Randomized, Controlled, Open-label

• Part A: Safety lead-in to determine the recommended dose of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) to be studied in Part B of the study

• Part B: Randomized, controlled, open-label, multinational Phase 3 study to assess the efficacy and safety of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) compared with standard chemotherapy alone

Zipalertinib in combination with standard chemotherapie

To determine the recommended dose of zipalertinib in combination with pemetrexed and a platinum agent to be studied in the Phase 3 portion of the study

• Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment for advanced or metastatic disease >6 months prior to first dose of study treatment is allowed for early-stage NSCLC.
• Documented EGFR mutation status, as determined by local testing performed at a CLIA certified or equivalent laboratory, defined as follows:
a. Part A: ex20ins or other common single or compound EGFR mutation
b. Part B: ex20ins EGFR mutation 6. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFR mutation status and, where possible, other biomarkers. Patients with insufficient tissue (details provided in laboratory manual) may be eligible following discussion with the sponsor; a fresh biopsy will not be required.
• Patients with previously treated brain metastasis(es) and stable CNS disease (defined as being neurologically stable and receiving a stable or decreasing corticosteroid dose at time of enrollment) are eligible

• 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.
• Prior treatment with any of the following within the specific time frame specified:
a. Zipalertinib (TAS6417/CLN-081) at any time.
b. Thoracic radiotherapy ≤28 days, palliative radiation of nonthoracic disease ≤14 days, or palliative radiation of a single lesion ≤7 days prior to first dose of study treatment.
c. Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment.
• Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment in the neoadjuvant or adjuvant setting, except for Grade 2 alopecia or skin pigmentation. Patients with other chronic but stable Grade 2 toxicities may be allowed to enroll after agreement between the investigator and Sponsor.