Abstract 2257: Phase II study of dual immune checkpoint blockade (ICB) with durvalumab (Durva) plus tremelimumab (T) following palliative hypofractionated radiotherapy (SBRT) in patients (pts) with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing on chemotherapy: NSABP FC-9
Authors: Lee James J. , Yothers Greg , George Thomas J. , Fakih Marwan G. , Mallick Atrayee Basu , Mitchell Edith P. , Wade James L. , Krauss John C. , Kayaleh Omar R. , Heron Dwight E. , Allegra Carmen J. , Lipchik Corey , Feng Huichen , Joy Marion , Srinivasan Ashok , Pogue-Geile Katherine L. , Lucas Peter C. , Warren Sarah E. , Cesano Alessandra , Jacobs Samuel A. 
Published: August 2019

Abstract
Background
Monotherapy with ICB has not been effective in MSS mCRC. Preclinical data demonstrate that immunomodulators synergize with radiotherapy (RT) resulting in tumor regression at irradiated sites and rarely at non-irradiated sites. Anecdotal reports in pts have confirmed an abscopal effect of RT and ICB. This phase II, open-label, single-arm study is testing dual ICBs following SBRT in pts with MSS mCRC who have progressed on chemotherapy. We report here efficacy and safety results.
Methods
Eligible pts have: MSS mCRC, progressed on prior oxaliplatin and irinotecan-based regimens, measurable lesions with at least one amenable to SBRT and another for core biopsy, and performance status &lt;2. Following 3 doses of SBRT at 9 Gy daily (D −2, −1, and D 0 prior to Cycle 1), pts received the combination of T (75 mg IV infusion) and Durva (1500 mg IV infusion) on D 1 of Cycles 1-4. Beginning with Cycles 5-12, pts received Durva alone on D 1 q 28d. Pts were considered evaluable using RECIST 1.1 if a tumor response at non-irradiated target lesions was measured at baseline and after 2 cycles. Subsequent scans were performed every 8 wks. Toxicity was graded according to NCI CTCAE v4.0. Primary aim is to determine overall objective response rate (ORR) in non-irradiated metastasis. Secondary aims are clinical benefit rate, duration of response, tolerability, and correlates of response. Archived and fresh tumor biopsies were obtained at study entry and after cycle 2, blood samples were collected before treatment, at cycle 1 D 15, and on D 1 of cycles 2, 4, and 6.
Results
FC-9 is open at six academic centers. From October 2017 to November 1, 2018, 33 pts enrolled with 20 pts evaluable. Median age was 58 y (range, 37-71). Toxicity was assessed without regard to attribution. One pt had grade 5 unexplained sudden death (3%); two had grade 4 (6%, colitis, dehydration, pneumonitis); and 12 had grade 3 (38%, primarily GI, other than colitis, and nutrition). Partial responses were seen in 2 pts lasting 44 wks and 44+ wks; two pts had stable disease of 12 and 16 wks duration. Correlative studies will be presented including PD-L-1 expression, CD8+ T cell infiltration into tumor tissues, and gene expression of immune pathways.
Conclusions
The combination of SBRT and dual immunotherapy was safe and well tolerated following immunotherapy standard guidelines. In this refractory group of MSS mCRC pts, we observed 2 partial responses of 44 and 44+ wks among 20 evaluable pts. Correlative analyses will be presented.
Support: Astra-Zeneca; NSABP Foundation, Inc.
Citation Format: James J. Lee, Greg Yothers, Thomas J. George, Marwan G. Fakih, Atrayee Basu Mallick, Edith P. Mitchell, James L. Wade, John C. Krauss, Omar R. Kayaleh, Dwight E. Heron, Carmen J. Allegra, Corey Lipchik, Huichen Feng, Marion Joy, Ashok Srinivasan, Katherine L. Pogue-Geile, Peter C. Lucas, Sarah E. Warren, Alessandra Cesano, Samuel A. Jacobs. Phase II study of dual immune checkpoint blockade (ICB) with durvalumab (Durva) plus tremelimumab (T) following palliative hypofractionated radiotherapy (SBRT) in patients (pts) with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing on chemotherapy: NSABP FC-9 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2257.