Sponsor: Summit Therapeutics (industry)
Phase: 3
Start date: Oct. 26, 2023
Planned enrollment: 1080
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)
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)
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)
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)
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
Goal: To compare efficacy and safety of ivonescimab plus platinum-based chemotherapy versus pembrolizumab plus chemotherapy as first-line treatment for metastatic non-small cell lung cancer, with the aim of improving overall survival and progression-free survival across PD-L1 expression levels.
Patients: Adults ≥18 years with histologically or cytologically confirmed metastatic (stage IV) squamous or non-squamous NSCLC, ECOG 0–1, life expectancy ≥3 months, at least one measurable noncerebral lesion per RECIST 1.1, no prior systemic therapy for metastatic disease, and documented PD-L1 TPS (any level). Patients with small cell histology, actionable driver alterations with approved first-line therapies (EGFR, ALK, ROS1, BRAF V600E; and other genes with approved first-line options), or high-risk tumor invasion/encasement were excluded. For non-squamous disease, negative driver testing is required prior to randomization.
Design: Multiregional, randomized, double-blind Phase 3 trial with two parallel arms comparing ivonescimab plus chemotherapy to pembrolizumab plus chemotherapy in the first-line metastatic setting. Approximately 1080 patients will be enrolled and followed for survival and disease control.
Treatments: Arm A: Ivonescimab plus chemotherapy. Ivonescimab is a first-in-class bispecific tetravalent antibody targeting PD-1 and VEGF with cooperative binding; VEGF presence increases PD-1 affinity and vice versa, aiming to combine immune checkpoint blockade with anti-angiogenesis and to remodel the tumor microenvironment. Early-phase studies showed manageable safety and antitumor activity across solid tumors, and a separate Phase 3 trial in PD-L1–positive first-line NSCLC reported improved PFS and higher objective response rates versus pembrolizumab monotherapy. The agent has a 6–7 day half-life and employs Fc-silencing mutations to mitigate Fc-mediated effects. Arm B: Pembrolizumab plus chemotherapy, a standard-of-care PD-1 inhibitor regimen for first-line metastatic NSCLC without actionable drivers.
Outcomes: Co-primary endpoints are overall survival in the intent-to-treat population and investigator-assessed progression-free survival per RECIST v1.1. Key secondary endpoints include objective response and safety, including incidence and severity of adverse events and clinically significant laboratory abnormalities; safety is tracked from consent through 30 days after last dose for AEs and 90 days for serious AEs related to study drugs or until start of new anticancer therapy.
Burden on patient: Moderate. As a double-blind, active-comparator Phase 3 study using IV immunotherapy with chemotherapy, visit frequency and assessments will be similar to standard first-line chemo-immunotherapy: regular infusion visits every 3 to 6 weeks, routine labs, and periodic imaging per RECIST. There are no stated protocol-mandated serial pharmacokinetic draws or research biopsies, which limits additional burden. However, the combination with chemotherapy entails infusion time, potential supportive care visits, and management of overlapping toxicities, resulting in more clinic time and monitoring than single-agent therapy.
Last updated: Oct 2025
Inclusion Criteria:
* Age ≥ 18 years old at the time of enrollment
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
* Expected life expectancy ≥ 3 months
* Metastatic (Stage IV) NSCLC
* Histologically or cytologically confirmed squamous or non-squamous NSCLC
* Recorded measurement of the Tumor Proportion Score (TPS) for PD-L1 expression, irrespective of the PD-L1 expression, prior to randomization
* At least one measurable noncerebral lesion according to RECIST 1.1
* No prior systemic treatment for metastatic NSCLC
Exclusion Criteria:
* Histologic or cytopathologic evidence of the presence of small cell lung carcinoma
* Known actionable genomic alterations (EGFR, ALK, ROS1, and BRAF V600E) or genes for which first-line approved therapies are available.
* For non-squamous histology patients, actionable driver mutation testing results are required before randomization.
* Has received any prior therapy for NSCLC in the metastatic setting
* Tumor invasion, encasement of organs (e.g. heart, trachea, esophagus, central bronchi), or major blood vessels (e.g aorta, central veins), if poses a significant increased risk of bleeding.
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