Around 5% of patients with metastatic colorectal cancer (mCRC) have tumors that are characterized by deficiencies in the mismatch repair system (dMMR), which result in high microsatellite instability (MSI-H). These biomarkers can be identified either by immunohistochemistry (IHC, dMMR), polymerase chain reaction (PCR, MSI) or with next-generation sequencing (NGS). In general, these patients benefit less from conventional chemotherapy and have a poor prognosis. Since MSI-H mCRC is associated with high mutational burden and tumor antigen load, these tumors are highly immunogenic and thus sensitive to immune checkpoint blockade. Several clinical trials have demonstrated high and durable responses with immune checkpoint inhibitors in patients with metastatic dMMR/MSI-H CRC and non-CRC cancers. These data led to regulatory approvals of pembrolizumab for previously treated MSI-H/dMMR solid tumors, including mCRC, and nivolumab (with and without low dose ipilimumab) for previously treated mCRC with the presence of these biomarkers.

At the ASCO 2020 virtual plenary session, eagerly awaited results from the randomized, open label, phase III KEYNOTE-177 trial (LBA4) were presented by Thierry André, MD (Sorbonne Université and Hôpital Saint Antoine, Paris, France). The trial, which enrolled 307 previously untreated patients with MSI-H/dMMR mCRC, compared the efficacy and safety of first-line pembrolizumab with standard chemotherapy-based therapy. Patients were assigned to receive either first line pembrolizumab or investigator-choice of chemotherapy (modified FOLFOX6 or FOLFIRI) with or without bevacizumab or cetuximab. Patients continued treatment until disease progression (PD), unacceptable toxicity, withdrawal, or completion of 35 cycles of pembrolizumab. Optional crossover to pembrolizumab for patients with verified PD in the chemotherapy arm was permitted. Progression-free survival (PFS) and overall survival (OS) were the dual-primary endpoints for the trial; key secondary endpoints included objective response rate (ORR) and safety. At median follow up of 32 months, treatment with pembrolizumab provided a clinically meaningful and statistically significant improvement in median PFS compared with standard therapy (16.5 versus 8.2 months; hazard ratio (HR) 0.60, P=0.0002). Of note, there was the 2.5-fold increase in rate of PFS at 24 months with pembrolizumab treatment (48.3% versus 18.6%). Subgroup analysis indicated consistent benefit with pembrolizumab across all subgroups, although patients with RAS mutant mCRC and those with ECOG PS1 appear to benefit less. Confirmed ORR in the pembrolizumab arm was 43.8% versus 33.1% in the chemotherapy arm (P=0.027). However, progressive disease was higher in the pembrolizumab arm at 29.4% versus 12.3%, suggesting that around a third of patients may have an intrinsic resistance to anti-PD1 therapy. Median duration of response was not reached with pembrolizumab and was 10.6 months with chemotherapy-based treatment. Among patients with confirmed progression on chemotherapy-based treatment, 36% crossed over to receive pembrolizumab. The study remains blinded for OS, which is planned to be reported at final analysis. The safety profile of pembrolizumab was favorable compared with chemotherapy, and patients experienced a robust decrease in grade 3 or higher treatment-related adverse events (22% versus 66%).

Dr André concluded that “no medical treatment has shown such a difference in terms of improvement of progression-free survival in metastatic colorectal cancer” and that “pembrolizumab should be the new standard of care for these patients”. A discussant for KEYNOTE-177, Michael Overman MD (The University of Texas MD Anderson Cancer Center, Houston, Texas, USA) agreed that these results are practice changing. He pointed out that it is critical to test all patients with mCRC for MSI-H/dMMR mutations, and that biomarkers of resistance are needed to identify those patients who may benefit most from first-line pembrolizumab treatment.

Reference

André T, et al. J Clin Oncol. 2020;38 (suppl; abstract LBA4)