First-Line Pembrolizumab Outperforms Standard-of-Care Chemotherapy in Metastatic MSI-H/dMMR Colorectal Cancer

The following article features coverage from the American Society of Clinical Oncology 2020 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Results of a randomized, phase 3 trial of patients with advanced colorectal cancer characterized as microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) demonstrated a doubling of progression-free survival (PFS) in those who received pembrolizumab compared with standard-of-care chemotherapy in the first-line setting. These findings were presented at the ASCO20 Virtual Scientific Program.¹

Defects in the DNA mismatch repair (MMR) system, which functions to correct errors in the DNA sequence introduced during the process of DNA replication, are reflected in an accumulation of errors in the nucleotide sequences of microsatellites, repeated sequences of DNA of 1 to 6 bases that are randomly distributed throughout the genome.

Cancers characterized as MSI-H/dMMR are typically identified through immunohistochemical (IHC) analyses that reveal deficient quantities of specific proteins involved in DNA mismatch repair or using polymerase chain reaction (PCR) or next-generation sequencing (NGS) assays that show changes in the microsatellite sequences. Furthermore, this form of genomic instability has been shown to be a marker of response to immune checkpoint inhibitors. Pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated, advanced MSI-H/dMMR solid tumors, including advanced MSI-H/dMMR colorectal cancer, a characteristic of approximately 5% of advanced colorectal cancers.²

In this open-label, multicenter study (KEYNOTE-177; ClinicalTrials.gov Identifier: NCT02563002), patients with MSI-H/dMMR metastatic colorectal cancer were randomly assigned in a 1:1 ratio to receive first-line therapy with pembrolizumab, a programmed cell death-1 inhibitor, or investigator’s choice of chemotherapy with FOLFOX or FOLFIRI with or without bevacizumab or cetuximab, the current standard-of-care in this setting.

The coprimary endpoints of the study were progression-free survival (PFS) and overall survival (OS), with secondary study endpoints including overall response rate (ORR) and safety. Patients with confirmed disease progression on chemotherapy were given the option to crossover to receive treatment with pembrolizumab.

Results of the interim efficacy analysis reported here included data for the intent-to-treat population of 307 randomly assigned patients at a median follow-up of approximately 32 months. At baseline, median patient age was 62 to 63 years in the 2 study arms, which were well balanced with respect to performance status, tumor location and genomic characteristics, as well as previous receipt of (neo)adjuvant therapy.

Notably, median PFS was 16.5 months and 8.2 months in the pembrolizumab arm (153 patients) and chemotherapy arm (154 patients), respectively (hazard ratio [HR], 0.60; 95% CI, 0.45-0.80; P =.0002).

In addition, confirmed ORR was 43.8% for patients receiving pembrolizumab compared with 33.1% for those treated with chemotherapy (P =.0275), with a median duration of response not reached in the pembrolizumab arm and 10.6 months in the chemotherapy arm. OS analysis is ongoing.

In the population of randomly assigned patients who had received at least 1 dose of therapy, treatment-related grade 3 or higher adverse events (AEs) were reported for 22% of patients receiving pembrolizumab and 66% of those treated with chemotherapy. However, a higher frequency of immune-mediated AEs and infusion reactions was observed in the pembrolizumab arm (31%) compared with the chemotherapy arm (13%). One patient death due to intestinal perforation occurred in the chemotherapy arm.

Following confirmation of disease progression, 36% of patients assigned to the chemotherapy arm crossed over to the pembrolizumab arm. Data related to the coprimary study endpoint of OS will remain blinded until the final analysis of the study results.

“These long-awaited trial results will change clinical practice,” Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in France, who is the lead author and presenter of the study stated in a press release. “This randomized study demonstrates a huge benefit in first line with pembrolizumab and should be the new standard of care.”³ 

Disclosure: Research funding for this study was provided by Merck & Co., Inc. For a complete list of author disclosures please refer to the reference.

Read more of Cancer Therapy Advisor‘s coverage of the ASCO 2021 meeting by visiting the conference page.

References

1. Andre T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr LBA 4.
2. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2020.
3. Press Release from the American Society of Clinical Oncology (ASCO). Pembrolizumab doubles time to disease progression in patients with advanced colorectal cancer with specific DNA mutations. Published May 28, 2020. Accessed May 31, 2020.