Lenvatinib Plus Pembrolizumab Did Not Significantly Improve Overall Survival Among Patients With pMMR or Not MSI-High Metastatic Colorectal Cancer

Final Analysis Results from the Phase 3 LEAP-017 Trial

Final analysis results from the phase 3 LEAP-017 trial demonstrated that lenvatinib plus pembrolizumab did not significantly improve overall survival (OS) among patients with previously treated mismatch repair proficient (pMMR) or not microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). 

According to Akihito Kawazoe, MD, National Cancer Center Hospital East, Kashiwa, Japan, and coauthors, “Despite advances in treatment and earlier detection, the prognosis remains poor for patients with recurrent or metastatic colorectal cancer (mCRC) that is mismatch repair proficient or not microsatellite instability-high.” 

In this multicenter, open-label trial, 480 patients who experienced disease progression on or after prior treatment or could not tolerate standard treatment were randomized on a 1-to-1 basis to receive either 20 mg of once daily lenvatinib plus 400 mg of pembrolizumab once every 6 weeks (n = 241) or investigator’s choice of regorafenib or trifluridine/tipiracil (n = 239). Patients were stratified based on the presence or absence of liver metastases. The primary end point was OS. A key secondary end point was safety. 

At a median follow up of 18.6 months, median OS was 9.8 months in the investigational arm and 9.3 months in the control arm (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.68 to 1.02; P = .0379). Per the prespecified statistical analysis plan, the significance of secondary end points such as progression-free survival and overall response rate were not tested. Adverse events of any grade occurred in 100% of patients in the investigational arm and 98% of patients in the control arm. The most common adverse events occurring in ≥30% of patients included hypertension, proteinuria, diarrhea, hypothyroidism, decreased appetite, fatigue and nausea. Grade ≥3 adverse events occurred in 77% of patients in the investigational arm and 59% of patients in the control arm and most frequently included hypertension, proteinuria, and diarrhea. There were 2 treatment-related deaths in the investigational arm due to cerebral hemorrhage and pneumonitis. 

As Dr Kawazoe and coauthors concluded, “the difference between lenvatinib plus pembrolizumab and standard of care with regorafenib or trifluridine/tipiracil did not meet prespecified significance for improved OS in patients with previously treated pMMR or not MSI-H mCRC.” They noted, “Novel therapeutic options for patients with previously treated pMMR or not MSH-H [metastatic colorectal cancer] are needed” and “future studies should further identify subgroups of patients who could benefit from novel immunotherapeutic approaches.”

Journal of Clinical Oncology Associate Editor Andrew H. Ko, MD, University of California, San Francisco, California, added, “The negative results of this oral tyrosine kinase inhibitor plus immune checkpoint inhibitor strategy highlight the need to develop alternative immune-based combinatorial approaches for treating microsatellite stable colorectal cancer.” 

Source:

Kawazoe A, Xu RH, García-Alfonso P, et al. 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. J Clin Oncol. Published online: July 9, 2024.doi:10.1200/JCO.23.02736