Regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy-resistant MSS metastatic colorectal cancer (mCRC)

• Published in: Journal of clinical oncology Vol. 41; no. 4_suppl; p. 110
• Main Authors: Fakih, Marwan, Sandhu, Jaideep Singh, Lim, Dean, Li, Sierra, Wang, Chongkai
• Format: Journal Article
• Language: English
• Published: 01.02.2023
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2023.41.4_suppl.110

110 Background: We recently reported on the activity of regorafenib (R), ipilimumab (I) and nivolumab (N) (RIN) in microsatellite stable (MSS) mCRC. Here, we describe mature efficacy data at the recommended phase 2 dose (RP2D) and the results of a new escalation (ESC) cohort of 40 mg to 80 mg regorafenib. Methods: Patients (pts) with chemotherapy resistant MSS mCRC received RIN at (R) at 80 mg QD x 21 days in 4-week(w) cycle, (I) at 1mg/kg Q6w and (N) at 240 mg Q 2w. If no more than 1 dose limiting toxicity (DLT) was noted in 6 evaluable pts, an expansion cohort was assessed at that dose level. Following RP2D establishment and given the increased rate of transient skin toxicity on cycle (C) 1, the protocol was amended to explore a 10-pt cohort with 40 mg/day (R) on C1 with escalation to 80mg/day on C2+. Results: 39 pts with chemotherapy resistant MSS mCRC were enrolled. 29 pts enrolled on the RP2D and 10 pts at the amended 40 to 80mg cohort. At the RP2D and ESC cohorts, 7 and 3 pts had liver metastases (LM), respectively. No significant clinical activity was noted in LM pts (ORR = 0%, median progression free survival (mPFS) = 2 months (mo)). Overall response rate (ORR), disease control rate (DCR), mPFS, median overall survival (OS) in the 22 pts with non-LM (NLM) pts in the RP2D and ESC cohorts were 36% (41% iRECIST), 68% (82% iRECIST), 5.0 mo (6.0 mo iRECIST), > 22 mo (not reached) and 0%, 57% (71.4% iRECIST), 4 mo (4 mo iRECIST), and > 10 mo (not reached). 6/22 NLM at the P2RD remain without PD at 22 mo and beyond. All 7 NLM pts in the ESC cohort progressed by 7 mo from enrollment. ctDNA (Guardant 360) assays were available at baseline and at 4-6 weeks in 23/39 pts. Early ctDNA clearance was confirmed in 8/17 pts at RP2D (4PR and 4SD > 6 mo; mPFS = 11 mo) and 2/6 pts at the ESC cohort (PFS 4.5 mo and 7mo). An ESC vs. RP2D strategy mitigated skin rash (10% vs. 38% grade (G) 3; 20% vs. 66% any G). Other immune related ≥ G3 toxicities are summarized. Conclusions: RIN (80/1/240) has substantial activity in MSS NLM mCRC patients. An ESC strategy of 40/1/240 to 80/1/240 on C2+ reduced transient skin rash and other immune-mediated toxicities but was associated with less favorable clinical outcome. These data suggest that a starting R dose of 80 mg is important in priming the immune response to RIN. The RP2D of 80/1/240 mg is recommended for further investigation in NLM mCRC. Clinical trial information: NCT04362839 . [Table: see text]