Adjuvant ctDNA-Adapted Treatment With Zipalertinib in Early-Stage Atypical EGFR-Mutant NSCLC

Inclusion Criteria: 1. Histological documentation of NSCLC (squamous histology is permitted). 2. Clinical or pathological stage IA2 to IIIC or locoregionally recurrent disease based on AJCC 9th edition. Stage IA1 tumors are excluded unless radiographic solid component or pathologic invasive component of \> 10 mm. 3. Documented atypical EGFR mutation (defined as non-exon 19 deletion or L858R) including but not limited to exon 20 insertion, E709X, G719X, S768I, L861X, exon 19 insertion, and others (which may be allowed with study PI/Co-PI permission) as demonstrated by a test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. Tumors harboring more than one atypical EGFR mutation are permitted; but patients with tumors harboring compound EGFR mutations including a classical mutation (exon 19 deletion or L858R mutation) are excluded. 4. Completed all planned curative-intent therapy with surgery and/or radiation. May have received neoadjuvant/adjuvant chemotherapy; but patients that received prior concurrent chemotherapy and radiation are excluded. For patients with non-squamous NSCLC in whom neoadjuvant and/or adjuvant chemotherapy is standard-of-care (i.e., patients with stage IIA-IIIA disease), these patients must have received chemotherapy in the neoadjuvant and/or adjuvant setting, unless they refused or were considered unsuitable for chemotherapy. 5. No known current radiographic or pathologic residual/recurrent disease after completion of all intended therapy (for example, positive margins after surgery without adjuvant radiotherapy, or unequivocal radiographic evidence of residual or recurrent disease). 6. A known positive or negative result from a commercial tumor-informed MRD test that was collected as standard-of care between 2 weeks and 24 weeks of completion of curative-intent therapy (including adjuvant chemotherapy) and has resulted, with intention for serial testing to continue for at least 3 years. Note: Recommended assay is second-generation "Signatera Genome". Other tumor-informed commercial assays and/or a longer window since completion therapy of may be considered but require study PI/Co-PI approval for enrollment. 7. Age ≥ 18 years old 8. Has not received immune checkpoint inhibitor (ICI) therapy (PD-1, PD-L1, or CTLA-4 antibodies) within 12 weeks prior to enrollment, and not planned to receive ICI therapy. 9. Has not received another systemic anti-cancer investigational product during the 4 weeks prior to enrollment. 10. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 11. Have the following laboratory values: 1. Serum creatinine \< 1.5 × ULN or if higher than normal range, calculated creatinine clearance (CrCl) must be ≥ 50 mL/min/1.73 m2 (by Cockroft-Gault formula); actual body weight must be used for CrCl unless BMI \>30 kg/m2 then lean body weight must be used 2. Total bilirubin ≤ 1.5 × ULN unless prior history of Gilbert's syndrome 3. Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN 4. Hemoglobin ≥ 9.0 g/dL in the absence of transfusion ≤ 14 days prior to study enrollment 5. Platelets ≥ 100 × 109 cells/L and no platelet transfusion within 14 days 6. Absolute neutrophil count ≥ 1.5 ×109 cells/L 12. Ability to understand and the willingness to sign a written informed consent document. 13. Female participants must use adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug and during the study and 30 days after last dose of zipalertinib; or female patients must have evidence of non-childbearing potential. Male participants must use adequate contraceptive measures during the study and 30 days after last dose of zipalertinib. Exclusion Criteria: 1. Any component of small cell lung cancer, for example mixed small cell and non-small cell lung cancer histology. 2. Tumor harbors a classical EGFR mutation (exon 19 deletion or L858R), even in combination with atypical mutations. 3. Prior treatment with any EGFR targeting drug, including zipalertinib. 4. Prior treatment with any adjuvant immune checkpoint inhibitor. Neoadjuvant immune checkpoint inhibitor may be allowed with study PI/Co-PI review and permission. 5. Have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except for alopecia and skin pigmentation. Patients with chronic but stable Grade 2 toxicities may be allowed to enroll after agreement from the PI/Co-PI. 6. Past medical history of drug-induced interstitial lung disease or treatment-related pneumonitis which required steroid treatment. OR History of or clinically active interstitial lung disease. 7. Cardiac conditions as follows: Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment. 8. Persistent resting corrected QT interval by Fridericia (QTcF) \> 470 msec during screening. 9. Unable to take study therapy orally, for example due to disorders or diseases that may affect gastrointestinal function, including but not limited to inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy. 10. Have any condition or illness that, in the opinion of the investigator, might compromise the efficacy or safety of the drug, such as active bleeding disorders, uncompensated respiratory, cardiac, hepatic, or renal disease, conditions causing GI malabsorption, or issues swallowing pills. 11. History of another primary malignancy and currently undergoing active treatment. Exception: May participate if receiving adjuvant endocrine therapy for breast or prostate cancer with approval from PI/Co-PI. 12. Clinically significant ongoing or active infection (for example, requiring IV antibiotics). For patients with a history of hepatitis B, active infection as defined by a positive HBsAg test and detectable HBV DNA. Note: Patients ineligible due to detectable levels of HBV DNA at baseline may be rescreened for enrollment if their HBV DNA levels become undetectable after treatment with antiviral agents. For patients with a history of hepatitis C, active infection as defined by a reactive HCV antibody test and detectable HCV RNA. 13. In the Investigator's opinion, unable or unwilling to comply with the trial procedure, for example due to psychiatric illness/social situations.