Irinotecan plus anlotinib or further in combination with penpulimab as second-line treatment of metastatic colorectal cancer (ZL-IRIAN).

3570 Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/ microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m 2 d6, q2w) (n=23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m 2 d6, q2w) + penpulimab (200mg, d6, q2w) (n=23). Pts were initially enrolled in Cohort A. If the ORR in Cohort A was ≥15% (at least four patients in Cohort A reached CR/PR), the enrollment of Cohort B started. The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. Results: A total of 23 Pts were enrolled in A cohort from March 9 2022 to December 3 2023. With an ORR of 39.1% (9/23) and DCR of 87.0% (20/22), the median PFS was 9.57 months (95% CI 5.24-13.90 months), and the 6-month and 12-month PFS rates were 70.9% and 38.2%, respectively. Pts in B cohort were enrolled from October 25 2022 to November 22 2023, a total of 23 pts were enrolled, 2 pts withdrew their informed consent before treatment and 21 pts received at least one dose of treatment. ORR of 21 pts was 42.9% (9/21), and the DCR was 90.5% (19/21). The median PFS had not reached, with the 6-month and 12-month PFS rates as 70.7% and 55%, respectively. Safety profile indicated that 65.2% (15/23) and 57.1% (12/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Conclusions: The combination of anlotinib with irinotecan +/- PD-1 blockade in second-line treatment for mCRC had shown promising efficacy and good safety. Whether PD-1 blockade could bring extra survival benefits required longer follow-up. Clinical trial information: NCT05229003 .