Dr Khushman on the Rationale for Investigating INCA33890 in MSS/pMMR mCRC

“This trial [is asking] a clinically clean question: Does adding INCA33890 improve outcomes beyond an active standard regimen, rather than just replacing an effective therapy?”

Moh’d Khushman, MD, an associate professor of medicine in the Division of Oncology at Washington University School of Medicine in St. Louis and a gastrointestinal medical oncologist at Siteman Cancer Center, discussed the mechanistic rationale for and design of the phase 3 INCA033890-303 trial (NCT07284849) evaluating the bispecific antibody INCA33890 in combination with FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) and bevacizumab (Avastin) in patients with microsatellite stable (MSS)/mismatch repair–proficient (pMMR) metastatic colorectal cancer (mCRC).

What distinguishes INCA33890 from a combination regimen of a systemic TGF-β inhibitor plus a checkpoint inhibitor is its bispecific design, Khushman explained. The antibody targets both PD-1 and TGF-β receptor 2; it is designed to inhibit TGF-β receptor 2 signaling preferentially in PD-1–positive immune cells but spare PD-1–negative cells from broad TGF-β inhibition. That targeted approach is intended to preserve antitumor immune effects and potentially avoid some of the toxicity that has complicated previous attempts to therapeutically inhibit the TGF-β pathway, he noted.

FOLFOX plus bevacizumab is a well-established first-line treatment approach for patients with unresectable MSS/pMMR mCRC, Khushman said. This phase 3 trial is investigating whether adding INCA33890 to this regimen improves outcomes. According to Khushman, chemotherapy induces tumor cytoreduction and antigen release, bevacizumab targets VEGF-mediated angiogenesis and immune suppression, and INCA33890 is designed to target both PD-1– and TGF-β–mediated suppression of antitumor immune cells.

Trial investigators are randomly assigning patients 1:1 to receive 1 of 2 regimens: INCA33890 in combination with FOLFOX plus bevacizumab, or FOLFOX plus bevacizumab and placebo, Khushman said. The primary end point is progression-free survival, and a key secondary end point is overall survival. Additional end points include overall response rate, duration of response, safety, tolerability, and patient-reported outcomes. Randomization is stratified by tumor sidedness and the presence of liver metastases, as well as PD-L1 score, Khushman concluded.

This content was supported in part by Incyte. Content independently developed and published by OncLive.