A Study of Trastuzumab Deruxtecan in People With Non-Small Cell Lung Cancer
A Phase II Trial of Neoadjuvant Trastuzumab Deruxtecan for Patients With Stage II-III HER2-Amplified or HER2-Mutated Non-Small Cell Lung Cancer (HERCULES)
1 other identifier
interventional
14
2 countries
10
Brief Summary
The purpose of this study is to find out how many people with HER2-amplified or HER2-mutated non-small cell lung cancer (NSCLC) experience a decrease in tumor viability when they receive trastuzumab deruxtecan before routine surgery to remove tumors.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_2 nonsmall-cell-lung-cancer
Started Feb 2026
Shorter than P25 for phase_2 nonsmall-cell-lung-cancer
10 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
February 13, 2026
CompletedFirst Submitted
Initial submission to the registry
February 17, 2026
CompletedFirst Posted
Study publicly available on registry
February 23, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 13, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
February 13, 2027
February 23, 2026
February 1, 2026
1 year
February 17, 2026
February 17, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Major Pathologic Response/MPR Rate
Determine the MPR rate to neoadjuvant T-DXd, as assessed by central pathologic review, in patients with resectable stage II-IIIB (T3-4N2) HER2-amplified or HER2-mutated NSCLC. MPR is defined as the presence of ≤10% residual viable tumor in the primary tumor bed after neoadjuvant chemotherap
up to 1 year
Study Arms (1)
Participants with Non-Small Cell Lung Cancer
EXPERIMENTALParticipants with Stage II, IIIA or IIIB Non-Small Cell Lung Cancer
Interventions
Trastuzumab deruxtecan (T-DXd, fam-trastuzumab deruxtecan-nxki) is a novel HER2- targeting antibody-drug conjugate (ADC).
Eligibility Criteria
You may qualify if:
- Patients must meet the following criteria for study entry:
- Neoadjuvant Therapy
- Signed informed consent form
- Age ≥18 years
- Able to comply with the study protocol, in the investigator's judgment
- Pathologically documented NSCLC
- o Stage II, IIIA, or selected IIIB, including T3N2 or T4 (by size criteria, not by mediastinal invasion), NSCLC (on the basis of the 8th edition of the AJCC NSCLC staging system)
- Note: Patients may be enrolled on the basis of clinical stage, but documentation of nodal involvement by invasive mediastinal staging (e.g., endobronchial ultrasound or mediastinoscopy) is strongly encouraged
- Molecular testing results on tissue and/or cfDNA from a CLIA-certified laboratory showing presence of a mutation or amplification (defined as ≥ 4 copies) of HER2. (See Appendix C for a list of known activating HER2 mutations in NSCLC. This is not intended to be a comprehensive list. The presence of any activating HER2 mutation is suitable.)of HER2including via Foundation Medicine testing on the LCMC4 LEADER protocol.
- Molecular testing results used for patient eligibility should be obtained from a recent tumor biopsy (up to 6 months before enrollment). Alternatively, molecular testing results used to determine patient eligibility could have been obtained from a recent blood sample (up to 3 months before enrollment)\]
- Measurable disease as defined by RECIST v1.1 (exceptions may be made in cases of PERCIST-measurable disease \[e.g., T0N2 cancer otherwise appropriate for induction therapy\])
- NSCLC must have a solid or subsolid appearance on CT scan and cannot have a purely ground-glass-opacity appearance. For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured on the basis of the solid component only, exclusive of the ground-glass-opacity component
- Evaluated by the attending surgeon before study enrollment to verify that the primary tumor and any involved lymph nodes are technically completely resectable and to verify that the patient is medically operable
- Adequate pulmonary function to be eligible for surgical resection with curative intent
- Pulmonary function tests (PFTs) must be performed at screening and before surgery,in accordance with the preoperative calendar of events, and should include lung volumes, spirometry, and diffusion capacity
- +34 more criteria
You may not qualify if:
- NSCLC that is clinically T4 by virtue of mediastinal organ invasion or stage IIIB by virtue of N3 disease
- Patients who on initial assessment by treating thoracic surgeon, appear to require a total pneumonectomy to achieve a complete resection are ineligible for study enrollment
- Any previous therapy for lung cancer, including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, within 3 years
- Previous lung cancer in remission for \<3 years, with the exception of minimally invasive adenocarcinoma or incidental typical carcinoid tumors
- History of (noninfectious) ILD or pneumonitis that required steroids or current ILD or pneumonitis or suspected ILD or pneumonitis that cannot be ruled out by imaging at screening
- Lung-specific intercurrent clinically significant illnesses including but not limited to any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion)
- Any autoimmune, connective tissue, or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis) where there is documentation or suspicion of pulmonary involvement, at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study
- Previous pneumonectomy (complete)
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Active primary immunodeficiency, known uncontrolled active HIV infection, or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle, 1 Day 1. Participants with past or resolved hepatitis B virus infection who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-)
- Corrected QT interval prolongation to \>470 msec (women) or \>450 msec (men) on the basis of the average of the screening triplicate 12-lead electrocardiogram (ECG)
- Receipt of live, attenuated vaccine (mRNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days before the first dose of T-DXd.
- Note: Patients, if enrolled, should not receive live vaccine during the study and for up to 30 days after the last dose of the study drug
- Known allergy or hypersensitivity to the study treatment or any of the study drug excipients
- History of severe hypersensitivity reactions to other monoclonal antibodies
- +8 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Memorial Sloan Kettering Cancer Centerlead
- AstraZenecacollaborator
Study Sites (10)
University of Michigan (Data Collection Only)
Ann Arbor, Michigan, 48109, United States
Mayo Clinic (Data Collection Only)
Rochester, Minnesota, 55905, United States
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
Basking Ridge, New Jersey, 07920, United States
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
Middletown, New Jersey, 07748, United States
Memorial Sloan Kettering Bergen (Limited Protocol Activities)
Montvale, New Jersey, 07645, United States
Memorial Sloan Kettering Suffolk-Commack (Limited Protocol Activities)
Commack, New York, 11725, United States
Memorial Sloan Kettering Westchester (Limited Protocol Activities)
Harrison, New York, 10604, United States
Memorial Sloan Kettering Cancer Center (All Protocol Activites)
New York, New York, 10065, United States
Memorial Sloan Kettering Nassau (Limited Protocol Activites)
Rockville Centre, New York, 11553, United States
Centre Hospitalier de l'Université de Montreal (Data Collection Only)
Montreal, Quebec, H2L 4M1, Canada
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
James Isbell, MD
Memorial Sloan Kettering Cancer Center
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 17, 2026
First Posted
February 23, 2026
Study Start
February 13, 2026
Primary Completion (Estimated)
February 13, 2027
Study Completion (Estimated)
February 13, 2027
Last Updated
February 23, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.