Richard Kim, MD, Discusses Key Findings With Pembrolizumab Plus Chemo in Metastatic MSS/pMMR CRC

Richard Kim, MD, discussed key findings of the phase 1b KEYNOTE-651 trial, examining pembrolizumab plus standard chemotherapy in patients with microsatellite-stable or mismatch repair–proficient colorectal cancer.

In an interview with CancerNetwork® during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Richard Kim, MD, service chief of Medical Gastrointestinal Oncology and senior member in the Gastrointestinal Oncology Department at Moffitt Cancer Center in Tampa, Florida, highlights key findings from the phase 1b KEYNOTE-651 trial (NCT03374254) of patients with microsatellite-stable (MSS) or mismatch repair–proficient (pMMR) metastatic colorectal cancer.

Data that read out at ASCO included results from cohort B of patients with no prior systemic therapy who were treated with 200 mg of pembrolizumab (Keytruda) every 3 weeks and modified oxaliplatin, leucovorin, and fluorouracil (5-FU; mFOLFOX) every 2 weeks and cohort D of patients who were previously treated with a chemotherapy regimen who received pembrolizumab plus irinotecan, leucovorin, and 5-FU (FOLFIRI) every 2 weeks. The median follow-up in both respective arms was 30.2 months and 33.5 months and median progression-free survival (PFS) was 8.6 months and 8.3 months.


KEYNOTE-651 had 5 cohorts: A, B, C, D, and E. The B and D cohorts that I had the pleasure to present [looked at] a combination of chemotherapy [in the] first line with FOLFOX plus pembrolizumab or second-line FOLFIRI plus pembrolizumab. Just a little bit of background, cohort A, C, and E are [examining] a similar combination, but they added a MEK inhibitor. Combination A is just a combination of a MEK inhibitor plus pembrolizumab. Cohorts C and E are the same thing; it was FOLFOX plus pembrolizumab, but they added a MEK inhibitor with binimetinib [Mektovi] in those 2 arms. Cohorts B and D were straightforward without any targeted therapy—just adding chemotherapy with pembrolizumab in [patients with MSS] colorectal cancer. The result was not a randomized. What you saw was that there was activity with the combination in terms of response rate, along with some PFS and overall survival.

The caveat is that this is not a randomized study, so you cannot say whether this was better than historical numbers. At least, number-wise, it seems to be very comparable. One thing that does stand out was that the overall survival in the second line with FOLFIRI plus pembrolizumab seems to be over 20 months, which once again, with the caveat that this single-arm study, seems to be longer than the historical number. Therefore, based on that finding, we did a correlative [analysis] trying to find [whether] there is a potential biomarker that could predict response to chemotherapy and immunotherapy with pembrolizumab.

We looked at gene expression, PD-L1 status, tumor mutational burden, and we also looked at the KRAS status. Unfortunately, none of them panned out, even though there’s a trend towards a better response in patients [who have] a higher gene expression. Interestingly enough, with KRAS status, patients with KRAS wild-type [disease] tend to have a better response rate, [OS], and PFS, even though it was not significant by analysis. Based on our study, we definitely felt that the combination of chemotherapy and pembrolizumab was safe [and we saw] some activity. Once again, I cannot say it’s better than the historical numbers and, unfortunately, some of the biomarker [we tested] didn’t quite pan out to be predictive of [outcomes with] the combination.


Kim RD, Tehfe M, Kavan P, et al. Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D. J Clin Oncol. 2022;40(suppl 16):3521. doi:10.1200/JCO.2022.40.16_suppl.3521