Trial: Phase III Study of Ivonescimab or Bevac…

Trial Details

Sponsor: Summit Therapeutics (industry)

Phase: 3

Start date: Nov. 14, 2025

Planned enrollment: 600

Trial ID: NCT07228832

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: Ivonescimab (AK112/SMT112)

Overview

Ivonescimab (AK112; SMT112) is a tetravalent bispecific antibody that targets PD‑1 and VEGF. It has completed multiple phase 3 studies in non–small cell lung cancer (NSCLC). In China, ivonescimab received marketing authorization in May 2024 for use with chemotherapy in EGFR‑mutated, nonsquamous NSCLC after EGFR‑TKI therapy, and in April 2025 as first‑line monotherapy for PD‑L1–positive NSCLC; it remains investigational in the United States and other Summit Therapeutics territories. (akesobio.com)

Mechanism of action

Ivonescimab binds PD‑1 and VEGF simultaneously and exhibits “cooperative binding,” increasing affinity to one target in the presence of the other, which enhances blockade of both PD‑1/PD‑L1 and VEGF/VEGFR signaling. The Fc region is engineered to reduce effector functions. These properties are proposed to increase activity in the tumor microenvironment while maintaining a favorable safety profile. (pmc.ncbi.nlm.nih.gov)

Efficacy

First‑line PD‑L1–positive (TPS ≥1%) advanced NSCLC (HARMONi‑2, randomized, double‑blind, phase 3, China): Ivonescimab monotherapy significantly improved progression‑free survival (PFS) vs pembrolizumab at interim analysis (median PFS 11.1 vs 5.8 months; HR 0.51, 95% CI 0.38–0.69; P<0.0001). Results were consistent in PD‑L1 TPS 1–49% (HR 0.54) and TPS ≥50% (HR 0.48) subgroups. Objective response rate (ORR) was higher with ivonescimab (50.0% vs 38.5%) in the WCLC late‑breaking presentation. (thelancet.com)
Post‑EGFR‑TKI, EGFR‑mutated nonsquamous NSCLC (HARMONi‑A, randomized, double‑blind, phase 3, China): Adding ivonescimab to carboplatin/pemetrexed significantly improved PFS vs chemotherapy alone (median 7.1 vs 4.8 months; HR 0.46, 95% CI 0.34–0.62). ORR was 50.6% vs 35.4%. Benefits were observed across key subgroups, including those previously treated with third‑generation EGFR‑TKIs and those with brain metastases. Primary HARMONi (global MRCT) subsequently confirmed a clinically meaningful PFS benefit (HR 0.52; median PFS 6.8 vs 4.4 months) with consistent effects across regions. (ascopubs.org)
Phase 2 (first‑line advanced/metastatic NSCLC without EGFR/ALK alterations): Ivonescimab plus platinum doublet chemotherapy produced ORR 75% in squamous and 55% in nonsquamous cohorts, with durable responses in an open‑label multi‑center study. (ascopubs.org)

Safety

In HARMONi‑2, grade ≥3 treatment‑related adverse events (TRAEs) occurred in 29% with ivonescimab vs 16% with pembrolizumab; the most common high‑grade TRAE with ivonescimab was hypertension (5%). Rates of grade ≥3 immune‑related AEs were similar (7% vs 8%). (ascopost.com)
In HARMONi‑A, grade ≥3 treatment‑emergent AEs were 61.5% with ivonescimab plus chemotherapy vs 49.1% with chemotherapy (largely chemotherapy‑related). Grade ≥3 immune‑related AEs were 6.2% vs 2.5%; grade ≥3 VEGF‑related AEs were 3.1% vs 2.5%. (ascopubs.org)

Overall, the safety profile reflects expected immune‑checkpoint and anti‑VEGF class effects (e.g., immune‑related AEs, hypertension/proteinuria), with manageable toxicity in randomized studies. (ascopost.com)

TrialFetch AI Analysis

Goal: To determine whether ivonescimab plus mFOLFOX6 improves efficacy compared with bevacizumab plus mFOLFOX6 as first-line therapy for metastatic colorectal cancer, with progression-free survival as the primary endpoint.

Patients: Approximately 600 adults with histologically/cytologically confirmed metastatic colorectal cancer, ECOG 0–1, life expectancy at least 6 months, and at least one measurable noncerebral lesion, who have not received prior systemic therapy for metastatic disease. Key exclusions include MSI-H/dMMR tumors, known BRAF V600E mutation, resectable disease, significant GI obstruction, recent paracentesis-requiring ascites, prior immunotherapy or anti-angiogenic therapy for colorectal cancer, and active/prior inflammatory bowel disease or chronic diarrhea.

Design: Phase 3, multiregional, multicenter, randomized (1:1), active-controlled, double-blind study comparing an investigational anti–PD-1/anti-VEGF bispecific antibody regimen against a standard anti-VEGF regimen, each combined with mFOLFOX6. Treatment is administered every 2 weeks with induction followed by maintenance, with independent radiology review committee assessment per RECIST v1.1 for key efficacy endpoints.

Treatments: Experimental arm: ivonescimab plus mFOLFOX6 IV every 2 weeks for up to 8 cycles, followed by maintenance ivonescimab plus 5-FU/leucovorin every 2 weeks for up to 2 years. Control arm: bevacizumab plus mFOLFOX6 IV every 2 weeks for up to 8 cycles, followed by maintenance bevacizumab plus 5-FU/leucovorin every 2 weeks for up to 2 years. Ivonescimab (AK112/SMT112) is a first-in-class tetravalent bispecific antibody targeting PD-1 and VEGF, intended to combine immune checkpoint blockade with anti-angiogenic effects and to modulate the immunosuppressive tumor microenvironment. Its design aims for cooperative binding between VEGF and PD-1 targets, potentially enhancing activity where VEGF is present. Across earlier studies in solid tumors it demonstrated antitumor activity and a generally manageable safety profile, and in a phase 3 study in PD-L1–positive advanced NSCLC it improved progression-free survival versus pembrolizumab, supporting continued development across tumor types.

Outcomes: Primary endpoint is progression-free survival assessed by independent radiology review committee per RECIST v1.1 (followed up to ~2.5 years). Secondary endpoints include overall survival (up to ~4 years), overall response rate and duration of response by independent review per RECIST v1.1 (up to ~2.5 years), and safety including incidence and severity of adverse events and clinically significant laboratory abnormalities (captured from consent through 30 days after last dose for AEs and 90 days for related serious AEs, with longer follow-up up to ~4 years).

Burden on patient: Moderate burden. Treatment requires IV infusions every 2 weeks with combination chemotherapy during induction (up to 8 cycles) and continued every-2-week maintenance infusions for up to 2 years, which entails frequent clinic visits similar to standard first-line mFOLFOX6-based therapy. Efficacy assessment requires serial imaging for RECIST-based response and progression evaluation (frequency not specified but typically regular throughout first-line metastatic treatment). No protocol-mandated tumor biopsies or intensive pharmacokinetic sampling are described, and follow-up for survival and late toxicities extends for several years.

Last updated: Jan 2026

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Montreal, Quebec, H4A 3J1, Canada

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Hokkaido, 060-8648, Japan

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Fukuoka, 812-8582, Japan

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Chiba, 260-8717, Japan

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Aichi, 464-8681, Japan

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Tokyo, 104-0045, Japan

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Osaka, 541-8567, Japan

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Gifu, 501-1194, Japan

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Rio Piedras, 00935, Puerto Rico

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London, England, EC1M 6BQ, United Kingdom

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Goodyear, Arizona, 85338, United States

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Orange, California, 92868, United States

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Torrance, California, 90503, United States

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Upland, California, 91786, United States

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West Hollywood, California, 90048, United States

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Pasadena, California, 91030, United States

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Beverly Hills, California, 90212, United States

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Cerritos, California, 90703, United States

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Corona, California, 92882, United States

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Duarte, California, 91010, United States

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Huntington Beach, California, 92648, United States

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Irvine, California, 92612, United States

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Irvine, California, 92618, United States

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Los Angeles, California, 90027, United States

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Los Angeles, California, 90067, United States

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Murrieta, California, 92562, United States

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New Haven, Connecticut, 06520-8028, United States

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Norwich, Connecticut, 06360, United States

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Hialeah, Florida, 33013, United States

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Orlando, Florida, 32806, United States

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Port Saint Lucie, Florida, 34952, United States

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Newnan, Georgia, 30265, United States

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O'Fallon, Illinois, 62269, United States

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Chicago, Illinois, 60611, United States

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Elmhurst, Illinois, 60540, United States

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Fort Wayne, Indiana, 46804, United States

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Edgewood, Kentucky, 41017, United States

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Saint Louis Park, Minnesota, 55426, United States

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Billings, Montana, 59102, United States

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Lincoln, Nebraska, 68506, United States

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New Brunswick, New Jersey, 08901, United States

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The Bronx, New York, 10461, United States

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Mineola, New York, 11501, United States

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New York, New York, 10016, United States

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Cincinnati, Ohio, 45220, United States

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Philadelphia, Pennsylvania, 19111, United States

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Philadelphia, Pennsylvania, 19140, United States

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Hermitage, Tennessee, 37129, United States

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Fort Worth, Texas, 76104, United States

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Salt Lake City, Utah, 84106, United States

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Charlottesville, Virginia, 22908, United States

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Spokane, Washington, 99208, United States

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Tacoma, Washington, 98405, United States

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Charleston, West Virginia, 25304, United States

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A Randomized, Active-Controlled, Double-blind, Multicenter, Phase 3 Clinical Study of Ivonescimab in Combination With FOLFOX Versus Bevacizumab in Combination With FOLFOX for the First-line Treatment of Metastatic Colorectal Cancer

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: Ivonescimab (AK112/SMT112)

Overview

Mechanism of action

Efficacy

Safety

Further reading

TrialFetch AI Analysis

Eligibility

Show Criteria

Sites (54)

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