participants with advanced metastatic HER2-negative gastric and gastroesophageal junction adenocarcinoma. Kaplan-Meier estimate of PFS at interim analysis in (A) participants with PD-L1 CPS ≥1 (H2; P value boundary for significance = .007000) and (B) all participants (H4; P value boundary for significance = .005999). PFS was assessed per the RECIST version 1.1 by blinded, independent central review. Tick marks represent data censored at the time of last imaging assessment. CPS, combined positive score; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; Lenva, lenvatinib; Pembro, pembrolizumab; PFS, progression-free survival.

FIG 3.

OS in participants with advanced metastatic HER2-negative gastric and gastroesophageal junction adenocarcinoma. Kaplan-Meier estimate of OS at final analysis in (A) participants with PD-L1 CPS ≥1 (H1) and (B) all participants (H3). Tick marks represent data censored at the time of last imaging assessment. (C) Forest plot of OS at final analysis in prespecified subgroups. The unstratified Cox regression model with Efron's method of tie handling with treatment as a covariate was used to assess the magnitude of the treatment difference between arms. CAPOX, capecitabine and oxaliplatin; CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; Lenva, lenvatinib; mFOLFOX6, fluorouracil, leucovorin, oxaliplatin; MSI, microsatellite instability; MSI-H, microsatellite instability-high; NA, North America; OS, overall survival; Pembro, pembrolizumab.

FIG A1.

Multiplicity strategy for α reallocation. Hypotheses (H) are indicated in order of α reallocation. CPS, combined positive score; PFS, progression-free survival; ORR, objective response rate; OS, overall survival.

FIG A2.

Forest plot of progression-free survival at interim analysis in participants with advanced metastatic HER2-negative gastric and gastroesophageal junction adenocarcinoma. The unstratified Cox regression model with Efron's method of tie handling with treatment as a covariate was used to assess the magnitude of the treatment difference between arms. CAPOX, capecitabine and oxaliplatin; CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; mFOLFOX6, fluorouracil, leucovorin, and oxaliplatin; MSI, microsatellite instability; MSI-H, microsatellite instability-high; NA, North America.

FIG A3.

DOR in participants with advanced metastatic HER2-negative gastric and gastroesophageal junction adenocarcinoma. Kaplan-Meier estimate of DOR at interim analysis. Tick marks represent data censored at the time of last imaging assessment. DOR, duration of response; HER2, human epidermal growth factor receptor 2; Lenva, lenvatinib; Pembro, pembrolizumab; ORR, objective response rate.