Sponsor: Summit Therapeutics (industry)
Phase: 3
Start date: Oct. 26, 2023
Planned enrollment: 1080
Ivonescimab, also known as AK112 or SMT112, is a first-in-class, humanized tetravalent bispecific antibody designed to simultaneously target programmed death-1 (PD-1) and vascular endothelial growth factor A (VEGF-A). This dual-targeting approach aims to enhance antitumor activity by combining immune checkpoint inhibition with anti-angiogenic effects.
Ivonescimab binds to PD-1 receptors on T cells, blocking the PD-1 pathway and thereby restoring T cell activity against tumor cells. Concurrently, it targets VEGF-A, inhibiting angiogenesis within the tumor microenvironment. This combined mechanism is intended to improve immune response and reduce tumor vascularization, potentially leading to enhanced therapeutic efficacy.
In a Phase 1a dose-escalation study involving 51 patients with advanced solid tumors, ivonescimab demonstrated promising antitumor activity. The confirmed objective response rate (ORR) was 25.5%, and the disease control rate (DCR) was 63.8%. Notably, responses were observed in patients with platinum-resistant ovarian cancer, endometrial cancer, microsatellite stable colorectal cancer, small cell ovarian cancer, pleural mesothelioma, and anal cancer. Among 19 patients with platinum-resistant ovarian cancer, the ORR was 26.3%, with a higher response rate at the 20 mg/kg dose level compared to 10 mg/kg (30.0% vs. 14.3%). (pmc.ncbi.nlm.nih.gov)
In a Phase II study (AK112-201), ivonescimab combined with chemotherapy was evaluated in patients with non-small cell lung cancer (NSCLC). For first-line treatment of advanced or metastatic squamous NSCLC without actionable genomic alterations, the estimated 1-year overall survival rate was 85.6%, and the 2-year overall survival rate was 64.8%. The median overall survival was not reached after a median follow-up of 21.0 months. (investor.wedbush.com)
Ivonescimab was generally well-tolerated in clinical studies. In the Phase 1a study, treatment-related adverse events (TRAEs) occurred in 74.5% of patients, with grade ≥3 TRAEs in 27.5%. The most common TRAEs included rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), and diarrhea (15.7%). Hypertension was the most common grade ≥3 TRAE (13.7%). Immune-related toxicities such as pruritus, rash, and hypothyroidism were mostly grade 1 or 2. (pmc.ncbi.nlm.nih.gov)
In the Phase II study, the frequency of TRAEs leading to discontinuation of ivonescimab was 11%, with no TRAEs resulting in patient death. The most frequent treatment-emergent adverse events were anemia, decreased neutrophil counts, and decreased white-blood cell counts. (investor.wedbush.com)
Last updated: Apr 2025
Goal: To compare the efficacy and safety of ivonescimab plus chemotherapy versus pembrolizumab plus chemotherapy as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC).
Patients: Adult patients (≥18 years) with stage IV squamous or non-squamous NSCLC, ECOG 0 or 1, no prior systemic therapy for metastatic disease, and absence of actionable oncogenic mutations (EGFR, ALK, ROS1, BRAF V600E) or small cell carcinoma. Patients must have at least one measurable noncerebral lesion and available PD-L1 Tumor Proportion Score, but enrollment is irrespective of PD-L1 status.
Design: Randomized, double-blind, active-controlled, multiregional phase 3 trial.
Treatments: One arm receives ivonescimab in combination with chemotherapy. Ivonescimab is a first-in-class tetravalent bispecific antibody targeting both PD-1 and VEGF, aiming to block angiogenesis and reverse immunosuppression. Previous studies show it improves progression-free survival and objective response rates compared to pembrolizumab in PD-L1-positive NSCLC, with a manageable safety profile and approval in China for certain indications. The comparator arm receives pembrolizumab with chemotherapy, the current standard first-line immunotherapy regimen for metastatic NSCLC without known driver mutations.
Outcomes: Co-primary endpoints are overall survival and progression-free survival by investigator assessment using RECIST 1.1. Key secondary outcomes include objective response rate and safety, including incidence and severity of adverse events and laboratory abnormalities.
Burden on patient: The trial is phase 3, double-blind, and uses standard chemotherapy and immunotherapy regimens, so burden is typical for first-line metastatic NSCLC trials. Required assessments likely mirror standard of care, with regular imaging and routine labs per protocol. No additional or unusual invasive procedures such as mandatory fresh biopsies or frequent pharmacokinetic sampling are described, making the patient burden low to moderate and in line with current clinical practice.
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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