423P Fruquintinib plus sintilimab in refractory repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Preliminary clinical results and biomarker analyses from a phase II study

Addition of immune checkpoint inhibitor to anti-angiogenesis inhibitors is expected to have the potential to improve efficacy in pMMR/MSS refractory mCRC. This study aimed to evaluate the efficacy and safety of fruquintinib plus sintilimab in refractory mCRC, and to explore the potential biomarker associated with efficacy and prognosis. This is a prospective, single arm phase II trial (NCT04695470). Patients with pMMR/MSS mCRCs who had failed with at least 2 lines of standard therapy including bevacizumab were treated with fruquintinib (5mg/day, orally, d1-14, Q3w) plus sintilimab (sintilimab 200mg, intravenous infusion, d1, Q3w). The primary endpoint was the 6-month PFS rate, and secondary endpoints included ORR, PFS, OS and safety, with biomarker analyses from ctDNA being the exploratory endpoint. Between Sep 18, 2020 and Apr 19, 2022, 55 patients (pts) were enrolled. 43 pts with a follow-up time of at least 3 months (median 9.8 m) were included in this analysis. The median age was 57 (IQR, 34-73); 69% were male. 7 pts achieved PR and 26 achieved SD, the ORR was 16% (95% CI, 7%-31%), and DCR was 77% (95% CI, 61%-88%). Pts with liver metastases had lower ORR than those without (7.1% vs 33.3%, P=0.0398). The 6-month PFS rate was 31% with a median PFS of 4.1 m and an estimated OS of 13.3 m, respectively. The present of liver metastasis was associated with shorter PFS (4.1 vs 6.4 m, P=0.0364). The most common adverse events were proteinuria (53.4%), palmar-plantar erythrodysesthesia syndrome (46.5%) and hypothyroidism (37.2%). 18.6% of the pts had grade 3 or 4 treatment-related adverse events. The median bTMB was 11.35 muts/Mb (IQR: 5.03-177.85muts/Mb). No statistically significant differences in ORR and PFS were observed according to bTMB status. Three pts with MYC amplification in ctDNA seemed to have worse PFS (1.3 m, 1.3 m, 2.1 m) and OS (3.0 m, 3.7 m, 5.4 m). Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in refractory MSS mCRC. MYC amplification identified by ctDNA sequencing seemed to associate with poor prognosis, which warrants future study.