A Study to Assess Zipalertinib Versus Placebo in Participants With Early Stage NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection

This study will evaluate zipalertinib, a novel EGFR tyrosine kinase inhibitor (TKI) versus placebo in participants with resected early stage NSCLC harboring uncommon EGFRmt.

Approximately 360 participants will be randomized to:

Arm A: Zipalertinib twice daily (BID) monotherapy OR

Arm B: Placebo BID monotherapy.

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

Inclusion criteria

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

• exon20 insertion mutations (ex20ins) or
• other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I) exons 18-21 of the EGFR tyrosine kinase domain
• Baseline imaging assessment of the brain (MRI [preferred modality] or CT scan) performed within 8 weeks prior to randomization must show no evidence of brain metastasis
• Complete surgical resection of the primary NSCLC is mandatory with negative surgical margins and systematic lymph node sampling or dissection.
• Complete recovery from surgery, including post-operative wound healing, and prior adjuvant chemotherapy (if applicable) at the time of randomization. Randomization timing is defined as follows:

• For participants without prior adjuvant chemotherapy: 4 weeks and 12 weeks following surgery.
• For participants with prior adjuvant chemotherapy: 4 weeks and 8 weeks after the last dose of adjuvant chemotherapy.
• Eastern cooperative oncology group performance status (ECOG PS) of 0 or 1.
• Pathologic (post-operative) Stage IB, IIA, IIB, or IIIA according to the AJCC 9th tumor nodes metastasis (TNM) staging system for lung cancer. In addition, participants with stage IIIB are eligible when regional lymph node involvement is N2.
• Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers.

Exclusion criteria

• Is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research.
• Treatment with any of the following within the time frame specified:

• Zipalertinib (TAS6417/CLN-081) or any other EGFR inhibitor at any time.
• Pre-operative or post-operative or planned radiation therapy for the current lung cancer.
• Any prior systemic anticancer therapy for NSCLC, including preoperative (neoadjuvant) chemotherapy, immunotherapy, or investigational therapy. (Exception: Participants who have received postoperative adjuvant platinum-based chemotherapy up to 4 cycles are permitted)
• Major surgery (including primary tumor surgery, excluding placement of vascular access) within 4 weeks prior to the first dose of study treatment.
• Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known.
• Has received only wedge resections (complete anatomic segmentectomy is acceptable).
• Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-induced ILD/pneumonitis or any evidence of clinically active ILD/pneumonitis.
• 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).
• Has a history of any other cancer except for any of the following:

• Non-melanoma skin cancer treated with curative intent
• Carcinoma in situ treated with curative intent
• 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.
• Concurrent malignancy of which natural history does not have the potential to interfere with the safety or efficacy assessment (eg, Gleason 6 prostate cancer)
• Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment.
• Active bleeding disorders.
• Known hypersensitivity to the ingredients in zipalertinib/placebo or any drugs similar in structure or class.