Phase Ib clinical evaluation of a novel CD55- and FcRn-bioselected RNA oncolytic virus, IVX037, combined with sintilimab (anti-PD-1) in advanced microsatellite-stable colorectal cancer

Background: Oncolytic viruses selectively lyse tumor cells and may potentiate responses to immune checkpoint blockade. Picornaviruses exploit MAPK signalling, to enhance replication and viral protein translation. IVX037 is a bioselected, non-genetically modified oncolytic RNA picornavirus targeting CD55 and FcRn often overexpressed in colorectal cancer (CRC) and enriched in KRAS/BRAF-mutated tumors. IVX037 exhibits selective lytic activity and multicycle replication in CRC models, with potentially enhanced oncolysis in KRAS/BRAF-mutant cells through MAPK-mediated increases in viral RNA replication, virion assembly, lytic release, and upregulation of CD55 and FcRn. This Phase Ib study evaluated intratumoral (IT) IVX037 combined with sintilimab in advanced MSS-CRC. Methods: Pts with MSS-CRC (n=15) received up to seven IT doses of IVX037 (~3×10⁸ TCID₅₀) every 2 weeks plus IV sintilimab every 3 weeks. MAPK pathway alterations were determined by NGS. Serial serum samples were analysed for CEA, anti-IVX037 neutralizing antibodies (nAbs), and systemic viral RNA (qPCR). Viral shedding was assessed via urine, faeces, throat swabs and injection-site samples. Pts receiving ≥3 IVX037 doses and ≥2 sintilimab doses were evaluable for efficacy. Results: Of the 15pts, 13 were response evaluable, including 4 pts with KRAS and 3 with BRAF mutations. Both injected and non-injected lesions were designated as target lesions. The overall target lesion disease control rate (DCR) was 38.5% (5/13). KRAS/BRAF-mutated pts achieved a higher DCR of 71.4% (5/7) in target lesions. Among evaluable pts, 92.3% (12/13) received liver lesion directed injections. The DCR of individual target liver lesions was 43% (9/21) compared to 52.6% (10/19) of non-liver target lesions. KRAS/BRAF-mutated liver target lesions achieved a DCR of 72% (8/11). Abscopal activity was demonstrated in non-injected visceral disease (liver, lung and lymph nodes). Rapid, extensive necrosis was observed in BRAF V600E-injected lesions in 3 of 3 pts. CEA reductions correlated with best lesion responses. qPCR confirmed systemic exposure to IVX037 in all pts at 1hr post-injection and persistence in 9 of 15 pts at day 8, suggesting multi-cycle viral replication. Three pts showed baseline evidence of natural prior exposure (nAb >1:16); all developed nAbs by day 29. Low-level transient faecal viral shedding occurred in some pts; none was detected in urine or throat swabs. Treatment was well tolerated with no grade ≥3 TRAEs. Conclusions: IT IVX037 plus sintilimab was well tolerated and demonstrated biological and clinical activity in MSS-CRC, including responses in injected lesions and abscopal activity in non-injected visceral disease. Enhanced activity in KRAS/BRAF-mutant tumors supports a MAPK-driven mechanism increasing viral replication/lysis and receptor expression. IVX037 systemic detectability and persistence, nAb induction confirm viral engagement and potential tumor immune activation. Such findings support continued development of IVX037 and justify enrichment of KRAS/BRAF-mutant MSS-CRC cohorts in ongoing trials.