Compugen’s lead candidate, COM701, is a potentially first-in-class immunotherapy targeting PVRIG, a novel immune checkpoint computationally discovered and validated in preclinical studies. Clinical data of COM701, as a monotherapy and in combination with PD-1 blockers, have demonstrated initial signs of antitumor activity, with encouraging disease control rate, durability of responses, and safety and tolerability in patients that have progressed or failed on many prior lines of therapy. COM902 is a therapeutic antibody against the immuno-oncology target TIGIT, a recently validated immune checkpoint. Compugen is ultimately developing COM902 to broaden the clinical potential of its PVRIG inhibitor, COM701 allowing it to comprehensively block the DNAM axis by the parallel inhibition of TIGIT and PVRIG. With wholly owned candidates targeting two of the three pathways involved in its triple pathway hypothesis, both PVRIG and TIGIT, Compugen can maximally control its clinical strategy. 

A proof-of-concept study is evaluating the combination of COM701 with COM902 and pembrolizumab in up to 20 patients with metastatic microsatellite stable colorectal cancer patients who have previously received up to 3 lines of therapy. The study includes patients with liver metastases. The initiation of the study is based on Phase I cohort expansion data reported at SITC 2022, showing anti-tumor activity and potent immune modulation with the combination of COM701 and nivolumab in metastatic MSS CRC patients.

The updated data presented at the ASCO 2024 was as follows: 

• In this Phase Ib expansion cohort of participants with heavily pre-treated advanced MSS-CRC, the majority with liver metastases, the triplet combination of COM701, COM902, and pembrolizumab administered every 3 weeks was well tolerated.

• The safety profile of the triplet combination was generally consistent with that of pembrolizumab and other approved PD-[L]1 inhibitors.

• Exploratory analysis demonstrated antitumor activity: ORR (1/20, 5%), DCR (8/20) 40%, best response of partial response in 1 patient with 3 patients (1PR, 2SDs) remaining on treatment at data cut.

• Pharmacodynamic activation of the immune system in the tumor and blood was observed, supportive of COM701-driven anti-tumor activity. Such activation was not previously reported in MSS-CRC with PD-[L]1 inhibitors.

• Among the cohort reported here and in the prior reported data, COM701 had a clinical benefit, was well tolerated, and induces immune activation in a traditionally immune therapy-resistant population of MSS-CRC.

KOL insights

“Dual blockade of DNAM axis members PVRIG and TIGIT has the potential to expand the number of patients who respond to treatment with immunotherapy” – Expert Opinion.

Conclusion

To conclude, there is a high unmet need for new treatments for patients with metastatic microsatellite stable colorectal cancer, which represents a challenging population to treat. Most patients (~70%) with advanced MSS-CRC have liver metastases and do not respond well to immune checkpoint inhibitor (ICI) therapy. The data presented at the conference is suggestive of COM701-driven effects in this resistant population and may warrant further evaluation of other COM701 drug combinations.