The phase II LEAP-005 trial evaluates the combination of lenvatinib and pembrolizumab in patients with previously treated advanced gastrointestinal cancers, including gastric cancer, biliary tract cancer (BTC), and pancreatic ductal adenocarcinoma (PDAC).
Treatment options remain limited after progression on standard therapies, particularly in later-line settings where effective strategies are still lacking.
The article is published in Cancer Research Communications on March 26, 2026.
Title: Lenvatinib plus Pembrolizumab for Patients with Previously Treated Advanced Gastric, Biliary Tract, or Pancreatic Cancer: Results from the Phase II LEAP-005 Study
Authors: Mariano Ponz-Sarvisé, Sun Young Rha, Carlos A. Gomez-Roca, Laura Ortega Morán, Sanjeev Gill, Giampaolo Tortora, Ravit Geva, Esma Saada-Bouzid, Armando Santoro, Tae Won Kim, Daniel Heudobler, Corina E. Dutcus, Chinyere E. Okpara, Razi Ghori, Yiwei Zhang, Amir Vajdi, E.J. Dettman, Fan Jin, Roman Groisberg, and Ronnie Shapira-Frommer.
Study Design and Population
LEAP-005 is a multicohort, open-label, phase II study evaluating the combination of lenvatinib and pembrolizumab in previously treated advanced solid tumors.
This analysis focuses on three gastrointestinal cohorts: gastric cancer (cohort C), biliary tract cancer (cohort F), and pancreatic ductal adenocarcinoma (cohort G).
Eligible patients had advanced, unresectable or metastatic disease with progression after prior systemic therapy and ECOG performance status 0–1.
Patients received:
- Lenvatinib 20 mg orally daily
- Pembrolizumab 200 mg intravenously every 3 weeks
Endpoints
- Primary: Objective response rate (ORR) and safety
- Secondary: Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS)
Exploratory analyses also evaluated biomarkers including PD-L1 expression, tumor mutational burden (TMB), and gene expression profiles.
Key Findings from LEAP-005
A total of 304 patients were enrolled across three gastrointestinal cohorts in the LEAP-005 study, including gastric cancer (n=99), biliary tract cancer (n=102), and PDAC (n=103).
The data cutoff for this analysis was February 6, 2023. Median times from first dose of study treatment to data cutoff were 23.7 months in gastric cancer, 24.2 months in biliary tract cancer, and 19.5 months in pancreatic cancer.
Results from Cohort C
The gastric cancer cohort included 99 patients enrolled between March 2019 and October 2021, all of whom had received at least two prior lines of therapy.
At the time of data cutoff, the combination of lenvatinib and pembrolizumab demonstrated an objective response rate of 15.2%, including 2 complete responses and 13 partial responses. Disease control was achieved in 53.5% of patients.
The median duration of response was 8.3 months. Median progression-free survival reached 3.5 months, while median overall survival was 4.7 months. Most patients had experienced disease progression or death by the time of analysis.
Higher response rates were observed in patients with PD-L1 CPS ≥10 compared with those with lower expression levels.
Results from Cohort F
The biliary tract cancer cohort included 102 patients enrolled between April 2019 and October 2021, most of whom had received one prior line of systemic therapy.
At data cutoff, the objective response rate was 17.6%, with disease control achieved in 64.7% of patients. The median duration of response was 6.2 months. Median progression-free survival was 4.1 months, and median overall survival reached 7.9 months. The majority of patients had experienced disease progression or death at the time of analysis.
Unlike gastric cancer, response rates were generally similar regardless of PD-L1 expression. However, exploratory biomarker analyses suggested a trend toward improved outcomes in patients with targetable genomic alterations, although these findings remain exploratory.
Results from Cohort G
The PDAC cohort included 103 patients enrolled between March 2021 and September 2021, all of whom had received one or two prior lines of therapy.
At the time of data cutoff, the objective response rate was 7.8%, with no complete responses observed. Disease control was achieved in 37.9% of patients. The median duration of response was 5.8 months. Median progression-free survival was 2.1 months, and median overall survival was 4.3 months.
Clinical activity in this cohort was limited, consistent with prior observations of modest immunotherapy activity in PDAC. Responses were observed regardless of PD-L1 status, but overall clinical benefit remained modest.
Safety
The safety profile of the combination was consistent with the known effects of VEGF inhibition and immune checkpoint blockade. Treatment-related adverse events were frequent, with more than half of patients experiencing grade 3 or higher adverse events across all cohorts, including grade 5 events in the gastric cancer cohort.
Common adverse events included hypertension, fatigue, diarrhea, and hypothyroidism. Treatment discontinuation due to toxicity occurred in a minority of patients, generally ranging from 10% to 16%, suggesting that the regimen, while intensive, remained manageable in a selected population.
Conclusion
In the phase II LEAP-005 study, lenvatinib plus pembrolizumab showed modest antitumor activity in previously treated advanced gastrointestinal cancers, with responses observed across cohorts and a safety profile consistent with the known effects of the combination.
Although these results provide important information on treatment outcomes in this setting, the overall clinical benefit was limited, and the findings did not justify further investigation of this combination in phase III studies.
The article is available in Cancer Research Communications.