Phase III Study of AK112 for NSCLC Patients

A Randomized, Double-blind, Multi-center, Phase III Study of AK112 or Placebo Combined With Pemetrexed and Carboplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous NSCLC Who Have Failed to EGFR-TKI Treatment

A Randomized, Double-blind, Multi-center, Phase III Clinical Study of AK112 or Placebo Combined With Pemetrexed and Carboplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Who Have Progressed on or Following Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment (HARMONi)

Study Overview

• Status: Active, not recruiting
• Conditions: Non-Squamous Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: AK112 Injection; Drug: Placebo Injection

Detailed Description

The trial will be performed as a randomized, Double-Blind, Multicenter trial to compare Ivonescimab (SMT112 /AK112) Plus Pemetrexed and Carboplatin to Placebo Plus Pemetrexed and Carboplatin in Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Harboring. Approximately 420 subjects will be randomized to two treatment arms at the ratio of 1:1. Each enrolled subject will receive an intravenous infusion of the Ivonescimab (SMT112 /AK112)/Placebo Plus Pemetrexed and Carboplatin (Q3W,up to 4 cycles) in treatment periods per the randomization schedule. Afterward, Ivonescimab (SMT112 /AK112)/ Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 420
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1V 4G5
    • Universite Hospital Laval
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Lung Cancer Canada
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blaire Cancer Centre
• France
  • Créteil, France, 94010
    • CHI Créteil
  • Lyon, France, 69008
    • Léon Bérard Cancer Center, Lyon
  • Paris, France, 75248
    • Institut Curie
  • Paris, France, 75018
    • Hospital Bichat-Claude Bernard
  • Villejuif, France, 94800
    • Gustave Roussy Cancer
• Italy
  • Milan, Italy, 20141
    • Instituto Europeo di Oncologia
  • Milan, Italy, 20133
    • Istituto Nazionale dei Tumori
  • Parma, Italy, 43126
    • University Hospital of Parma
  • Roma, Italy, 00128
    • Campus Bio-Medico University
  • Rome, Italy, 00144
    • Istituto Nazionale Tumori, Regina Elena
• Spain
  • A Coruña, Spain, 15006
    • Hospital Teresa Herrera
  • Barcelona, Spain, 08035
    • Vall d'Hebron Institute of Oncology
  • Barcelona, Spain, 08916
    • Badalona-Hospital Germans Trias i Pujol
  • Las Palmas, Spain, 35016
    • omplejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria
  • Lugo, Spain, 27002
    • Lucus Augusti University Hospital
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28040
    • Hospital Universitario Clínico San Carlos
  • Madrid, Spain, 28040
    • Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz
  • Majadahonda, Spain, 28222
    • Puerta de Hierro University Hospital
  • Málaga, Spain, 29011
    • Hospital Regional Universitario de Malaga
  • Seville, Spain, 41014
    • Hospital Universitario Nuestro Senora de Valme
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden
  • Manchester, United Kingdom, M20 4GJ
    • The Christie NHS Foundation Trust
• United States
  • California
    • Bakersfield, California, United States, 93309
      • CBCC Global Research
    • La Jolla, California, United States, 92093
      • UC San Diego
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90095
      • UCLA Department of Medicine - Hematology/Oncology
    • Los Angeles, California, United States, 90067
      • Valkyrie Clinical Trials
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation Research Institute
    • Orange, California, United States, 92868
      • UC Irvine
    • Orange, California, United States, 92868
      • Providence St. Joseph
    • Sacramento, California, United States, 95816
      • Sutter Cancer center
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • Santa Rosa, California, United States, 95403
      • Providence Medical Foundation
    • Whittier, California, United States, 90602
      • Presbyterian Intercommunity Hospital
  • Colorado
    • Lone Tree, Colorado, United States, 80124
      • Rocky Mountain Cancer Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • The Oncology Institute of Hope & Innovation
    • Miami, Florida, United States, 33136
      • University of Miami
    • Ocala, Florida, United States, 34474
      • Florida Cancer Associates - Ocala Oncology
    • Plantation, Florida, United States, 33322
      • BRCR Global
    • St. Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North
    • Tamarac, Florida, United States, 33321
      • BRCR Global
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists -East
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Hematology/Oncology Clinic - SCRI
  • Maine
    • Scarborough, Maine, United States, 04074
      • New England Cancer Specialists
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • HealthPartners Cancer Research Center
  • New York
    • Clifton Park, New York, United States, 12065
      • New York Oncology/Hematology
    • New York, New York, United States, 10029
      • Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Laura and Isaac Perlmutter Cancer Center
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • Sanford Roger Maris Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43219
      • Zangmeister Cancer Center
    • Fairfield, Ohio, United States, 45014
      • Oncology Hematology Care
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Williamette Valley Cancer Institute and Research
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Baptist Hospital
  • Texas
    • Austin, Texas, United States, 78745
      • Texas Oncology South Austin
    • Dallas, Texas, United States, 75246
      • Texas Oncology Baylor Charles A. Sammons Cancer Center
    • Houston, Texas, United States, 77030
      • MD Anderson University of Texas
    • Webster, Texas, United States, 77598
      • Texas Oncology Webster
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer specialisits
  • Washington
    • Vancouver, Washington, United States, 98684
      • Compass Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ability to understand and voluntarily sign a written informed consent form (ICF), which must be signed before the specified study procedures required for the study are performed.
2. Males or females aged ≥ 18 to ≤ 75 years at the time of signing informed consent. (For patients from North America and Europe, there will be no upper age cutoff)
3. ECOG performance status score of 0 or 1.
4. Expected survival ≥3 months.
5. Histologically or cytology-confirmed, locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) non-squamous NSCLC (according to TNM staging of lung cancer, 8th edition) that cannot be completely resected by surgery and cannot receive radical concurrent/sequential chemoradiation.
6. EGFR activation mutations that are confirmed by tumor histology or cytology or blood test before enrollment (eg, exon 18 point mutations, exon 19 deletions, exon 20 point mutations, and exon 21 point mutations). Patients must provide a previous EGFR mutation test report, otherwise tumor tissue samples, peripheral blood samples, or pleural fluid samples will need to be collected for EGFR status testing prior to enrollment.
7. Prior treatment with EGFR TKI and treatment failure, meeting any of the following requirements: Progression after treatment with first- or second-generation EGFR TKI, and confirmation of absence of T790M mutation after progression (only for patients enrolled in China). Progression after treatment with a third-generation EGFR TKI (eg, osimertinib, ametinib, vometinib). Note, for North America and Europe patients only.
8. According to RECIST v1.1, there is at least 1 measurable noncerebral lesion.
9. Adequate organ function determined by the following requirements
10. Female patients of childbearing age have a negative serum pregnancy test result within 3 days before the first dose
11. If a female patient of childbearing potential has sex with an unsterilized male partner, the patient must use a highly effective method of contraception from the beginning of screening and must agree to continue using these precautions until 120 days after the last dose of the study drug or until 6 months after the last carboplatin and pemetrexed dose (whichever is longer).
12. If an unsterilized male patient has sex with a female partner of childbearing potential, the patient must use an effective method of contraception from the beginning of screening to day 120 after the last dose or until 6 months after the last carboplatin and pemetrexed dose (whichever is longer). The decision to stop contraception after this time point should be discussed with investigator.

Exclusion Criteria:

1. Histologic or cytopathologic evidence of the presence of a small cell carcinoma component, or a predominantly squamous cell carcinoma.
2. Patients who have received immune checkpoint inhibitors (eg, anti-PD-1/L1 antibodies, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, etc.)
3. Received prior systemic chemotherapy, anti-angiogenic therapy, or more than one prior line of antitumor therapy (other than EGFR inhibitors) for advanced stage (IIIB to IV) NSCLC.
4. Concurrent enrollment in another clinical study, unless it is a noninterventional clinical study or the follow-up period of the interventional study is more than 4 weeks from the last dose of the prior clinical study or more than 5 half-lives of the prior study drug, whichever is shorter.
5. Received EGFR inhibitor therapy within 2 weeks (with the exception of osimertinib to be within 7 days) prior to the first dose; received nonspecific immunomodulatory therapy (eg, interleukin, interferon, thymus peptide, tumor necrosis factor) within 2 weeks prior to the first dose, excluding IL-11 for the treatment of thrombocytopenia; have received Chinese herbal medicines or proprietary Chinese medicines with antitumor indications within 1 week before the first dose.
6. Imaging during the screening period shows that the tumor surrounds important blood vessels or has obvious necrosis and/or cavitation of tumor lesions within the lung parenchyma.
7. Imaging during the screening period shows that the tumor invades the surrounding vital organs and blood vessels, such as the heart and pericardium, trachea, esophagus, aorta, superior vena cava, or patient is at risk of esophageal tracheal fistula or esophageal pleural fistula.
8. Symptomatic metastases of the central nervous system.
9. Malignant tumors other than NSCLC within 3 years before the first dose.
10. Active autoimmune disease requiring systemic therapy (eg, with disease-modifying drugs, corticosteroids, immunosuppressant therapy) within 2 years prior to the first dose (excluding ir AEs due to PD-1/L1 inhibitors). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy (prednisone ≤ 10 mg daily or equivalent) for adrenal or pituitary insufficiency) is permitted.
11. There is a history of major diseases before the first dose
12. History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea) within 6 months before the first study drug administration.
13. Patients with >30 Gy of chest radiation therapy within 6 months prior to the first dose, nonthoracic radiation therapy >30 Gy within 4 weeks prior to the first dose, and palliative radiation therapy of ≤30 Gy within 2 weeks prior to the first dose and failed to recover from the toxicity and/or complications of these interventions to NCI CTCAE Grade ≤1 (except hair loss and fatigue). Palliative radiotherapy for symptom control is permitted if it has been completed at least 2 weeks before the first dose, and no additional radiotherapy for the same lesion is planned.
14. Inactivated vaccines are allowed. Patients are excluded if they have received a live vaccine or live attenuated vaccine within 4 weeks prior to the first dose, or if they are scheduled to receive a live vaccine or live attenuated vaccine during the study period.
15. Severe infection within 4 weeks prior to the first dose, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection that has received systemic anti-infective therapy within 2 weeks prior to the first dose (excluding antiviral therapy for hepatitis B or C)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AK112 in combination with Pemetrexed and Carboplatin; Subjects will receive AK112 Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles. Afterward, AK112 Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.	Drug: AK112 Injection; Subjects will receive AK112 Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles. Afterward, AK112 Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.; Other Names: Carboplatin; Pemetrexed
Active Comparator: Placebo in combination with Pemetrexed and Carboplatin; Subjects will receive Placebo Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles in treatment periods per the randomization schedule. Afterward, Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.	Drug: Placebo Injection; Subjects will receive Placebo Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles in treatment periods per the randomization schedule. Afterward, Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.; Other Names: Carboplatin; Pemetrexed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Progression-free survival (PFS) assessed by IRC per RECIST v1.1 in the ITT population.	Up to 2 years
Overall Survival (OS) in the ITT population	Overall Survival (OS) in the ITT population	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AE	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results.	From the subject signs the ICF to 30 days (AE) and 90 days (SAE) after the last dose of study treatment or initiation of other anti-tumor therapy, whichever occurs first,up to 2 years
ORR	Efficacy measures such as overall response rate (ORR) and duration of response (DoR), which is the proportion of subjects with CR or PR by IRRC based on RECIST v1.1	Up to 2 years
Observed concentrations of AK112	The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration	through study completion, an average of 2 years
Number of subjects who develop detectable anti-drug antibodies (ADAs)	The immunogenicity of AK112 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs)	From first dose of AK112 through 90 days after last dose of AK112, up to 2 years
DoR	Duration of response (DoR) which is the proportion of subjects with CR or PR by IRRC based on RECIST v1.1	Up to 2 years

Collaborators and Investigators

• Sponsor: Summit Therapeutics
• Collaborators: Akeso

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2023
• Primary Completion (Actual): April 12, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 25, 2024
• First Submitted That Met QC Criteria: May 1, 2024
• First Posted (Actual): May 2, 2024

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; EGFR Positive; ivonescimab
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Pemetrexed; Carboplatin
• Other Study ID Numbers: AK112-301 (HARMONi)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No