• Provide written informed consent.
• ≥18 years of age (or meets the country’s regulatory definition for legal adult age, whichever is greater).
• Pathologically confirmed, locally advanced or metastatic nonsquamous NSCLC
• Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment received >6 months prior to first dose of study treatment is allowed for early-stageNSCLC. Prior monotherapy with an approved EGFR TKI (ie, gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib) as nonstandard first-line therapy for the treatment of locally advanced or metastatic disease is allowed if all of the following criteria are met:
  1. Treatment duration did not exceed 8 weeks;
  2. Lack of disease response was documented (radiographically) by an increase in tumor burden (a copy of the computerized tomography [CT] report showing increase in tumor burden from baseline should be submitted);
  3. Associated toxicities have resolved to baseline; and
  4. The EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to randomization, whichever is longer.

  Prior therapy with EGFR TKI agents targeting exon20ins mutations including amivantamab, mobocertinib, sunvozertinib, furmonertinib, and poziotinib is not allowed.

• Documented EGFR mutation status, as determined by local testing performed at a CLIA certified (US) or accredited (outside of the US) local laboratory, defined as follows:
  1. Part A: EGFR ex20ins or other uncommon single or compound EGFR mutation
  2. Part B: EGFR ex20ins mutation
• 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 brain metastasis(es) who have previously received definitive local treatment and have stable central nervous system (CNS) disease (defined as being neurologically stable and off corticosteroid for at least 2 weeks prior to enrollment) are eligible. If brain metastases are diagnosed on screening imaging, the patient may be rescreened for eligibility after definitive treatment.b. Asymptomatic brain metastases ≤2 cm in size can be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated.
• At least one measurable lesion as determined per RECIST 1.1 for patients enrolling to Part B. Patients enrolling to Part A may be enrolled without measurable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Adequate organ function, as defined by the laboratory value
• Have a life expectancy of at least 3 months as assessed by the investigator.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of childbearing potential if they are postmenopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
• Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 6 months after the last dose of study treatment or longer, based on local requirements.

• 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:
  1. Zipalertinib (TAS6417/CLN-081) at any time.
  2. 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.
  3. Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment.
  4. All prescribed medication, over-the-counter medication, vitamin preparations and other food supplements, or herbal medications that are strong or moderate CYP3A4 inducers or inhibitors within 7 days prior to first dose.
• 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.
• Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or any evidence of clinically active interstitial lung disease.
• Impaired cardiac function or clinically significant cardiac disease, including any of the following:
  1. History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification .
  2. Serious cardiac arrhythmias requiring treatment.
  3. Resting corrected QT interval (QTc) >470 msec calculated using Fridericia’s formula (QTcF).
• 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 GI resection).
• History of another primary malignancy ≤2 years prior to the date of first dose of study treatment unless at least one of the following criteria are met:
  1. Adequately treated basal or squamous cell carcinoma of the skin
  2. Cancer of the breast or cervix in situ
  3. Previously treated malignancy, if all treatment for that malignancy was completed at least 2 years prior to first dose of study treatment, and no current evidence of disease
  4. Concurrent malignancy determined to be clinically stable and not requiring tumor directed treatment
• Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment.
• History of COVID-19 infection within 4 weeks prior to enrolment and/or have persistent, clinically significant pulmonary symptoms related to prior COVID-19 infection.
• Active bleeding disorders.
• Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class. To platinum-containing drugs (ie, cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications toning drugs (ie, cisplatin, carboplatin) or pemetrexed according to the respective local labels.
• History of leptomeningeal disease and spinal cord compression.
• Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.
• Is pregnant or lactating or planning to become pregnant
• The patient is, in the investigator’s opinion, unable or unwilling to comply with the trial procedures.

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