Long-term follow-up results of ipilimumab and nivolumab for the treatment of mismatch repair deficient locally advanced rectal cancer.

Abstract

e15652 Background: Mismatch repair deficient (dMMR) colorectal cancers have unique biology and responses to therapy. In the advanced setting, first line immunotherapy has superior activity compared to chemotherapy. Recent studies have demonstrated improved responses with neoadjuvant anti-PD1 therapy for dMMR locally advanced rectal cancer (LARC). In this study, we review our experience with the combination of ipilimumab (ipi) and nivolumab (nivo) for the treatment of dMMR LARC. Methods: Patients (pts) with dMMR LARC treated with ipi/nivo at the University of Wisconsin Carbone Center were identified under an IRB-approved protocol. Baseline demographics, molecular testing, treatment history, clinical imaging, and pathological evaluations were collected and summarized. Pts were followed with serial imaging (CT/MRI), endoscopic evaluations, and ctDNA MRD assays. Results: Fours pts (median age: 63 [range: 59-68]; 50% female) with dMMR LARC treated with ipi/nivo were identified. 3 pts had T4 tumors and were node positive. 1 patient had a mutation in MSH6, 1 patient had 2 mutations in MSH2, another had loss of MLH1/PMS2 on IHC, and the last patient had loss of MSH2/MSH6 on IHC. None of the patients have known germline variants. 2 patients were treated initially with FOLFOX chemotherapy and had progressive disease prior to conversion to ipi/nivo. Median follow-up is 25.5 months [range: 9-42] and 1 pt continues on nivo treatment. Pts were treated with 1-4 infusions of ipi and 2-24 months of nivolumab. All patients achieved a complete clinical/pathologic response and remain without evidence of disease recurrence. None of the pts required additional surgery or radiation therapy for cancer recurrence/progression. 3 of the 4 patients developed grade 3/4 immune-related adverse events, including 2 patients with adrenal insufficiency and 1 patient with immune hepatitis. 1 pt developed a fibrotic stricture at the site of the prior cancer requiring resection. Conclusions: dMMR LARC is a unique subtype of rectal cancer sensitive to combination immunotherapy with high potential for complete responses and organ preservation. The use of ipi/nivo in this cohort of pts resulted in complete pathogenic responses for all that remain durable over an extended period of time, though with increased immune-related adverse events compared to anti-PD1 therapies alone. This regimen is currently being studied further in prospective studies.