Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer remains challenging. We conducted a single-arm, non-randomized, Phase 2 trial ( NCT03104439 ) combining radiation, ipilimumab and nivolumab in patients with metastatic MSS CRC (n=40) and PDAC (n=25) with an ECOG performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCR was 25% for CRC (10/40; 95% CI: 13–41%) and 20% for PDAC (5/25; 95% CI: 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (10/27; 95% CI: 19–58%) in CRC and 29% (5/17; 95% CI: 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples, but higher expression of NK cells and the HERVK repeat RNA in patients with disease control. This study provides proof-of-concept of combining radiation with immune checkpoint blockade in immunotherapy resistant cancers.

3514 Background: mCRC remains a lethal cancer and immunotherapy in MSS mCRC has yet to show significant activity. In preclinical models, radiation induced cellular damage may increase responsiveness to immunotherapy via the abscopal effect, with evidence for synergy between radiation therapy (RT) and dual checkpoint blockade. In this study, we assessed dual blockade of CTLA-4 and PD-1 combined with RT as a strategy to stimulate an immune response for patients with MSS mCRC. Methods: In this open-label, single arm phase-2 study, we enrolled 40 MSS mCRC patients (pts). Eligible pts had histologically-confirmed MSS mCRC, ECOG PS 0-1, and progression on at least two lines of therapy. Treatment (Tx) consisted of ipilimumab (1mg/kg q6 weeks), nivolumab (240 mg q2 weeks) and 3 fractions of 8 Gy of RT at cycle 2 every other day. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was Disease Control Rate (DCR), with radiological evaluations every 3 months. Exploratory endpoints included ORR, PFS, OS and safety. Response was defined as disease control outside the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone (cycle 1) and 2 weeks after initiation of radiation. Intention-to-treat analysis (ITT) includes all pts receiving at least one dose of study agent. Results: 40 pts (median age 59 years (26-83), 58% male) enrolled and started treatment from 7/2017 to 12/2018. DCR was 17.5% (7/40) with a 7.5% (3/40) ORR by ITT. Median duration of disease control was 77 days in the ITT; 252 days for those with disease control (n=7) based on the first re-staging scans at 3 months or censored (n=3) and 70.5 days for pts with PD (n=17) or who did not receive RT due to clinical progression (n=13). In the modified ITT (all pts receiving RT and restaged), N=24 pts, excluding 1 pt pending 1st scans post-RT, DCR was 29.2% (7/24) and ORR 12.5% (3/24). Median duration of disease control in mITT was 77.5 days: 252 days for those with disease control and 77 days for those with PD. TRAEs were reported in 22/40 (55%). 20/40 (50%) with grade ≥3 toxicities, with fatigue, nausea, vomiting, diarrhea, infusion-related reaction and dyspnea being the most common. 1(2%) pt died of respiratory failure possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with RT is feasible and demonstrates durable activity in pts with MSS mCRC. There are 3 pts who have not completed RT or had their post-RT re-staging. We will report updated efficacy data and outcomes from correlative serial tumor biopsies upon trial completion. Clinical trial information: NCT03104439.

391 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer. Immunotherapy (IO) has shown minimal activity. In preclinical models, radiation (XRT) increases likelihood of response to IO via an abscopal effect where local tx (treatment) of a tumor leads to an antitumor response distantly, with synergy between XRT and dual checkpoint blockade. In this study, we assessed CTLA-4 and PD-1 blockade with XRT as a strategy to stimulate an immune response for patients (pts) with PDAC. Methods: In this open-label, single arm phase-2 study, we enrolled 25 metastatic PDAC pts in an exploratory cohort. Eligible pts had histologically-confirmed PDAC, ECOG PS 0-1, and progression on at least 1 line of tx. Tx consisted of Ipilimumab (1 mg/kg every 6 wks), Nivolumab (240 mg every 2 wks) and 3 fractions of 8 Gy of XRT at cycle 2. Tx continued until PD, discontinuation or withdrawal. Endpoints include Disease Control Rate (DCR), ORR, PFS, OS and safety. Radiological evaluations were every 3 months. Response was defined as disease control outside of the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone and 2 weeks after XRT. Intention to treat analysis includes all pts receiving at least one dose of study tx. Results: 22 pts were enrolled and evaluable from 6/2017-6/2018, median age 60 years (32-75), 73% male and 100% MSS. DCR was 27% and ORR was 14% with 1 pt having a complete response. All responses were out of the radiation field. Median PFS was 76 days in the entire cohort; 163 days for pts with disease control vs 62.5 days for pts with PD or who came off study prior to initial imaging. 7 pts did not receive XRT due to clinical progression. Treatment-related adverse events (AEs) were reported in 12/22 pts (54.5%). 8/22 pts (36.4%) experienced grade ≥ 3 toxicities. Elevated lipase, lymphopenia, fatigue, hyperglycemia, mucositis and hepatitis were the most common AEs. 1/22 (4.5%) pt had a grade 5 AE possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with XRT is feasible and demonstrates promising activity in pts with metastatic PDAC. We will report the updated efficacy and safety data as well as outcomes from the correlative serial biopsies upon completion. Clinical trial information: NCT03104439.

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