Phase I study of GUCY2C CAR-T therapy IM96 in patients with metastatic colorectal cancer.

Abstract

2518 Background: The clinical outcomes of metastatic colorectal cancer (mCRC) therapies are limited, especially for liver metastasis. Guanylyl cyclase 2C (GUCY2C) is ectopically expressed in all stages of CRC and intestinally restricted. GUCY2C-targeted CAR-T (IM96) was developed and phase I study was conducted to evaluate the safety and efficacy (NCT05287165). Methods: In this open-label, 3+3 dose-escalation study, IM96 was evaluated in GUCY2C-positive mCRC patients (pts) failed to ≥3 lines of therapies. Pts were pre-treated with fludarabine and cyclophosphamide, and received a single infusion of IM96 at the dose of 3×108 (DL1), 6×108 (DL2), 12×108 (DL3), or 20×108 (DL4) CAR-T cells. Dose-expansion study was performed at DL3. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile. Results: As of December 2023, 20 pts were enrolled and infused with IM96. The follow-up time was 7-19 months for all pts. The median age was 52.5, and 11/20 cases were male. Liver metastasis was found in 11/20 cases (55%), proficient mismatch repair (pMMR) in 20/20 pts (100%), KRAS mutation in 12/20 pts (60.0%), NRAS mutation in 1/20 pts (5.0%), and BRAF mutation in 3/20 pts (15.0%). Bridging therapies were used in 19 pts. Only 1/20 pt (5.0%) showed neurotoxicity and ≥grade 3 cytokine release syndromes (CRS). Grade 1-2 CRS occurred in 16/20 pts (80.0%) with dramatic increase of interleukin-6. Grade 1-3 rash was observed in 14/20 pts (70.0%). Grade 3 diarrhea occurred in 11/20 pts (55.0%), and grade 1-3 oral mucositis appeared in 7/20 pts (35.0%), only in DL2, DL3 and DL4 groups. Dose-limiting toxicity and maximum tolerated dose were not achieved. Among 19 evaluable pts, the disease control rate (DCR) was 73.7%, and the objective response rate (ORR) was 26.3%. In DL3 group, pts showed an ORR of 40.0%, nevertheless of liver metastasis or not. The median progression-free survival time was 7 months, and the median duration of response was 10 months in DL3 group. No responding pts showed disease progression within 6 months. Tumor responses were correlated with significant decreases in carcinoembryonic antigen levels among all pts. Conclusions: This study demonstrated that IM96 has durable efficacy with acceptable safety profile in pMMR mCRC pts, in particularly, showing high therapeutic potential in liver metastasis pts. Clinical trial information: NCT05287165 .