Intravenous oncolytic virus IDOV-Safe in pMMR/MSS metastatic colorectal cancer.

Abstract

3536 Background: Proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC) is largely resistant to immune checkpoint inhibitors, with limited options after standard therapies. IDOV-Safe is a systemically deliverable, vaccinia virus-based oncolytic virotherapy. This phase 1 clinical trial evaluated the safety and preliminary efficacy of intravenous IDOV-Safe combined with toripalimab and fruquintinib in patients with pMMR/MSS mCRC (NCT06380309). Methods: Patients with pMMR/MSS mCRC who had progressed on or were intolerant to ≥2 prior systemic therapies were enrolled. Dose escalation used a 3+3 design across four dose levels (1×10 9 , 3×10 9 , 1×10 10 , and 3×10 10 PFU). In expansion, three combination strategies with immune-target therapy were evaluated: sequential, early, and IO free combinations using fruquintinib with or without toripalimab. Primary endpoints were safety and objective response rate (ORR). Results: Fifty-five patients were enrolled; 80% had received ≥3 prior treatment lines. Dose-limiting toxicities at 1×10 10 PFU led to selection of 1×10 9 and 3×10 9 PFU for expansion. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 62% of patients, most commonly fever, thrombocytopenia, and neutropenia; grade ≥3 immune-related events were infrequent (2%), and no grade ≥3 TRAEs were attributed to fruquintinib. In sequential combination cohorts, objective responses occurred only after initiation of combination therapy. ORR was 33.3% at 1×10 9 PFU (IIA1) and 30.0% at 3×10 9 PFU (IIA2), with disease control rates (DCRs) of 50.0% and 70.0%, respectively. In early combination cohorts, objective responses were observed at 3×10 9 PFU (IIC2; ORR 16.7%), with high DCRs (83.3% in IIC1 and 91.7% in IIC2). The DCR in the IO-free cohort (IID) was 50.0%. Median progression-free survival (mPFS) across five cohorts was 5.4 (IIA1), 8.7 (IIA2), 5.4 (IIC1), 5.5 (IIC2), and 4.6 months (IID). Conclusions: Intravenous IDOV-Safe demonstrated a favorable safety profile and encouraging preliminary antitumor activity when combined with toripalimab and fruquintinib, particularly using a sequential combination strategy in heavily pretreated patients with pMMR/MSS mCRC. Clinical trial information: NCT06380309 . Response to IDOV-safe and immuno-targeted therapy. Response IIA1 1×10 9 IIA2 3×10 9 IIC1 1×10 9 IIC2 3×10 9 IID 3×10 9 Best overall response — n (%) Partial response 2 (33.3) 6 (30.0) 0 2 (16.7) 0 Stable disease (SD) 1 (16.7) 8 (40.0)* 5 (83.3) 9 (75.0) 3 (50.0) Progressive disease 3 (50.0) 5 (25.0) 0 1 (8.3) 2 (33.3) Not evaluable 0 1 (5.0) 1 (16.7) 0 1 (16.7) ORR—Percent (95% CI) 33.3 (4.3, 77.7) 30.0 (11.9, 54.3) 0 16.7 (2.1, 48.4) 0 DCR —Percent (95% CI) 50.0 (11.8, 88.2) 70.0 (45.7, 88.1) 83.3 (35.9, 99.6) 91.7 (61.5, 99.8) 50.0 (11.8, 88.2) *One patient in IIA2 cohort had unconfirmed SD.