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.

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body’s natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.