A Study of Zipalertinib in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions or Other Uncommon Mutation.

Exclusion Criteria

• •Cohort B participants:
• •* Documented EGFR ex20instatus, as determined by local testing performed at a CLIA-certified (US) or locally certified laboratory (outside the US).
• •* Participants who have not received prior treatment for advanced or metastatic disease and who are not appropriate candidates for first-line doublet platinum-based chemotherapy based on Investigator judgment or has refused first-line doublet platinum-based chemotherapy following discussion with the Investigator. Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed \>6 months prior to the first dose of study treatment.
• •Cohort C participants:
• •* Documented ex20ins or other uncommon single or compound EGFR non-ex20ins status, as determined by local testing performed at a CLIA-certified (US) or locally certified laboratory (outside the US).
• •* Presence of brain metastasis(es) characterized as at least one of the following:
• •* Newly diagnosed and/or progressive brain metastasis(es) measurable by Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) criteria and not subjected to CNS-directed therapy, AND/OR
• •* LMD measurable or non-measurable by RANO-BM criteria and confirmed by a positive cerebrospinal fluid cytology, or unequivocal radiographic and/or clinical determination.
• •* Participants may not require other immediate CNS-directed therapy or will likely require other CNS directed anti-tumor therapy during the first cycle of study treatment, as judged by the Investigator.
• •Cohort D participants:
• •* Documented other uncommon single or compound EGFR non-ex20ins status (excluding C797S), as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US). A list of eligible mutations will be provided in a separate document.
• •* Participants who have not received prior systemic therapy for their locally advanced or metastatic NSCLC disease.
• •* Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed \>6 months prior to the first dose of study treatment. Participants may not have received prior adjuvant/neoadjuvant treatment with any EGFR tyrosine kinase inhibitor (TKI).
• •4. Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• •5. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers (details provided in a laboratory manual). Participants with insufficient tissue may be eligible following discussion with the Sponsor.
• •6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 17.
• •7. Adequate organ function, as defined by the hematologic, renal and hepatic laboratory values.
• •8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female participants are not considered to be of childbearing potential if they are post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
• •9. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose of study drug and for 1 month after the last dose of study treatment.
• •DDI Substudy:
• •1. Participant has pathologically confirmed, locally advanced or metastatic NSCLC:
• •a. Documented EGFRmt status as determined by local testing performed at a clinical laboratory improvement amendments (CLIA) certified (US) or locally certified laboratory (outside of the US) local laboratory, defined as either one of the following EGFRmts:
• •* ex20ins EGFRmt OR
• •* other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I) OR
• •* common EGFRmt (eg, ex19del or L858R)
• •2. Participant has progressed on or after receiving prior standard of care (SoC) systemic therapy for their locally advanced or metastatic NSCLC disease unless:
• •* Participant for whom no approved therapy with demonstrated clinical benefit is indicated or available,
• •* Participant is intolerant to the available first-line (1L) SoC treatment options, OR
• •* Participant has refused 1L SoC treatment options (after being appropriately informed of the treatment options, risks, and benefits).
• •1. Participant is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged to be scientifically or medically incompatible with this study.
• •2. Has received any of the following within the specific time frame specified:
• •1. Participant has received Zipalertinib (TAS6417/CLN081) at any time
• •2. CNS radiotherapy (gamma knife radiotherapy is allowed) ≤ 12 weeks, thoracic radiotherapy ≤ 28 days, or other palliative radiation ≤ 14 days prior to the first dose of study
• •3. Anticancer immunotherapy ≤28 days prior to the first dose of study treatment
• •4. Major surgery (excluding placement of vascular access) ≤28 days prior to the first dose of study treatment.
• •5. Any prior treatment with an EGFR exon20ins- targeted TKI
• •6. Participants with leptomeningeal CNS disease.
• •3. Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment, except for Grade 2 alopecia or skin pigmentation. Participants with other chronic but stable Grade 2 toxicities may be allowed to enroll after agreement between the Investigator and Sponsor.
• •4. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or evidence of clinically active interstitial lung disease.
• •5. 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 using Fridericia's formula (QTcF).
• •6. Is unable to swallow tablets or has any disease or condition that may significantly affect gastrointestinal absorption of zipalertinib (eg, inflammatory bowel disease, malabsorption syndrome, or prior gastric/bowel resection).
• •7. 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 in situ of the breast or cervix
• •3. Participants with previously treated malignancy if all treatment for that malignancy was completed at least 2 years prior to first dose and no evidence of disease
• •4. Participants with concurrent malignancy clinically stable and not requiring tumor-directed treatment
• •8. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is not controlled with treatment.
• •9. History of Coronavirus disease 2019 (COVID-19) infection within 4 weeks prior to enrollment and/or has persistent clinically significant pulmonary symptoms related to prior COVID-19 infection.
• •10. Active bleeding disorders.
• •11. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class.
• •12. Is pregnant, lactating, or planning to become pregnant.
• •13. The participant is, in the Investigator's opinion, unable or unwilling to comply with the trial procedures.