Pembrolizumab Triplet Induces Deep, Durable Responses in Some Patients With Treatment-Refractory mCRC

The use of pembrolizumab (Keytruda) plus binimetinib (Mektovi) and bevacizumab (Avastin) in patients with microsatellite-stable, treatment-refractory metastatic colorectal cancer (mCRC) induced a median progression-free survival (PFS) of 5.8 months, according to preliminary findings presented at the 2022 ASCO Gastrointestinal Cancers Symposium.

The phase 2 trial (NCT03475004) data also demonstrated that the toxicities observed with the triplet regimen were consistent with what has been demonstrated in previous studies. Long-term survival, despite the many approved lines of therapy, is poor and responses to later lines of treatment are rather short for this patient population according to the study authors.

In a poster on their findings, the authors also noted that all 3 treatments assessed in this trial have been associated with clinical benefits across different patient subgroups with colorectal cancer.

“It is well documented that the MAPK pathway is integral in carcinogenesis of mCRC, and that both MEK and WEGF-targeted agents can alter the immune micro-environment and may lead to additive activity when combined with immune checkpoint blockade, providing rationale to study this particular combination,” they said.

Forty-seven patients (median age, 53.6 years; 53% male) were enrolled into the trial. Enrolled patients were aged at least 18 years old, had an ECOG performance status of 0-1 and had disease that progressed after at least 2 previous lines of treatment.

Patients in the trial were administered 7.5 mg of bevacizumab intravenously every 3 weeks, 200 mg of pembrolizumab intravenously every 3 weeks and 45 mg of binimetinib orally twice a day until disease progressed or patients experienced unacceptable toxicities.

The primary endpoint of this trial was response rate using RECIST v1.1 via investigator review. Secondary endpoints included PFS, objective response rate (ORR), disease control rate at 2 months (which was time of first re-staging), duration of response (DOR), overall survival (OS), safety and tolerability.

Five patients achieved a partial response, 24 patients reached stable disease and 29 patients derived a clinical benefit at the first re-staging at 2 months. The analysis also demonstrated that the triplet induced a median PFS of 5.8 months (95% CI, 4.2-8.9).

In terms of binimetinib dose reductions, 14 patients had to be switched to 30 mg twice per day, 12 were reduced to 15 mg twice per day and 1 patient discontinued treatment. The most common grade 1/2 adverse events included, but were not limited to, 34 cases of rash, 24 cases of diarrhea and 18 cases of nausea.

“Toxicity from these three approved drugs is well-established and observed toxicity in this trial was as expected,” the authors concluded in the poster. “The combination…has promising activity in treatment-refractory mCRC with some patients achieving deep and durable responses and a majority of patients deriving clinical benefit at time of first disease re-staging.”

Reference

Friedrich T, Blatchford PJ, Lentz RW, Davis SL, et al. A phase II study of pembrolizumab, binimetinib, and bevacizumab in patients with microsatellite-stable, refractory, metastatic colorectal cancer (mCRC). Presented at: 2022 ASCO Gastrointestinal Cancers Symposium. January 20-22, 2022. Abstract 118.