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ASCO GI 2026 | KEYSTEP-008: pembro-based combinations for MSI-H/dMMR mCRC
Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, discusses results from the Phase II KEYSTEP-008 platform trial (NCT04895722) in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). In heavily pre-treated patients, pembrolizumab plus quavonlimab showed higher response rates than pembrolizumab alone, though without statistical significance. In the first-line setting, multiple pembrolizumab-based combinations failed to improve outcomes over monotherapy, highlighting challenges in surpassing current immunotherapy standards. This interview took place at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco, CA.
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Transcript
The KEYSTEP-008 study is a platform phase II randomized clinical trial dedicated to patients with MSI-high or deficient mismatch repair metastatic colorectal cancer. Basically, there were two cohorts in the study.
In cohort A, patients were pre-treated with the three main chemotherapy agents—fluoropyrimidines, irinotecan, and oxaliplatin—and anti-EGFR monoclonal antibodies, if clinically indicated...
The KEYSTEP-008 study is a platform phase II randomized clinical trial dedicated to patients with MSI-high or deficient mismatch repair metastatic colorectal cancer. Basically, there were two cohorts in the study.
In cohort A, patients were pre-treated with the three main chemotherapy agents—fluoropyrimidines, irinotecan, and oxaliplatin—and anti-EGFR monoclonal antibodies, if clinically indicated. In this cohort, patients were randomized to either standard-of-care pembrolizumab or a combination of pembrolizumab with the anti-CTLA-4 monoclonal antibody quavonlimab, which is a co-formulation.
In this heavily pre-treated patient population, the overall response rate was higher with the combination: 45% overall response rate versus 30% with pembrolizumab alone. There was a numerical increase in terms of efficacy endpoints, including progression-free and overall survival. However, the patient number—60 patients per arm—was not sufficient to show any statistically significant difference.
It’s also important to note that nowadays, the use of immune checkpoint inhibitors is recommended by all major guidelines in the first-line setting. So cohort B of the study investigated different pembrolizumab-based combinations in the first-line setting in patients not previously treated for metastatic disease. The five arms of the second cohort investigated pembrolizumab alone or in combination with other agents, including quavonlimab as in cohort A, but also other agents such as the anti-LAG-3 favezelimab, the anti-TIGIT vibostolimab, and the ILT4 inhibitor acting on macrophage receptors, MK-7684.
In these cohorts, there were no significant differences in terms of response rate, progression-free survival, or overall survival. So basically, in this population, combining pembrolizumab with an additional immune checkpoint inhibitor didn’t provide any additional benefit compared to monotherapy with pembrolizumab alone.
Of course, we know that today the standard of care for most patients is the combination of ipilimumab and nivolumab in the first-line setting, so this is the current standard of care. Additional agents are needed to further improve the outcomes, but the outcomes are really, really good with the combination of ipi/nivo, so it will be difficult to achieve better results than the current standard of care.
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