Investigational Drug
Ivonescimab
TrialFetch 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 14 active trials using this drug:
TrialFetch AI summary: Adults with ECOG 0–1 squamous or non-squamous NSCLC and 1–3.5 cm brain metastases suitable for SRS receive investigational ivonescimab, a bispecific PD-1/VEGF antibody, with platinum-based chemotherapy followed by fractionated SRS. This single-arm study includes dose finding then expansion to assess safety and preliminary intracranial efficacy.
ClinicalTrials.gov ID: NCT07535463
TrialFetch AI summary: Adults with metastatic activating EGFR-mutant NSCLC progressing after prior third-generation EGFR TKI and platinum chemotherapy, or platinum-ineligible, receive ivonescimab, a bispecific PD-1/VEGF antibody, combined with either datopotamab deruxtecan, a TROP2-directed topoisomerase I ADC, or osimertinib. The study includes patients with ECOG 0–1 and measurable disease, allowing controlled/asymptomatic CNS disease.
ClinicalTrials.gov ID: NCT07535437
TrialFetch AI summary: Adults with unresectable or metastatic leiomyosarcoma, ECOG 0–2, measurable disease, and 1–3 prior systemic therapy lines are treated with single-agent IV ivonescimab every 3 weeks for up to 24 months. Ivonescimab is a bispecific antibody targeting PD-1 and VEGF, combining checkpoint blockade with anti-angiogenic activity; patients with prior PD-1/PD-L1 or VEGF-targeted therapy are excluded.
ClinicalTrials.gov ID: NCT07516925
TrialFetch AI summary: Adults with locally advanced/metastatic solid tumors harboring KRAS/NRAS/HRAS mutations (ECOG 0–1, measurable disease) who have progressed on/intolerant to standard therapy are eligible for dose exploration, with expansions in previously untreated non-squamous NSCLC without another actionable driver and in solid tumors/CRC with ≤2 prior advanced lines (HNSCC excluded). Patients receive an oral RAS(ON) inhibitor—daraxonrasib (pan-RAS(ON)), elironrasib (KRAS G12C(ON)), or zoldonrasib (KRAS G12D(ON))—combined with ivonescimab (PD-1/VEGF bispecific antibody), with select cohorts adding platinum/pemetrexed chemotherapy, cetuximab, or additional RAS(ON) inhibitor.
ClinicalTrials.gov ID: NCT07397338
TrialFetch AI summary: Adults with previously untreated metastatic colorectal cancer (ECOG 0–1) with at least one measurable noncerebral lesion are randomized, excluding MSI-H/dMMR tumors and known BRAF V600E mutation. Patients receive ivonescimab (AK112; bispecific anti–PD-1/anti-VEGF antibody) plus mFOLFOX6 every 2 weeks for up to 8 cycles followed by ivonescimab + 5-FU/leucovorin maintenance, versus bevacizumab plus mFOLFOX6 followed by bevacizumab + 5-FU/leucovorin maintenance (up to 2 years).
ClinicalTrials.gov ID: NCT07228832
TrialFetch AI summary: Adults with previously untreated locally advanced unresectable or metastatic HER2-negative adenocarcinoma of the esophagus, GEJ, or stomach receive first-line ivonescimab plus FOLFOX. Ivonescimab is an investigational tetravalent bispecific antibody that blocks both PD-1 and VEGF, combining checkpoint inhibition with anti-angiogenic activity.
ClinicalTrials.gov ID: NCT07070466
TrialFetch 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
TrialFetch AI summary: Enrolling adults with previously untreated extensive-stage small cell lung cancer, measurable disease (RECIST v1.1), ECOG 0–1, and adequate organ function, excluding symptomatic/high-risk CNS metastases and patients with significant bleeding/vascular risk or active autoimmune disease requiring systemic therapy. Patients are randomized to carboplatin/etoposide plus ivonescimab 10 mg/kg vs 20 mg/kg for 4 induction cycles, then ivonescimab maintenance; ivonescimab is a tetravalent bispecific antibody targeting PD-1 and VEGF (checkpoint blockade plus anti-angiogenic activity).
ClinicalTrials.gov ID: NCT07057791
TrialFetch 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
TrialFetch 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
TrialFetch 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
TrialFetch 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
TrialFetch 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
TrialFetch 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
