Association between Liver Metastases and Treatment Response in Patients with Metastatic, Microsatellite Stable Colorectal Cancer Treated with Radiation Therapy and Dual Immune Checkpoint Blockade.

PURPOSE/OBJECTIVE(S): Most patients with metastatic colorectal cancer (CRC) have microsatellite stable (MSS) disease with a limited response to immune checkpoint inhibitors (ICIs). In our phase 2 trial (NCT03104439), 27 patients with metastatic MSS CRC received ipilimumab, nivolumab, and RT (24 Gy/3 fractions) on C2D1 with a disease control rate (DCR) of 37% (10/27) and overall response rate (ORR) of 15% (4/27). Our follow up phase 2 study with ipilimumab, nivolumab, and RT moved to C1D1 (NCT04361162) showed a DCR of 33% (10/30) and an ORR of 13% (4/30). Clinical and preclinical data suggest liver metastases are less responsive to systemic ICIs and complementary liver-directed RT can potentially overcome this effect. To address this, we investigated the association between liver metastases and response rates among patients treated with and without liver-directed RT in a pooled analysis of our phase 2 studies of nivolumab and ipilimumab with RT.MATERIALS/METHODS: In this pooled secondary analysis of two open-label, single-arm, phase 2 studies, eligible patients had metastatic MSS CRC, ECOG PS 0-1, and progressed on at least one line of chemotherapy. Treatment consisted of ipilimumab 1 mg/kg q6weeks for 4 cycles, nivolumab 240 mg q2weeks on a 6-week cycle, and RT (24 Gy/3 fractions) on C1D1 or C2D1 to one site. Responses were defined outside of the RT field by RECIST 1.1 with centrally reviewed imaging q3months. ORR/DCR and PFS/OS were compared between patients with and without liver metastases with the Fisher's exact and log-rank tests, respectively. P-values are two-sided.RESULTS: We treated 57 patients (median age 57 years [range, 26-85], 61% male, 88% white, 65% with liver metastases) from 07/2017 to 05/2022. Patients received a median of 3 (range, 1-10) prior lines of systemic therapy. The combined ORR was 14% (8/57; 95% CI, 6-26%) and DCR was 35% (20/57; 95% CI, 23-49%). The ORR was 30% (6/20; 95% CI, 12-54%) in patients without liver metastases and 5% (2/37; 95% CI, 1-18%) in patients with liver metastases (p = 0.017). The DCR was 55% (11/20; 95% CI, 32-77%) in patients without liver metastases and 24% (9/37; 94% CI, 12-41%) in patients with liver metastases (p = 0.040). 76% (28/37) of patients with liver metastases received liver-directed RT including 2/2 (100%) patients with a PR. The ORR was 0% in patients with liver metastases without liver-directed RT. The median PFS was 1.8 months (95% CI, 1.2-2.4 months) and OS was 9.8 months (95% CI, 6.8-12.8). OS was longer in patients without liver metastases (median 13.6 v 6.8 months, p = 0.010) and in patients treated with liver-directed RT among those with liver metastases (median 7.5 months v 4.5 months, p = 0.025).CONCLUSION: Among patients with metastatic MSS CRC treated with ICIs and RT in two phase 2 studies, ORR, DCR, and OS are significantly higher in patients without liver metastases. Liver-directed RT may improve ICI efficacy and OS in patients with liver metastases. Further analysis of PFS and prospective study of ICIs with comprehensive liver-directed RT are warranted.