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The phase 2 study presented at the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium reported a total of 2 responses at the interim analysis, meeting criteria to continue accrual.
The combination use of pembrolizumab (Keytruda) with capecitabine (Xeloda) and bevacizumab (Avastin) was suggested to be tolerable in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), with an anticipated safety profile, according to results from a phase 2 study (NCT03396926) presented at the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.
“With 2 responses, the study met interim analysis criteria to continue accrual, and tissue and blood-based immune correlatives are planned,” Andrea Grace Bocobo, BS, a medical student at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, said during a virtual poster presentation of the data.
This single-arm, open-label, single-site, phase 2 trial was designed to evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in patients with MSS mCRC. Patients with stable disease (SD) or progressive disease (PD) on prior fluoropyrimidine-based therapy were eligible for the study. Treatment consisted of the recommended phase 2 dose PO capecitabine on days 1-14 plus 200 mg pembrolizumab intravenously (IV) and 7.5 mg/kg bevacizumab IV on day 1 in 21-day cycles.
Of note, the study followed a Simon’s 2-stage design with a safety lead-in to confirm the recommended phase 2 dose for capecitabine and expansion cohorts. In the first stage, ≤1 response among 29 patients required trial suspension. Otherwise, 15 additional patients will be accrued for a total study cohort of 44 patients.
The safety lead-in confirmed a recommended phase 2 dose for capecitabine of 1000 mg/m2 PO BID.
At the planned interim analysis (April 2018 to September 2020), a total of 29 patients had been enrolled in the study, of whom 15 (52%) were female and 21 (72%) were white; the median age was 55 years (range 36-77 years). Additionally, 26 (90%) patients had PD on fluoropyrimidine-containing regimens and 24 (83%) patients had prior exposure to bevacizumab. The median prior lines of systemic therapy was 3 (range, 1-5).
As of the data cutoff of December 7, 2020, 3 (10%) patients remained on active treatment. The median time on treatment was 4 months (range 1-26 months) and 45% of patients were on treatment for ≥6 months.
Overall, no unexpected treatment-related adverse events (AEs) were reported, and no treatment-related AEs led to treatment discontinuation or death. Complete toxicity data was available for 26 off-treatment patients.
The most commonly reported adverse events (AEs) were palmar-plantar erythrodysesthesia (PPE; 62%) and fatigue (65%). Grade ≥3 related AEs occurred in 10 (38%) patients, including immune-related AEs of grade 3 dyspnea, hypophosphatemia, and pancreatitis in 1 patient each. Grade 3 hypertension also occurred in 2 patients and 1 patient had a grade 4 treatment-related AE of pneumoperitoneum; there were no grade 5 treatment-related AEs. Treatment related AEs which led to dose interruptions, reductions, or delays occurred in 15 (60%) patients, the most common being PPE in 13 (50%) patients.
Overall, per RECIST 1.1 criteria, 24 (83%) patients were considered evaluable, including 2 patients with a partial response (PR; 8%), 14 with SD (59%), and 8 (33%) with PD. Of the 5 patients considered unevaluable, 4 patients had discontinued treatment due to clinical progression prior to restaging and 1 patient had not yet completed restaging scans.
Of those with a PR, one patient had a time to response of 11 months and the other had a time to response of 2 months. Moreover, the first patients had 12 months until disease progression while the other had 15 months. The first patient was on treatment for 26 months and the second was on treatment for 17 months as of the cut-off date, though their treatment remains ongoing.
Notably, both patients with a PR had KRAS-mutant colon cancers, metastatic to liver, with progressive disease on prior fluoropyrimidine-based therapy.
Bocobo AG, Wang R, Behr S, et al. Phase II study of pembrolizumab plus capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Interim analysis. J Clin Oncol. 2021;39(suppl 3). Abstract: 77.