INCA33890 Plus SOC Elicits Responses and Is Tolerable Across In First- and Third-Line MSS CRC

INCA33890 combined with standard-of-care (SOC) therapy was tolerable and elicited responses in patients with metastatic microsatellite stable (MSS) colorectal cancer (CRC) in the first-line and third-line settings, according to data from the phase 1 INCA33890-101 trial (NCT05836324) presented at the 2026 ESMO Congress.¹

Among efficacy-evaluable patients in the first-line cohort receiving INCA33890 plus FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and bevacizumab (Avastin; n = 42), the objective response rate (ORR) was 71.4%, the confirmed ORR (cORR) was 66.7%, and the disease control rate (DCR) was 100%. The 6-month progression-free survival (PFS) rate was 81.4% at a median follow-up of 5.6 months. The ORR was 82.8% in patients with liver metastases (n = 29), 61.5% in those with peritoneal metastases (n = 13), 80.8% in those with a PD-L1 tumor area positivity (TAP) of 1% or higher (n = 26), and 50.0% in those with a PD-L1 TAP below 1% (n = 6). The ORR was 91.7% in patients with right-sided tumors (n = 12) and 64.3% in those with left-sided tumors (n = 28).

Among patients in the third-line or later cohort receiving INCA33890 plus bevacizumab (n = 39), the ORR was 28.2%, the cORR was 25.6%, and the DCR was 46.2%. The ORR was 25.0% in patients with liver metastases (n = 24), 46.2% in those with peritoneal metastases (n = 13), and 33.3% in those with a PD-L1 TAP of 1% or higher (n = 18). In smaller cohorts of patients receiving INCA33890 plus FOLFIRI (folinic acid, fluorouracil, and irinotecan) and bevacizumab (n = 6) or INCA33890 plus cetuximab (Erbitux; n = 6), the ORRs were 50.0% and 16.7%, and the DCRs were 66.7% and 100%, respectively.

“INCA33890 in combination with SOC chemotherapy in patients with MSS CRC [was] tolerable, and no DLTs were noted,” Sreenivasa R. Chandana, MD, PhD, of START Midwest in Grand Rapids, Michigan, stated in a presentation of the data.

What was the design of the phase 1 INCA33890-101 trial of INCA33890 plus SOC therapy in MSS CRC?

INCA33890 is a bispecific immune checkpoint inhibitor that blocks signaling through both TGF-β receptor 2 and PD-1 in PD-1–positive T cells. TGF-β signaling in the tumor microenvironment dampens antitumor immunity and is associated with weaker benefit from anti–PD-1 therapy. In an earlier presentation given at the 2025 ESMO Congress, INCA33890 monotherapy was tolerated at doses up to 1200 mg every 2 weeks; 900 mg every 2 weeks was set as the recommended phase 2 dose, and responses were durable in patients with MSS CRC, including those with liver metastases.

The current combination analysis enrolled 94 adult patients with advanced or metastatic stage IV MSS CRC and an ECOG performance status of 0 or 1. Every patient received INCA33890 at 900 mg intravenously every 2 weeks alongside a SOC regimen matched to prior treatment: FOLFOX plus bevacizumab for treatment-naive patients (n = 43), FOLFIRI plus bevacizumab for those who had received oxaliplatin but not irinotecan (n = 6), bevacizumab alone for those who had been previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 39), and cetuximab for those who had previously received anti-EGFR therapy (n = 6). Safety, tolerability, and DLTs were the primary end points; ORR, DCR, duration of response (DOR), and pharmacokinetics were among the secondary end points.

The median age was 56 years (range, 20-89), 53.2% of patients were male, and 55.3% of patients had an ECOG performance status of 0. In the first-line cohort, 67.4% of patients had liver metastases, 32.6% of patients had peritoneal metastases, 60.5% of patients had a PD-L1 TAP of 1% or higher, and 62.8% of patients had RAS-mutated tumors. Among patients in the third-line or later bevacizumab cohort, 61.5% had liver metastases, 33.3% had peritoneal metastases, 46.2% had a PD-L1 TAP of 1% or higher, and 69.2% had RAS-mutated tumors.

What was the safety profile of INCA33890 plus FOLFOX and bevacizumab in MSS CRC?

None of the cohorts reported DLTs. Among evaluable patients in the INCA33890/FOLFOX/bevacizumab cohort (n = 43), any-grade treatment-emergent adverse effects (TEAEs) occurred in 100%, grade 3 or higher TEAEs were seen in 72.1%, immune-related TEAEs were reported in 53.5% (grade ≥ 3, 14.0%), and serious TEAEs were seen in 44.2%. Of evaluable patients in the INCA33890/bevacizumab cohort (n = 39), these corresponding rates were 94.9%, 33.3%, 41.0% (grade ≥ 3, 10.3%), and 23.1%. No TEAEs were fatal in any cohort.

Among patients in the FOLFOX cohort, the most common any-grade TEAEs were neuropathy (76.7%), neutropenia (58.1%; grade ≥ 3, 34.9%), stomatitis (46.5%), nausea (44.2%), diarrhea (41.9%), and fatigue (41.9%); hypertension occurred in 27.9% of patients (grade ≥ 3, 9.3%). TEAEs led to INCA33890 dose delays in 60.5% of patients and to INCA33890 discontinuation in 9.3% of patients. No patients in the other cohorts discontinued INCA33890 because of TEAEs.

What is the design of the phase 3 NEXERA-303 trial of INCA33890 in patients with first-line MSS CRC?

The randomized, double-blind phase 3 NEXERA-303 trial (NCT07284849) is currently recruiting and is comparing first-line FOLFOX plus bevacizumab and INCA33890 vs placebo plus FOLFOX and bevacizumab in patients with metastatic MSS CRC.² The study opened March 5, 2026, aims to enroll 700 patients, and has an estimated primary completion date of December 29, 2028.

The primary end point is investigator-assessed PFS per RECIST 1.1 criteria, and secondary end points include overall survival, ORR, DOR, TEAEs, and changes in quality of life. Eligible patients must have unresectable stage IV colorectal adenocarcinoma, have not received systemic therapy for unresectable or metastatic disease, and have measurable disease per RECIST 1.1 criteria with an ECOG performance status of 0 or 1. The trial excludes patients with microsatellite instability–high or mismatch repair–deficient tumors, BRAF V600E–mutated disease, or immune checkpoint inhibitor exposure within the past 3 years.

Disclosures: Chandana reported receiving research funding to the institution from AbbVie, Adcentrx Therapeutics, Amgen, Arvinas, AstraZeneca, BioNTech, BMS, Cardiff Oncology, Chugai Pharma, Dicephera, Elevation Oncology, Exact Sciences, Exelixis, Genentech, Halda Therapeutics, IDEAYA Biosciences, IGM Biosciences, Incyte Corporation, Ipsen, Johnson & Johnson, Medilink Therapeutics, Merck, Mirati Therapeutics, Monte Rosa Pharmaceuticals, Novocure, Qualigen Therapeutics, Rondo Therapeutics, Tizona Therapeutics, and ZymeWorks; serving on speakers’ bureaus for Immunocore, Natera Inc, and Revolution Medicines; and performing advisory board roles for AstraZeneca and Novocure.

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

References

1. Chandana SR, Berz D, Papadopoulos KP, et al. INCA33890, a TGFβR2×PD-1 bispecific antibody, with standard of care (SoC) anticancer therapies for microsatellite stable colorectal cancer (MSS CRC). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 1954RO.
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. Accessed October 24, 2026. https://clinicaltrials.gov/study/NCT07284849