Investigational Drug
Ivonescimab
HealthScout AI Analysis
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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
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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)
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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)
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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
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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)
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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)
Further reading
- Lancet: HARMONi‑2 randomized phase 3 (ivonescimab vs pembrolizumab) in PD‑L1–positive advanced NSCLC. (thelancet.com)
- JCO/ASCO 2024 abstract: HARMONi‑A randomized phase 3 (ivonescimab + chemo vs chemo) post‑EGFR‑TKI. (ascopubs.org)
- IASLC WCLC coverage: HARMONi‑2 late‑breaking results and summary. (iaslc.org)
- iScience 2025: Mechanistic study describing cooperative binding and Fc engineering. (sciencedirect.com)
- ASCO 2023 abstract: Phase 2 ivonescimab + chemotherapy in first‑line NSCLC. (ascopubs.org)
Notes on regulatory status: Ivonescimab is approved in China (EGFR‑mutant post‑TKI in May 2024; first‑line PD‑L1–positive in April 2025) and is investigational elsewhere. Ongoing global development includes additional registrational studies. (akesobio.com)
Last updated: Oct 2025
Active trials using Ivonescimab
Found 7 active trials using this drug:
HealthScout AI summary: Adults with metastatic colorectal adenocarcinoma, grouped into three cohorts: dMMR/MSI-H refractory to prior PD-1/PD-L1 ± CTLA-4, pMMR/MSS with active non-bulky liver metastases, or pMMR/MSS without liver metastases (cohorts 2–3 post–fluoropyrimidine/oxaliplatin/irinotecan), receive ivonescimab monotherapy. Ivonescimab is a bispecific antibody targeting PD-1 and VEGF to relieve immune suppression and inhibit angiogenesis; primary endpoint is ORR by iRECIST.
ClinicalTrials.gov ID: NCT06959550
HealthScout AI summary: Adults with metastatic/advanced clear cell RCC who progressed after at least one systemic line including a PD-1/PD-L1 inhibitor (two cohorts based on prior VEGF/HIF-2α exposure) receive ivonescimab monotherapy IV q3w. Ivonescimab is a bispecific PD-1/VEGF antibody designed to simultaneously restore antitumor immunity and inhibit angiogenesis.
ClinicalTrials.gov ID: NCT06940518
HealthScout AI summary: Single-arm study of ivonescimab, a tetravalent bispecific antibody targeting PD‑1 and VEGF, in adults with metastatic or recurrent endometrial or cervical cancer that has progressed after at least one platinum regimen; prior PD‑1 or VEGF therapy allowed, ECOG 0–2, measurable disease required. Ivonescimab is given IV every 3 weeks for up to 24 months, aiming to combine immune checkpoint blockade with anti‑angiogenesis; primary endpoint is RECIST ORR.
ClinicalTrials.gov ID: NCT06925724
HealthScout AI summary: This trial enrolls adults with treatment-naïve, metastatic squamous or non-squamous NSCLC and high PD-L1 expression (TPS >50%, no driver mutations), randomizing them to receive either pembrolizumab or ivonescimab, a bispecific antibody targeting both PD-1 and VEGF. Patients with actionable mutations or symptomatic CNS metastases are excluded.
ClinicalTrials.gov ID: NCT06767514
HealthScout AI summary: Adults with recurrent/metastatic or unresectable salivary gland carcinoma (any histology, including adenoid cystic), ECOG 0–1, measurable non-CNS disease, and no prior PD‑1 or VEGFR TKI therapy receive ivonescimab every 21 days; treated/stable brain metastases allowed. Ivonescimab is a bispecific tetravalent antibody targeting PD‑1 and VEGF to combine immune checkpoint blockade with anti‑angiogenesis.
ClinicalTrials.gov ID: NCT06805617
HealthScout AI summary: Single-arm study for adults with unresectable or metastatic cSCC that has progressed on prior anti–PD-1 therapy (ECOG 0–1), treating with ivonescimab IV every 21 days. Ivonescimab is a bispecific tetravalent antibody targeting PD-1 and VEGF to enhance antitumor immunity and inhibit angiogenesis; key exclusions include significant prior immune toxicity, active autoimmune disease, and uncontrolled cardiovascular or thromboembolic risk.
ClinicalTrials.gov ID: NCT06567314
HealthScout AI summary: Enrolling treatment-naive adults with stage IV squamous or non-squamous NSCLC without actionable driver mutations, this trial compares ivonescimab (a bispecific antibody targeting PD-1 and VEGF) plus chemotherapy to pembrolizumab plus chemotherapy. Patients must have ECOG 0–1, at least one measurable noncerebral lesion, and available PD-L1 status, but enrollment is open regardless of PD-L1 expression.
ClinicalTrials.gov ID: NCT05899608
