The purpose of this study is to compare the efficacy of zipalertinib combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in participants with early stage (stage IB-IIIA) resected non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor mutation (EGFRmt).

This study will evaluate zipalertinib, a novel EGFR tyrosine kinase inhibitor (TKI) in combination with standard platinum-based adjuvant chemotherapy versus placebo in combination with chemotherapy in participants with resected stage IB-IIIA NSCLC harboring uncommon EGFRmt.

Approximately 360 participants will be randomized to:

Arm A: Platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed) in combination with zipalertinib twice daily (BID), followed by zipalertinib alone OR

Arm B: Platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed) in combination with placebo BID, followed by placebo BID alone.

An independent data monitoring committee (IDMC) will be established to monitor interim safety data.

Inclusion Criteria:

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

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

   1. exon20 insertion mutations (ex20ins) or
   2. other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I)

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

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

5. Complete recovery from surgery, including post-operative wound healing at the time of randomization. Randomization must occur between 4 weeks and 12 weeks following surgery.

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

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

   - Participants with Stage IB NSCLC should be considered when disease has high-risk features (eg, visceral pleural invasion, lymphovascular invasion or high-grade histology) and participants are suitable for adjuvant chemotherapy according to international guidelines such as the 2025 European Society for Medical Oncology guideline.

8. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate 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 participating in any other type of medical research judged not to be scientifically or medically compatible with this study.

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

   1. Zipalertinib (TAS6417/CLN-081) or any other EGFR inhibitor at any time.
   2. Pre-operative or post-operative or planned radiation therapy for the current lung cancer.
   3. Any prior systemic anticancer therapy (e.g., neoadjuvant chemotherapy), including investigational therapy, for treatment of NSCLC.
   4. Major surgery (including primary tumor surgery, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
   5. Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known.

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

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

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

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

   1. Non-melanoma skin cancer treated with curative intent
   2. Carcinoma in situ treated with curative intent
   3. Other curatively treated cancer, with no evidence of disease for >3 years following the end of treatment and, in the opinion of the treating physician, has no substantial risk of recurrence.

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

8. Active bleeding disorders.

9. Known:

   a. Hypersensitivity: i. To the ingredients in zipalertinib/placebo or any drugs similar 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) or pemetrexed according to the respective local labels.

10. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.