NEXERA-303 Trial Aims to Bring TGFβR2×PD-1 Bispecific Antibody INCA33890 Into First-Line MSS CRC

INCA33890, an investigational bispecific antibody that targets TGF-β receptor 2 (TGFβR2) and PD-1, may extend an immunotherapy-based option into the first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a population that has historically derived little benefit from checkpoint blockade, according to Aparna R. Parikh, MD, MS.

The phase 3 NEXERA-303 trial (NCT07284849) is randomly assigning approximately 700 patients with previously untreated, MSS mCRC 1:1 to receive INCA33890 or placebo, each added to FOLFOX and bevacizumab (Avastin), building on phase 1 data with INCA33890 monotherapy in patients with MSS CRC.¹

“TGF-β has been an axis that has been explored across many solid tumor types, not just CRC, and it has not been without difficulty,” Parikh said in an interview with OncLive^®. “This bispecific antibody is a bit different in terms of how it works compared with previous TGF-β–targeted agents, and that unique mechanism is what is now showing us that there may be an opportunity [for these agents] to have efficacy in mCRC.”

Parikh discussed the rationale for pairing TGF-β and PD-1 blockade in MSS CRC, detailed findings with INCA33890 from a phase 1 trial (NCT05836324), and outlined what the NEXERA-303 trial may mean for patients with previously untreated disease.

Parikh holds academic appointments at Harvard Medical School, where she is an associate professor of medicine, and at Massachusetts General Hospital Cancer Center in Boston, Massachusetts, where she directs the Global Cancer Care Program and the Colorectal Medical Oncology Research Program.

What is the rationale for targeting TGF-β and PD-1 together in MSS CRC?

MSS CRC is considered immunologically “cold” and has shown little response to single-agent checkpoint inhibition, in contrast to the durable responses seen with PD-1 blockade in mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) disease. Multiple combination strategies pairing PD-1 inhibitors with other checkpoint blockers or targeted agents have failed to overcome this resistance, leaving first-line treatment anchored to cytotoxic chemotherapy with or without bevacizumab.

Parikh attributed that resistance to a TGF-β–driven physical and immunologic barrier within the tumor microenvironment.

“TGF-β is overexpressed in the tumor microenvironment of cold tumors like MSS CRC. We think it activates what are called cancer-associated fibroblasts, and these cancer-associated fibroblasts tend to deposit dense physical collagen barriers around the tumor that traps the T cells outside of the tumor matrix,” she said. “[It employs] this synergistic...dual-route immunosuppression where you have the PD-1/PD-L1 pathway exhausting infiltrating T cells and causing immune escape, and then you have the TGF-β pathway that activates other pathways and upregulates suppressive pathways. This bispecific platform is hitting both networks simultaneously, neutralizing the TGF-β while also unleashing the T cells to promote tumor cell lysis.”

INCA33890 is designed with that dual mechanism in mind. Rather than blocking TGF-β broadly, it is engineered to concentrate TGFβR2 inhibition on PD-1–positive T cells.

“One of the distinctions with this molecule is to focus on TGF-βR2 in the PD-1–positive cells, sparing the PD-1–negative cells from the TGF-β inhibition, and perhaps this might mitigate [some] toxicity,” Parikh said.

Several PD-1/VEGF bispecific antibodies are also advancing rapidly toward first-line MSS CRC, alongside KRAS-targeted agents moving into earlier lines of therapy, making the TGF-β/PD-1 axis one of several immunotherapy approaches now being tested against a historically chemotherapy-only population.²

What have phase 1 data shown with INCA33890 in MSS CRC?

The first-in-human phase 1 trial of INCA33890 enrolled patients with advanced solid tumors, including a monotherapy dose-escalation and dose-expansion program that spanned doses of 100 mg to 1500 mg intravenously every 2 weeks, or 900 mg every 4 weeks; the regimens carried into dose expansion were 300 mg, 600 mg, and 900 mg every 2 weeks.¹ As of the July 25, 2025, data cutoff, 260 patients had been enrolled.

In the MSS CRC cohort treated at the recommended dose-expansion regimens (n = 105), of whom 93.3% had received more than 2 prior lines of therapy and 71.4% had active liver metastases, 16 patients responded (14 confirmed), for a confirmed overall response rate (ORR) of 15.2% and a median duration of therapy of 7.3 months. Response rates diverged by liver involvement. In patients with liver metastases, the ORR was 12.0%, and the disease control rate (DCR) was 20.0%. In patients without liver metastases, the ORR was 23.3%, and the DCR was 50.0%. Across all 260 enrolled patients, the safety findings were consistent with what has been reported for other approved checkpoint inhibitors, including a similar pattern of immune-related adverse effects (AEs); the most common treatment-related AEs at the recommended dose-expansion regimens (n = 239) were fatigue (13.8%), pruritus (8.8%), and infusion-related reactions (8.4%).

“From the safety perspective, [there was] nothing that stood out that you might otherwise not expect from just immunotherapy [in terms of] immune-related AEs. And then from the efficacy standpoint, [INCA33890 showed] activity in a large number of patients, in those without liver metastases, where we’ve seen some immuno-oncology agents work, but also in those with liver metastases, which is encouraging,” Parikh said.

A combination cohort of INCA33890 at 900 mg every 2 weeks plus standard-of-care chemotherapy and bevacizumab in patients with MSS CRC also completed dose escalation with no dose-limiting toxicities identified, supporting the regimen that NEXERA-303 now carries into the first-line setting.

How is the NEXERA-303 trial designed?

NEXERA-303 is a randomized, double-blind, trial that is randomly assigning approximately 700 patients with stage IV, mismatch repair–proficient (pMMR) and MSS colorectal adenocarcinoma not amenable to curative resection 1:1 to receive INCA33890 or placebo, each combined with FOLFOX and bevacizumab administered every 2 weeks.^2,3 Eligible patients must have measurable disease, an ECOG performance status of 0 or 1, and received no prior systemic treatment for unresectable or metastatic disease; prior neoadjuvant or adjuvant therapy is permitted if recurrence occurred more than 12 months after its completion. Exclusion criteria include BRAF V600E–mutant tumors, MSI-high/dMMR status, untreated or progressing central nervous system metastases, prior exposure to a checkpoint inhibitor, and tumors that invade or encase major vasculature. Randomization is stratified by tumor sidedness, liver metastasis status, and PD-L1 score, and the trial is enrolling internationally. The primary end point is investigator-assessed progression-free survival, the key secondary end point is overall survival, and additional secondary end points include ORR, duration of response, safety, tolerability, and patient-reported outcomes.

Parikh pointed to the chemotherapy backbone as essential to translating the phase 1 signal into first-line benefit.

“With immunotherapy alone, you need the cytotoxic chemotherapy to really harness the ability to get the maximum cytoreduction,” she explained. “Immunotherapy for patients with metastatic disease alone is probably not going to be sufficient. There are some data showing that bevacizumab may synergize with the...PD-L1 pathway as well, so mechanistically, there’s a lot of rationale for combining the immunotherapy with bevacizumab, but the chemotherapy component is probably crucial to get the tumor response [patients] need.”

Regarding enrollment criteria, Parikh characterized the trial as following standard eligibility for the population.

What could INCA33890 mean for the MSS CRC treatment paradigm?

If NEXERA-303 data are positive, Parikh framed the result as a long-awaited entry point for immunotherapy in first-line MSS CRC, set against a crowded field of competing approaches.

“It would be amazing to be able to offer an [immuno-oncology] option in the first-line setting,” she emphasized. “We’ll have to see how that stands in the context of all the PD-1/VEGF first-line clinical trials that are going on right now. It’s a competitive landscape, and many trials that are ongoing could change the landscape. If there are a couple positive trials with [agents with] different mechanisms [of action], now even with targeted therapies with the different KRAS inhibitors coming to the first-line setting, the hope is that we’ll have plenty of options for patients over the next few years, but it’s hard to know which particular [mechanism of action] is going to come to the forefront, at least from the immunotherapy perspective.”

Other TGF-β/PD-1 bispecific antibodies are not yet far along in CRC development, Parikh said, but PD-1/VEGF bispecific antibodies, KRAS inhibitors, and CCR8-directed antibodies aimed at depleting immunosuppressive regulatory T cells are among the other approaches advancing through the MSS CRC pipeline.

Parikh also pointed to liver metastases and durability of response as the gaps that remain even if INCA33890 succeeds.

“We need to understand what’s happening with most patients who have liver metastases,” she noted. “Hopefully an approach like [INCA33890] will work, but we need better therapies and [a better] understanding [of] why the liver microenvironment is hard to tackle. We also need more durable therapies. With the RAS inhibitors, we may see the landscape change, but the durability still seems to be potentially a limiting factor. How do we combine therapies? How do we move therapies earlier in [the] lines of the patient’s journey to give them the best outcome for the long term?”

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

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 31, 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 (NEXERA-303). ClinicalTrials.gov. Updated July 17, 2026. Accessed October 31, 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