Fruquintinib and pirfenidone in combination with anti-PD-1 antibody in pMMR/MSS metastatic colorectal carcinoma: A prospective, single-arm, phase Ib/II trial.

123 Background: The combination of fruquintinib and anti-PD-1 has synergistic anti-tumor effects. However, liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Our previous study had proved that anti-fibrotic agent pirfenidone combined with anti-PD-1 can enhance the therapeutic efficacy of liver metastasis by remodeling the immune microenvironment (Hepatology. 2022;76(4) ). The study aimed to assess the safety and efficacy of PD-1 antibody and pirfenidone in combination with fruquintinib in the treatment of patients with pMMR/MSS mCRC. Methods: This is a single-arm, open-label, single-center phase Ib/II study. Patients with pMMR/MSS mCRC who had received at least 2 lines of treatment were included. Enrolled patients received anti-PD-1pucotenlimab (200mg q3w iv), fruquintinib (3mg po qd) and pirfenidone (d1-d14: 200mg po tid; d15-d29: 400mg po tid; d30-PD: 600mg po tid). The primary endpoint is the progression-free survival (PFS). The secondary endpoints include disease control rate (DCR), objective response rate (ORR), overall survival (OS) rate, safety, and molecular biomarker. Results: 25 patients were included and 24 in the efficacy analysis. The median age was 59.5 years, 15 patients (62.5%) were men, 19 (79.2%) had a left-sided tumor, 10(41.7%) had RAS/BRAF mutations, and 13 (54.2%) had received≥3 prior lines of systemic therapy. Notably, 16 patients (66.7%) had liver metastases, including 9 patients (37.5%) with 5 or more hepatic metastatic lesions. Median study follow-up was 8.3 months, median PFS was 5.9 months. Among patients with peritoneal metastasis, the median PFS was 2.5 months, compared to 7.3 months in those without peritoneal metastasis (p < 0.05). The partial response (PR) rate was 12.5% (n=3), the stable disease (SD) rate was 66.7% (n=16), and the progressive disease (PD) rate was 20.8% (n=5). Secondary endpoints include an ORR of 12.5% and a DCR of 79.2%. Interestingly, the DCR of liver metastasis patients was higher than that without liver metastasis (81.3% vs 62.5%). The most frequent TEAEs included hypertension (41.7%), fatigue (41.7%), arthralgia (33.3%), elevated aminotransferases (25%) and poor appetite (25%). Grade 3-4 TEAEs were hypertension (n=3, 12.5%) and elevated aminotransferases (n=2, 8.3%). Conclusions: Our study suggests that the combination of PD-1 antibody, pirfenidone, and fruquintinib could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer, especially for liver metastases. Clinical trial information: NCT06484153 .