Part A:
Safety lead-in to determine the recommended dose of zipalertinib in combination with standard chemotherapy 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 to standard chemotherapy alone.

Zipalertinib plus Chemotherapy versus Chemotherapy alone

Incidence of dose-limiting toxicities (DLTs) graded according to the NCI-Common Terminology Criteria of Adverse Events (CTCAE) v5.0 during Cycle 1

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 non-squamous NSCLC
Has not received any prior systemic treatment for their locally advanced or metastatic Non-squamous 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
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.
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.
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:
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.

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:
a. History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification (Appendix A).
b. Serious cardiac arrhythmias requiring treatment.
c. Resting corrected QT interval (QTc) >470 msec calculated using Fridericia's formula (QTcF).

Unable to swallow tablets/capsules 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:
a. Adequately treated basal or squamous cell carcinoma of the skin
b. Cancer of the breast or cervix in situ
c. 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
d. 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.

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

Is pregnant or lactating.

The patient is, in the investigator’s opinion, unable or unwilling to comply with the trial procedures.