Regorafenib and trifluridine–tipiracil, also known as TAS-102, is the standard treatment option for patients with metastatic colorectal cancer with median PFS of approximately 2 months and a median OS of approximately 27 months. In the phase II LEAP-005 study, lenvatinib plus pembrolizumab had promising anti-tumour activity with manageable safety in patients with previously treated, no MSI metastatic colorectal cancer. So based on the promising result of the phase II study we conducted the phase III randomised LEAP-017 study of lenvatinib plus pembrolizumab versus standard of care with regorafenib or TAS-102 in patients with previously treated no MSI metastatic colorectal cancer.
What was the methodology?
Eligible patients were adults with no MSI or not mismatch repair deficient metastatic colorectal cancer that progressed on or after or could not tolerate standard therapy. A total of 434 patients were planned to be randomised to receive either pembrolizumab 400mg every six weeks plus lenvatinib 20mg once daily or investigator choice of standard of care therapy chosen before randomisation. Randomisation was stratified for the presence or absence of liver metastases.
The primary endpoint was overall survival and the secondary endpoints were progression free survival and objective response rate by central review. The protocol had specified one interim and one final analysis. The final analysis of OS was performed after 336 deaths and 7 months after the interim analysis had occurred. The overall type was controlled at [inaudible] of 2.5% or was allocated to OS. The PFS and overall hypothesis were tested only if the OS null hypothesis was rejected.
What were the findings in the phase III?
Baseline characteristics were relatively well-balanced between the treatment groups. Approximately 70% of patients in each treatment group had liver metastases present. 35 patients in the lenvatinib plus pembrolizumab group and 40% in the associate group had a PD-1 CPS 1 or more status. 58% of patients in lenvatinib plus pembrolizumab and 54 patients in the associate group had a RAS mutation. The proportion of patients who chose regorafenib or TAS-102 before randomisation was similar among the treatment groups.
So at final analysis overall survival was longer with lenvatinib plus pembrolizumab versus standard of care with a median of 9.8 months versus 9.3 months. The hazard ratio was 0.83 with a p-value of 0.0379. Unfortunately, it did not meet the prespecified threshold for statistical significance. Also, at final analysis the median PFS was 3.8 months in the lenvatinib plus pembrolizumab group but 3.3 months in the standard of care therapy group. The hazard ratio was 0.69, although this was not formally tested according to the [inaudible] strategy. Objective response was 10.4% in the lenvatinib plus pembrolizumab group versus 1.7% in the associate group with a percentage difference of 8.7%. The median duration of response was 11.1 months versus 7.6 months.
Treatment-related AEs occurred in 95% of patients in the lenvatinib plus pembrolizumab group versus 86% in the associate group, most commonly hypertension, proteinuria and hyperthyroidism. Grade 3 or higher treatment-related AEs occurred in 58% versus 42% of patients.
So, in summary, in the phase III LEAP-017 study, although there was a trend towards longer OS with lenvatinib plus pembrolizumab versus standard of care therapy at final analysis, the combination did not meet the prespecified threshold for statistical significance for the OS primary endpoint. There was also a trend towards improvement in the key secondary endpoints of PFS and objective response rate with lenvatinib plus pembrolizumab versus standard of care.
No new safety signals were observed and the safety profile was consistent with that previously reported for the combination. The normal treatment-related option for patients with previously no MSI high metastatic colorectal cancer remains an unmet medical need.
What’s next for this research?
In the LEAP-017 study a biomarker analysis was conducted, gathering tumour tissue and broad specimens. So we should predict a biomarker for this combination in the future development in immunotherapy for metastatic colorectal cancer.