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

Abstract

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. 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. 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). 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.