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.

Inclusion Criteria:

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
  • Abnormal PFT results may be further evaluated with quantitative ventilation or perfusion scanning or cardiopulmonary exercise testing, at the discretion of the surgeon
  • Postoperative percent predicted forced expiratory volume in 1 second and diffusion capacity must be ≥40% and/or preoperative maximal oxygen consumption (VO2 max) must be >15 mL/kg/min
  • It is acceptable to have the screening PFTs performed within 4 months of Cycle 1, Day 1, but they must be repeated before Cycle 1, Day 1, if clinically indicated
  • The postinduction and preoperative PFTs must be performed at least 2 weeks after Cycle 2, Day 1

• Echocardiogram demonstrating left ventricular ejection fraction (LVEF) ≥50% within 28 days before enrollment. If clinically indicated, patients with underlying ischemic or valvular heart disease should be evaluated preoperatively by a cardiologist

• ECOG Performance Status of 0 or 1

• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days before the first dose of study treatment:

  • Absolute neutrophil count ≥1500/uL (granulocyte-colony stimulating factor administration is not allowed within 1 week before Cycle 1, Day 1)
  • Platelet count ≥100,000/uL (platelet transfusion is not allowed within 1 week before Cycle 1, Day 1)
  • International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤1.5 × the upper limit of normal (ULN)
  • Hemoglobin ≥9.0 g/dL
  • AST and ALT ≤3 × ULN
  • Serum bilirubin ≤1.5 × ULN (up to 3 × ULN for patients with Gilbert syndrome)
  • Creatinine clearance ≥30 mL/min (as calculated using the Cockcroft-Gault equation)
  • Serum albumin ≥2.5 g/dL

• Male and female participants of reproductive or childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4.5 months after the last dose of the study drug. Methods considered to be highly effective forms of contraception include:

  o Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation:

• Oral

• Intravaginal

• Transdermal

  o Progestogen-only hormonal contraception associated with inhibition of ovulation:

• Oral

• Injectable

• Implantable

  • Intrauterine device
  • Intrauterine hormone-releasing system
  • Bilateral tubal occlusion
  • Vasectomized partner
  • Complete sexual abstinence, defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 4.5 months after the last dose of the study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
  • Women of nonchildbearing potential, defined as premenopausal women with a documented tubal ligation or hysterectomy, or postmenopausal women, defined as those with 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone >40 mIU/mL and estradiol <40 pg/mL [<147 pmol/L] is confirmatory). Women on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. After confirmation of their postmenopausal status, they can resume use of HRT during the study without the use of a contraceptive method

• Male participants must not freeze or donate sperm starting at screening and throughout the study period and for at least 4.5 months after the final administration of the study drug. Preservation of sperm should be considered before enrollment in this trial

• Female participants must not donate or retrieve for their own use ova from the time of randomization or enrollment and throughout the study treatment period and for at least 7 months after the final administration of the study drug

• Participants should be willing and able to comply with protocol visits and procedures

Adjuvant Therapy Adjuvant systemic therapy (i.e., platinum-based chemotherapy and/or immunotherapy) may be given to patients at the discretion of the treating physician.

Exclusion Criteria:

• 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
• Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study,in the opinion of the investigator
• Major surgical procedure within 28 days before Cycle 1, Day 1
• Malignancies other than the disease under study within 3 years before Cycle 1, Day 1, with the exception of patients with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, non-muscle invasive bladder cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or patients undergoing active surveillance per standard-of-care management (e.g., Rai stage 0 chronic lymphocytic leukemia, prostate cancer with Gleason score ≤6, and prostate-specific antigen [≤10 ng/mL])
• Treatment with an investigational agent for any condition within 4 weeks before Cycle 1, Day 1 (or within 5 half-lives of the investigational product, whichever is longer)
• Medical history of myocardial infarction, symptomatic congestive heart failure (CHF; New York Heart Association class II-IV), unstable angina, or serious cardiac arrhythmia
• Social, familial, or geographical factors that would interfere with study participation or follow-up
• Concomitant medical condition that would increase the risk of toxicity, in the opinion of the investigator
• Pregnant or lactating or intending to become pregnant during the study o Women of childbearing potential must have a negative serum pregnancy test result within 7 days before initiation of treatment

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.