Phase II Study of Ipilimumab, Nivolumab, and Panitumumab in Patients With <i>KRAS</i> / <i>NRAS</i> / <i>BRAF</i> Wild-Type Microsatellite Stable Metastatic Colorectal Cancer

PURPOSE Panitumumab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), is standard therapy for patients with KRAS/NRAS/BRAF wild-type (WT), microsatellite stable (MSS), metastatic colorectal cancer (mCRC). We hypothesized that the addition of ipilimumab (anti–cytotoxic T-cell lymphocyte-4) and nivolumab (anti-PD1) to panitumumab would increase response rate. METHODS This is a phase II, multicenter, single-arm trial of panitumumab, ipilimumab, and nivolumab in KRAS / NRAS / BRAF WT, MSS mCRC. Eligible patients had received ≥1 previous lines of therapy and no previous anti-EGFR or immune checkpoint inhibitor. Patients received ipilimumab 1 mg/kg IV once every 6 weeks, nivolumab 240 mg IV once every 2 weeks, and panitumumab 6 mg/kg IV once every 2 weeks until progression, toxicity, or patient withdrawal. The primary outcome was overall response rate at 12 weeks. Using a Simon's two-stage design, with null and alternative hypothesis response rates of 22% and 35%, responses in ≥17 patients of 56 would be considered worthy of additional study. RESULTS In 56 patients enrolled between March 2018 and June 2020, the response rate was 32.1% (95% CI, 21.4 to 45.2; n = 18). The median progression-free survival was 6.0 months (95% CI, 5.5 to 7.4), and the median overall survival was 17.4 months (95% CI, 14.2 to 27.5). With a median follow-up of 43.3 months (95% CI, 41 to 55), four patients (10.7%) were alive without progression, including two patients with liver metastases. There was one treatment-related grade 5 myocarditis. The most common treatment-related grade 3 to 4 toxicities included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). CONCLUSION The combination of panitumumab, ipilimumab, and nivolumab demonstrated an acceptable response rate including a signal of durable response even among patients with liver metastases, suggesting activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC.