Early-Phase INCA33890 Data Lay the Foundation for Phase 3 Combination Research in MSS CRC

Early-phase, single-agent activity with INCA33890 produced durable objective responses in heavily pretreated patients with microsatellite stable (MSS) colorectal cancer (CRC) and supports the advancement of the agent into the phase 3 NEXERA-303/INCA033890-303 trial (NCT07284849), which is testing INCA33890 plus FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and bevacizumab (Avastin) vs chemotherapy alone in the first-line metastatic setting, according to Moh’d Khushman, MD.

In the phase 1 INCA33890-101 trial (NCT05836324), INCA33890 monotherapy produced an objective response rate (ORR) of 15.2% among patients with MSS CRC treated at the recommended doses for expansion (n = 105), including ORRs of 12.0% among those with liver metastases (n = 9) and 23.3% among those without.¹ At doses of 900 mg or less every 2 weeks, the drug was generally well tolerated, with the most common treatment-related adverse effects (fatigue, pruritus, and infusion-related reactions) occurring at rates below 15%.

NEXERA-303 is currently enrolling patients at least 18 years of age with stage IV colorectal adenocarcinoma that is not amenable to curative resection and who have received no prior systemic therapy for unresectable or metastatic disease.^2,3

“[Positive data from NEXERA-303] would be a big deal,” Khushman said in an interview with OncLive®. “They would be practice-changing, with a major implication: immunotherapy could move into first-line treatment for MSS mCRC. This is a population [in which] checkpoint inhibition has historically had limited activity, so it would represent a major expansion of immunotherapy to this cohort of patients. The NEXERA-303 trial is an important trial that we need to follow. It addresses an unmet need, and if it’s positive, it will be practice-changing. INCA33890 is a novel compound. I look forward to seeing how the results look, as well as the [results of] other studies that are ongoing.”

In the interview, Khushman discussed the mechanism of action of INCA33890, the rationale for targeting the TGF-β pathway in MSS CRC, phase 1 safety and efficacy findings with this agent, the design and eligibility criteria for NEXERA-303, and where emerging bispecific antibodies and biomarker-driven approaches may address remaining unmet needs in this disease.

Khushman is a professor of medicine in the Division of Medical Oncology at Washington University School of Medicine and a member of the Siteman Cancer Center in St. Louis, Missouri.

OncLive: What is the mechanism of action of INCA33890, and what makes this agent unique in the CRC treatment paradigm?

Khushman: What makes INCA33890 conceptually different from simply combining a systemic TGF-β inhibitor with a checkpoint inhibitor is its bispecific design. It targets both PD-1 and TGF-β receptor 2 and is designed to inhibit TGF-β receptor 2 signaling preferentially in PD-1–positive immune cells while sparing 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.

What was the rationale for investigating INCA33890 in patients with MSS CRC?

The fundamental challenge is that most patients with mCRC that is mismatch repair proficient [pMMR]/MSS have historically derived little benefit from conventional PD-1/PD-L1 blockade. One potential mechanism [for managing this disease] is an immunosuppressive, immune-excluded microenvironment driven in part by TGF-β signaling that suppresses T-cell proliferation and effector function. That’s the rationale for combining this compound with chemotherapy and bevacizumab.

What safety and efficacy data have been previously reported in the phase 1 INCA33890-101 study?

INCA33890 monotherapy in heavily pretreated patients with MSS mCRC demonstrated both efficacy and safety. The ORR in all patients was 15.2%.¹ Responses occurred even in patients with active liver metastases, a population in which immunotherapy approaches in MSS CRC have generally been challenging. In this population, the ORR was 12.0%, which is encouraging, especially with monotherapy, and the responses appear to be durable. Regarding safety, at doses of 900 mg or less every 2 weeks, the drug was generally well tolerated; higher doses were associated with more toxicity, but this dose was generally described as well tolerated.

What is important to note about the design and rationale of the NEXERA-303 trial?

FOLFOX plus bevacizumab is a well-established first-line treatment approach in patients with unresectable, pMMR/MSS mCRC. This trial asks a clinically clean question: Does adding INCA33890 improve outcomes beyond an active standard regimen, rather than just replace an effective therapy? Conceptually, chemotherapy can provide tumor cytoreduction and antigen release. Bevacizumab targets VEGF-mediated angiogenesis and immunosuppression. INCA33890 is designed to target both PD-1– and TGF-β–mediated suppression of antitumor cells. That’s the rationale for combining INCA33890 with FOLFOX and bevacizumab.

This is a randomized, 1:1 comparison between INCA33890 in combination with FOLFOX and bevacizumab, given every 2 weeks, vs FOLFOX plus bevacizumab and placebo. The primary end point is progression-free survival, and a key secondary endpoint is overall survival. Other end points include ORR, duration of response, safety, tolerability, and patient-reported outcomes. Randomization is stratified by tumor sidedness; presence of liver metastases, which many of us would be looking for; and PD-L1 score.

What NEXERA-303 enrollment criteria should colleagues keep in mind?

Patients should have stage IV colorectal adenocarcinoma and pMMR/MSS status. They should have measurable disease, an ECOG performance status of 0 to 1, and have received no prior systemic treatment in the metastatic setting. Prior neoadjuvant or adjuvant therapy is permitted as long as recurrence did not happen within 12 months.

A few things to emphasize about the exclusion criteria: patients with BRAF V600E-mutant disease are excluded, and MSI-high or dMMR status is exclusionary. Other exclusions include untreated or progressing central nervous system metastases, prior treatment with a checkpoint inhibitor, and tumors known to invade or encase major blood vessels because of the risk of potential bleeding.

What other TGF-β/PD-L1 bispecific antibodies are in development?

There is another molecule, SHR-1701. It’s a bifunctional PD-L1/TGF-β fusion protein, and I look forward to seeing how it develops over time. There are also other bispecific antibodies in development and in trials. One targets VEGF with either PD-1 or PD-L1, which is an interesting drug to watch develop over time. Others that are in development target EGFR [and] MET or LGR5. I look forward to seeing how those results come about. All of those studies will likely challenge the current standard of care, so the future will be bright if those studies come back positive.

What remaining unmet needs for patients with CRC should future research address?

If you divide patients into early-stage and late-stage disease, in early-stage disease, I would like to see how we can use circulating tumor DNA to select treatment. As of now, especially with perioperative treatment, we give treatment to most patients; I would like to limit that cohort to patients who truly need it. Additionally, in patients with stage IV disease, I’d like to see more molecular targets that can be addressed with hopefully novel, effective, and safe drugs.

Editor’s Note: This interview has been edited for length and clarity.

References

1. Incyte announces phase 1 results for its TGFβR2×PD-1 bispecific antibody in advanced colorectal cancer and KRAS G12D inhibitor in advanced pancreatic ductal adenocarcinoma. Incyte. News release. October 19, 2025. Accessed October 16, 2026. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-phase-1-results-its-tgfbr2pd-1-bispecific/
2. A study to evaluate the efficacy and safety of standard-of-care chemotherapy and bevacizumab with or without INCA33890 in the first-line treatment of metastatic microsatellite stable colorectal cancer. ClinicalTrials.gov. Updated July 17, 2026. Accessed October 16, 2026. https://clinicaltrials.gov/study/NCT07284849
3. Morris VK, Donate MC, Seligmann J, et al. INCA033890-303: A randomized, double-blind, phase 3 study of FOLFOX and bevacizumab with or without INCA33890 in the first-line treatment of metastatic microsatellite-stable colorectal cancer. J Clin Oncol. 2026;44(suppl 16):TPS3683. doi:10.1200/JCO.2026.44.16_suppl.TPS3683