Phase II single-arm study of palbociclib and cetuximab in anti-EGFR naïve patients with KRAS/NRAS/BRAF wild-type, metastatic colorectal cancer

Background Standard therapy for patients with KRAS/NRAS/BRAF wild-type (WT), microsatellite stable (MSS), L-sided metastatic colorectal cancer (mCRC) often includes chemotherapy with a monoclonal antibody (mAb) that targets epidermal growth factor receptor (EGFR) such as cetuximab. Preclinical studies suggest the role of CDK4/6 activity downstream of EGFR as a possible resistance mechanism to anti-EGFR therapy. Therefore, we hypothesized that the addition of the CDK4/6 inhibitor palbociclib would increase the disease control rate of patients with anti-EGFR naïve KRAS/NRAS/BRAF-WT mCRC. Methods LCCC1717 was a phase II trial with a Simon two-stage design in which patients with KRAS/NRAS WT mCRC having progressed on at least two lines of therapy were given palbociclib and cetuximab. The primary end point was four-month disease control rate (DCR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). If six or more patients achieved disease control at four months, the study would continue enrollment, otherwise the study would be discontinued. Results A total of 12 subjects were enrolled, 11 of whom had left-sided colon cancer. The four-month DCR was 41.7% (95% CI 15% to 72%) with median OS at 13.9 months and median PFS of 5.3 months, which did not meet the pre-specified endpoint of efficacy. The treatment combination was well tolerated with the most common treatment-related toxicity being decreased lymphocyte and neutrophil counts. Conclusion While clinical benefit was observed with the combination, it did not meet its pre-specified endpoint for efficacy in patients with KRAS/NRAS/BRAF WT EGFR therapy-naïve mCRC patients. Clinicaltrials.gov Identifier: NCT03446157