Sponsor: Summit Therapeutics (industry)
Phase: 3
Start date: Oct. 26, 2023
Planned enrollment: 400
Last updated in HealthScout: Dec 2024
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
No interim or early results, independent expert analyses, or safety signals from HARMONi-3 have been published as of the search date.
Last updated: Apr 2025
Goal: The primary goal of the trial is to evaluate the efficacy and safety of ivonescimab combined with chemotherapy compared to pembrolizumab with chemotherapy as a first-line treatment for patients with metastatic squamous non-small cell lung cancer (NSCLC), focusing on overall survival.
Patients: The trial targets adults aged 18 and over diagnosed with metastatic squamous NSCLC, who have not received prior systemic treatment for their metastatic condition. Patients must have an ECOG performance status of 0 or 1 and a life expectancy of at least three months. Individuals with small cell lung carcinoma, non-squamous NSCLC, or known actionable genomic alterations are excluded.
Design: This is a multicenter, Phase 3 trial employing a randomized and controlled design to assess comparative outcomes across multiple regions. A total of 400 participants will be allocated to either the experimental or active comparator arm.
Treatments: The investigational treatment arm involves the administration of ivonescimab in combination with chemotherapy. Ivonescimab is a novel antibody targeting potentially multiple pathways implicated in tumor cell survival and proliferation. Previous studies have suggested its efficacy in enhancing the anti-tumor effects of chemotherapy by modulating the immune system and directly inhibiting cancer growth. In contrast, the standard treatment arm will use pembrolizumab, an established checkpoint inhibitor that has shown efficacy in prolonging survival in NSCLC by blocking the PD-1/PD-L1 pathway, thus reinvigorating immune response against cancer cells.
Outcomes: Primary endpoint: Overall Survival (OS). Secondary endpoints include Progression-Free Survival (PFS) per RECIST v1.1 criteria, and safety assessment through the incidence and severity of adverse events. The study also observes the time to any significant abnormal laboratory test results, spanning up to four years.
Burden on patient: The trial places a moderate to low burden on patients. Routine blood work and imaging follow standard protocols similar to current care regimens which typically involve periodic assessments. Travel-related commitments are expected to be manageable, with potential visits spread over extended intervals. Participation does not necessitate frequent additional procedures or high-frequency assessments beyond those integral to standard cancer care. Realistically, patients will undergo evaluations common in oncological practice, which may not significantly disrupt daily life or exceed expectations for similar Phase 3 trials.
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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Brest, 29200, France
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Caen, 14033, France
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Créteil, 94010, France
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Le Mans, 72000, France
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Heidelberg, 69126, Germany
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Thessaloníki, 54622, Greece
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Poznań, 60-693, Poland
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Belgrade, 11080, Serbia
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Niš, 18000, Serbia
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Badalona, 08916, Spain
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Barcelona, 08003, Spain
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Barcelona, 08025, Spain
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Barcelona, 08107, Spain
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Girona, 17007, Spain
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Lugo, 27003, Spain
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Pamplona, 31008, Spain
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Sevilla, 41013, Spain
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Valencia, 46010, Spain
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Valencia, 46206, Spain
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Vigo, 36312, Spain
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London, EC1A 7BE, United Kingdom
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Manchester, M20 4BX, United Kingdom
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Tucson, Arizona, 85711, United States
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Little Rock, Arkansas, 72205, United States
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Sacramento, California, 95817, United States
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Los Angeles, California, 90067, United States
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Los Angeles, California, 90033, United States
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Santa Rosa, California, 95403, United States
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Santa Monica, California, 90404, United States
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Lone Tree, Colorado, 80124, United States
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Saint Petersburg, Florida, 33705, United States
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Plantation, Florida, 33322, United States
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Palm Bay, Florida, 32901, United States
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Ocala, Florida, 34474, United States
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Jacksonville, Florida, 32256, United States
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Fort Myers, Florida, 33901, United States
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West Palm Beach, Florida, 33401, United States
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Lexington, Kentucky, 40503, United States
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Burlington, Massachusetts, 01805, United States
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Detroit, Michigan, 48202, United States
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Ann Arbor, Michigan, 48109, United States
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Saint Paul, Minnesota, 55101, United States
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New York, New York, 10065, United States
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Chapel Hill, North Carolina, 27514, United States
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Charlotte, North Carolina, 28204, United States
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Cleveland, Ohio, 44106, United States
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Cincinnati, Ohio, 45242, United States
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Cleveland, Ohio, 44195, United States
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Eugene, Oregon, 97401, United States
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Greenville, South Carolina, 29605, United States
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Nashville, Tennessee, 37203, United States
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Austin, Texas, 78745, United States
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Dallas, Texas, 75246, United States
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Tyler, Texas, 75702, United States
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Houston, Texas, 77030, United States
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Reston, Virginia, 20190, United States
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Norfolk, Virginia, 23502, United States
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Spokane, Washington, 99202, United States
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Seattle, Washington, 98103, United States
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Madison, Wisconsin, 53792, United States
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