A Randomized, Double-blind, Multiregional Phase 3 Study of Ivonescimab Combined with Chemotherapy Versus Pembrolizumab Combined with Chemotherapy for the First-line Treatment of Metastatic Non-small Cell Lung Cancer (HARMONi-3)

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Investigational drug late phase More information Active drug More information Low burden on patient More information

Trial Details

Sponsor: Summit Therapeutics (industry)

Phase: 3

Start date: Oct. 26, 2023

Planned enrollment: 1080

Trial ID: NCT05899608
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More trial details at ClinicalTrials.gov More info

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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

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No email / No phone

Status: Recruiting

University of Michigan

Ann Arbor, Michigan, 48109, United States

No email / No phone

Status: Recruiting

Park Nicollet Institute

Saint Paul, Minnesota, 55101, United States

No email / No phone

Status: Recruiting

American Oncology Partners, PA

Kansas City, Missouri, 64132, United States

No email / No phone

Status: Recruiting

Washington University St.Louis

St Louis, Missouri, 63110, United States

No email / No phone

Status: Recruiting

St. Vincent Cancer Center

Billings, Montana, 59102, United States

No email / No phone

Status: Recruiting

University of Nebraska Medical Center (UNMC)

Omaha, Nebraska, 68105, United States

No email / No phone

Status: Recruiting

Memorial Sloan Kettering

New York, New York, 10065, United States

No email / No phone

Status: Recruiting

Mount Sinai

New York, New York, 10029, United States

No email / No phone

Status: Recruiting

Levine Center

Charlotte, North Carolina, 28204, United States

No email / No phone

Status: Recruiting

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

No email / No phone

Status: Recruiting

Cleveland Clinic

Cleveland, Ohio, 44195, United States

No email / No phone

Status: Recruiting

Oncology Hematology Care (OHC), Inc

Cincinnati, Ohio, 45242, United States

No email / No phone

Status: Recruiting

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

No email / No phone

Status: Recruiting

Willamette Valley Cancer Institute and Research Center (WVCI)

Eugene, Oregon, 97401, United States

No email / No phone

Status: Recruiting

Medical University of South Carolina (MUSC)

Charleston, South Carolina, 29425, United States

No email / No phone

Status: Recruiting

Prisma Health-Upstate

Greenville, South Carolina, 29605, United States

No email / No phone

Status: Recruiting

SCRI-Nashville

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Recruiting

West Cancer Center

Memphis, Tennessee, 38138, United States

No email / No phone

Status: Recruiting

MD Anderson Cancer Center

Houston, Texas, 77030, United States

[email protected] / 713-563-6096

Status: Recruiting

Texas Oncology- Austin

Austin, Texas, 78745, United States

No email / No phone

Status: Recruiting

Texas Oncology-Dallas

Dallas, Texas, 75246, United States

No email / No phone

Status: Recruiting

Texas Oncology-San Antonio

San Antonio, Texas, 78216, United States

No email / No phone

Status: Recruiting

Texas Oncology-Tyler

Tyler, Texas, 75702, United States

No email / No phone

Status: Recruiting

UT Southwestern

Dallas, Texas, 75390, United States

No email / No phone

Status: Recruiting

University of Texas at Tyler

Tyler, Texas, 75708, United States

No email / No phone

Status: Recruiting

Virginia Cancer

Reston, Virginia, 20190, United States

No email / No phone

Status: Recruiting

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

No email / No phone

Status: Recruiting

Cancer Care NW Centers

Spokane, Washington, 99202, United States

No email / No phone

Status: Recruiting

Swedish Cancer Institute

Seattle, Washington, 98103, United States

No email / No phone

Status: Recruiting

Carbone Cancer Center

Madison, Wisconsin, 53792, United States

No email / No phone

Status: Recruiting

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