Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study

Abstract

Purpose: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC.

Methods: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment.

Results: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm.

Conclusion: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

FIG 1.

OS in patients with unresectable, pMMR or not MSI-H metastatic colorectal cancer at final analysis. Kaplan-Meier estimates of OS in the intention-to-treat population. HR, hazard ratio; MSI-H, microsatellite instability high; OS, overall survival; pMMR, mismatch repair proficient; SOC, standard of care.

FIG 2.

Forest plot of overall survival across prespecified subgroups of patients with unresectable, pMMR or not MSI-H metastatic colorectal cancer. The Cox proportional hazard model with Efron's method of tie handling was used to assess the magnitude of the treatment difference between arms. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; MSI-H, microsatellite instability high; pMMR, mismatch repair proficient; SOC, standard of care.

FIG 3.

PFS in patients with unresectable, pMMR or not MSI-H metastatic colorectal cancer. Kaplan-Meier estimates of progression-free survival in the intention-to-treat population. Progression-free survival was assessed per the RECIST version 1.1 by blinded, independent central review. HR, hazard ratio; MSI-H, microsatellite instability high; PFS, progression-free survival; pMMR, mismatch repair proficient; SOC, standard of care.

FIG A1.

Study disposition at final analysis. ^aTwo patients assigned to lenvatinib + pembrolizumab received regorafenib or trifluridine/tipiracil instead and were moved to the standard-of-care treatment arm.

FIG A2.

Forest plot of progression-free survival across prespecified subgroups. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; SOC, standard of care.

FIG A3.

Forest plot of difference in overall response rate across prespecified subgroups. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; SOC, standard of care.