A Study to Assess the Efficacy and Safety of Zipalertinib Versus Placebo for Adjuvant Treatment in Participants With Stage IB-IIIA NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection

Inclusion Criteria:

1. Histologically confirmed diagnosis of primary NSCLC on predominantly non-squamoushistology.

2. Documented EGFRmt status as determined by local testing performed at a clinicallaboratory improvement amendment (CLIA) certified (United States [US]) or accredited (outside of the US) local laboratory, defined as either one of the following EGFRmt:

3. exon20 insertion mutations (ex20ins) or

4. other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I)

5. Baseline imaging assessment of the brain (MRI or CT scan) performed within 8 weeksprior to randomization must show no evidence of brain metastasis

6. Complete surgical resection of the primary NSCLC is mandatory with negative surgicalmargins and systematic lymph node sampling or dissection.

7. Complete recovery from surgery, including post-operative wound healing at the timeof randomization. Randomization must occur between 4 weeks and 12 weeks followingsurgery.

8. Eastern cooperative oncology group performance status (ECOG PS) of 0 or 1.

9. Pathologic (post-operative) Stage IB, IIA, IIB, or IIIA according to the tumor nodesmetastasis (TNM) staging system for lung cancer. In addition, participants withstage IIIB are eligible when regional lymph node involvement is N2.

• Participants with Stage IB NSCLC should be considered when disease has high-riskfeatures (eg, visceral pleural invasion, lymphovascular invasion or high-gradehistology) and participants are suitable for adjuvant chemotherapy according tointernational guidelines such as the 2025 European Society for Medical Oncologyguideline.

8. Archival tumor tissue available for submission, with minimum quantity sufficient toevaluate EGFRmt status and, where possible, other biomarkers.

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Exclusion Criteria:

1. Is currently receiving an investigational drug in a clinical trial or participatingin any other type of medical research judged not to be scientifically or medicallycompatible with this study.

2. Treatment with any of the following within the time frame specified:

3. Zipalertinib (TAS6417/CLN-081) or any other EGFR inhibitor at any time.

4. Pre-operative or post-operative or planned radiation therapy for the currentlung cancer.

5. Any prior systemic anticancer therapy (e.g., neoadjuvant chemotherapy),including investigational therapy, for treatment of NSCLC.

6. Major surgery (including primary tumor surgery, excluding placement of vascularaccess) within 4 weeks of the first dose of study treatment.

7. Treatment with an investigational drug within five half-lives of the compoundor any of its related material, if known.

8. Has received only wedge resections (complete anatomic segmentectomy is acceptable).

9. Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-inducedILD/pneumonitis or any evidence of clinically active ILD/pneumonitis.

10. Unable to swallow tablets or has any disease or condition that may significantlyaffect gastrointestinal (GI) absorption of zipalertinib (such as inflammatory boweldisease, malabsorption syndrome, or prior significant bowel resection).

11. Has a history of any other cancer except for any of the following:

12. Non-melanoma skin cancer treated with curative intent

13. Carcinoma in situ treated with curative intent

14. Other curatively treated cancer, with no evidence of disease for >3 yearsfollowing the end of treatment and, in the opinion of the treating physician,has no substantial risk of recurrence.

15. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)that is unstable or not controlled with treatment. Screening not required.

16. Active bleeding disorders.

17. Known: a. Hypersensitivity: i. To the ingredients in zipalertinib/placebo or any drugssimilar in structure or class. ii. To platinum-containing drugs (i.e., cisplatin,carboplatin), pemetrexed, or any known excipients of these drugs. b.Contraindications to platinum-containing drugs (i.e., cisplatin, carboplatin) orpemetrexed according to the respective local labels.

18. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12supplementation during treatment with pemetrexed.