Proof of concept of the abscopal effect in MSS GI cancers: A phase 2 study of ipilimumab and nivolumab with radiation in metastatic pancreatic and colorectal adenocarcinoma

Abstract

Introduction: Metastatic PDAC and CRC remain lethal malignancies and except in MSI, immunotherapy has not shown significant activity. Preclinical data demonstrated that radiation (RT) increases the likelihood of response to immunotherapy via the abscopal effect where local treatment of tumor leads to distant response, with synergy between RT and dual checkpoint blockade. We assessed dual CTLA-4 and PD-1 blockade with RT to stimulate an immune response for patients (pts) with metastatic MSS PDAC and CRC. Method(s): In this open-label, single arm phase 2 study, we enrolled 25 PDAC and 40 MSS mCRC pts. Eligible pts had histologically-confirmed PDAC or MSS mCRC, ECOG PS 0-1, and progression on at least one line of previous therapy for PDAC and two lines for CRC. Treatment consisted of ipilimumab (1 mg/kg every 6 weeks), Nivolumab (240 mg every 2 weeks) and 3 fractions of 8Gy of radiation at cycle 2 every other day. Treatment continued until progression, discontinuation or withdrawal. The primary endpoint was the Disease Control Rate (DCR) in CRC. Exploratory include DCR in PDAC, ORR, PFS, OS, and safety. Imaging was done every 3months. Responses defined as disease control outside the radiation field. Intention to treat (ITT) analysis includes all patients receiving at least one dose of study treatment. Result(s): 40 CRC (median age 59 yrs (range 26-83), 58% male) and 25 PDAC pts (median age 60 yrs (range 32-75), 72% male) were enrolled and started treatment from 6/2017 to 12/2018. MSS CRC DCR was 25% (10/40) with a 10% (4/40) ORR by ITT. Median duration of disease control (DC) was 82 days in the ITT. 315 days for those with DC (n=10) based on best response or censored (n=2) and 75.5 days for pts with PD (n=15) or who did not receive RT due to progression (n=13). In the modified ITT (mITT), all patients receiving RT and restaged, N=27 patients, excluding 2 pt pending 1st scans post-XRT, DCR was 40% (10/25) and ORR 16% (4/25). Median duration of DC in mITT was 143 days: 252 days for those with DC and 82 days with PD. PDAC DCR was 20% (5/25) with a 13% (3/25) ORR by ITT. Median duration of DC was 126 days in the ITT cohort; 177 days for those with disease control (n=5) and 111 days for pts with PD (n=12) or who did not receive RT due to progression (n=8). In the mITT, N=16 patients DCR was 31% (5/16) and ORR 19% (3/16). Median duration of DC in mITT was 105 days: 177 days with DC and 92 days with PD. Treatmentrelated adverse events were reported in 35/65 pts (53.8%). 26/65 pts (40%) experienced grade>=3 toxicities, with fatigue, nausea, and lymphocyte count decrease being the main adverse events. 2 (3.1%) pts experienced a grade 5 adverse event probably/possibly related to treatment. Conclusion(s): Dual blockade of CTLA-4 and PD-1 with RT is feasible and demonstrates promising activity in patients with advanced MSS CRC and PDAC. Updated efficacy data and outcomes from correlative serial biopsies will be reported subsequently.