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.