In an interim analysis of the phase III LEAP-015 trial reported in the Journal of Clinical Oncology, Shitara et al examined the survival benefit of adding lenvatinib-pembrolizumab to chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma.
Study Details
In the open-label trial, 880 patients with EGF2-negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma from sites in 24 countries were randomly assigned between May 2021 and March 2023 to receive lenvatinib/pembrolizumab plus chemotherapy (n = 443) or chemotherapy alone (n = 437). A total of 334 patients in the lenvatinib/pembrolizumab group (75%) and 355 (81%) in the chemotherapy group had a PD-L1 combined positive score (CPS) of ≥ 1. Treatment consisted of induction with lenvatinib at 8 mg once daily plus pembrolizumab at 400 mg every 6 weeks (x2) and investigator's choice of capecitabine and oxaliplatin every 3 weeks (x4) or fluorouracil, leucovorin, and oxaliplatin every 2 weeks (x6), followed by consolidation with lenvatinib/pembrolizumab or chemotherapy alone.
The dual primary endpoints of the study were progression-free survival and overall survival in patients with PD-L1 CPS ≥ 1 and among all patients.
Key Findings
Median follow-up was 32.2 months (range = 19.0–41.7 months) among patients with PD-L1 CPS ≥ 1 and 31.8 months (range = 19.0–41.7 months) among all patients.
At interim analysis, median progression-free survival for the lenvatinib/pembrolizumab group vs the chemotherapy group was 7.3 vs 6.9 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.62–0.9, P = .0012) among patients with PD-L1 CPS ≥ 1 and 7.2 vs 7.0 months (HR = 0.78, 95% CI = 0.66–0.92, P = .0019) among all patients. Rates at 24 months were 20% vs 7% among patients with PD-L1 CPS ≥ 1 and 21% vs 8% among all patients, respectively.
Objective response rates were 59.5% vs 45.4% among patients with PD-L1 CPS ≥ 1 (P < .0001) and 58.0% vs 43.9% among all patients (P < .0001).
Median overall survival for the lenvatinib/pembrolizumab group vs the chemotherapy group was 12.6 vs 12.9 months (HR = 0.84, 95% CI = 0.71–1.00, P = .0244; not meeting the predefined significance boundary of P = .0204); the 24-month rate was 31% vs 23%. Overall survival among all patients was not statistically tested due to nonsignificance in the CPS ≥ 1 population; median overall survival was 13.1 vs 13.0 months (HR = 0.87, 95% CI = 0.75–1.01).
Grade ≥ 3 drug-related adverse events occurred in 65% of the lenvatinib/pembrolizumab group vs 48% of the chemotherapy group. The most common were decreased neutrophils (24%), hypertension (11%), and decreased platelets (5%) in the lenvatinib/pembrolizumab group and decreased neutrophils (23%), decreased platelets (8%), and anemia (6%) in the chemotherapy group. Treatment-related adverse events led to discontinuation of any study drugs in 27% vs 23% of patients.
The investigators concluded: “Lenvatinib plus pembrolizumab and chemotherapy vs chemotherapy provided a statistically significant improvement in [progression-free survival] 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 [overall survival] in participants with PD-L1 CPS ≥1.”
Kohei Shitara, MD, of National Cancer Center Hospital East, Kashiwa, Japan, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, and Eisai Inc. For full disclosures of all study authors, visit the Journal of Clinical Oncology.
