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.

Inclusion Criteria:

1. Written informed consent.

2. ≥18 years of age (or meets the country's regulatory definition of legal adult age,whichever is greater.

3. Pathologically confirmed, locally advanced or metastatic NSCLC meeting all thefollowing criteria: Cohort A participants:

• Documented EGFR ex20ins status, as determined by local testing performed at aClinical Laboratory Improvement Amendments (CLIA) certified (United States [US]) or locally certified laboratory (outside the US).

• Progressed on or after systemic therapy with an agent targeting ex20ins, eitheralone or in combination with standard platinum-based chemotherapy for thetreatment of advanced disease. Participants who discontinued previous treatmentdue to unacceptable toxicity are eligible. i. Permitted prior ex20ins therapies include: amivantamab, sunvozertinib (DZD9008), and BLU451. Other prior ex20ins--directed treatment may be discussedwith the Sponsor for eligibility assessment.

• Participants with brain metastasis must be neurologically stable. Participantsmust have received central nervous system (CNS)-directed therapy and have noevidence of progression for at least 4 weeks after CNS-directed treatment, asascertained by clinical examination and brain imaging (magnetic resonanceimaging [MRI] or computed tomography [CT] scan) during the Screening Period.Additionally, they must be on a stable or decreasing dose of corticosteroidsand/or anti-convulsant medications for at least 2 weeks prior to the first doseof study treatment. Participants with a history of uncontrolled seizures or LMDare not eligible. Cohort B participants:

• Documented EGFR ex20instatus, as determined by local testing performed at aCLIA-certified (US) or locally certified laboratory (outside the US).

• Participants who have not received prior treatment for advanced or metastaticdisease and who are not appropriate candidates for first-line doubletplatinum-based chemotherapy based on Investigator judgment or has refusedfirst-line doublet platinum-based chemotherapy following discussion with theInvestigator. Prior adjuvant/neoadjuvant treatment for early-stage disease musthave been completed >6 months prior to the first dose of study treatment.

• Participants with brain metastasis must be neurologically stable. Participantsmust have received CNS-directed therapy and have no evidence of progression forat least 4 weeks after CNS-directed treatment, as ascertained by clinicalexamination and brain imaging (MRI or CT scan) during the Screening Period, andthey must be on a stable or decreasing dose of corticosteroids and/oranti-convulsant medications for at least 2 weeks prior to the first dose ofstudy treatment. Participants with history of uncontrolled seizures or LMD arenot eligible. Cohort C participants:

• Documented ex20ins or other uncommon single or compound EGFR non-ex20insstatus, as determined by local testing performed at a CLIA-certified (US) orlocally certified laboratory (outside the US).

• Presence of brain metastasis(es) characterized as at least one of thefollowing:

• Newly diagnosed and/or progressive brain metastasis(es) measurable byResponse Assessment in Neuro-oncology Brain Metastases (RANO-BM) criteriaand not subjected to CNS-directed therapy, AND/OR

• LMD measurable or non-measurable by RANO-BM criteria and confirmed by apositive cerebrospinal fluid cytology, or unequivocal radiographic and/orclinical determination.

• Participants may not require other immediate CNS-directed therapy or willlikely require other CNS directed anti-tumor therapy during the first cycle ofstudy treatment, as judged by the Investigator. Cohort D participants:

• Documented other uncommon single or compound EGFR non-ex20ins status (excludingC797S), as determined by local testing performed at a CLIA certified (US) orlocally certified laboratory (outside the US). A list of eligible mutationswill be provided in a separate document.

• Participants with brain metastasis must be neurologically stable. Participantsmust have received CNS-directed therapy and have no evidence of progression forat least 4 weeks after CNS- directed treatment, as ascertained by clinicalexamination and brain imaging (MRI or CT scan) during the Screening Period, andthey must be on a stable or decreasing dose of corticosteroids and/oranti-convulsant medications for at least 2 weeks prior to the first dose ofstudy treatment. Participants with history of uncontrolled seizures or LMD arenot eligible.

• Participants who have not received prior systemic therapy for their locallyadvanced or metastatic NSCLC disease.

• Prior adjuvant/neoadjuvant treatment for early-stage disease must have beencompleted >6 months prior to the first dose of study treatment. Participantsmay not have received prior adjuvant/neoadjuvant treatment with any EGFRtyrosine 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 toevaluate EGFRmt status and, where possible, other biomarkers (details provided in alaboratory manual). Participants with insufficient tissue may be eligible followingdiscussion 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 laboratoryvalues.

8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy testprior to administration of the first dose of study treatment. Female participantsare not considered to be of childbearing potential if they are post-menopausal (nomenses 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 birthcontrol during the study prior to the first dose of study drug and for 1 month afterthe 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 clinicallaboratory improvement amendments (CLIA) certified (US) or locally certifiedlaboratory (outside of the US) local laboratory, defined as either one of thefollowing 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 isindicated or available,

• Participant is intolerant to the available first-line (1L) SoC treatmentoptions, OR

• Participant has refused 1L SoC treatment options (after being appropriatelyinformed of the treatment options, risks, and benefits).

3. Participants with brain metastasis are eligible if they fulfill all of the criteriabelow:

• Have received CNS-directed therapy and have no evidence of progression for atleast 4 weeks after CNS- directed treatment, as ascertained by brain imaging (MRI or CT scan) during the Screening Period,

• Are on a stable or decreasing dose of corticosteroids and/or anti-convulsantmedications for at least 2 weeks prior to the first dose of study treatment,

• Are neurologically stable with no history of uncontrolled seizures.

4. ECOG PS of 0 or 1.

Dose Optimization Substudy:

1. Has pathologically confirmed, locally advanced or metastatic NSCLC meeting all thefollowing criteria:

2. Documented EGFR ex20ins status, as determined by local testing performed at aCLIA certified (US) or locally certified laboratory (outside the US)

3. Progressed on or after systemic therapy standard platinum-based chemotherapyfor the treatment of advanced disease. Participants who discontinued previoustreatment due to unacceptable toxicity are eligible. Note: Progression on or after systemic therapy with amivantamab is permitted (eg,given as monotherapy or in combination with chemotherapy).

4. Participants with CNS metastases are eligible if both of the following criteria aremet:

i. Measurable lesions according to RANO-BM defined as a contrast-enhancing lesionthat can be accurately measured in at least one dimension, with a minimum size of 10millimeters (mm), or at least 5 mm if MRI slice thickness is ≤ 1.5 mm ii. Previouslyreceived definitive local treatment and have stable CNS disease (defined as beingneurologically stable and off corticosteroid for at least 2 weeks prior toenrollment) OR Asymptomatic CNS metastases ≤ 2 cm in size if, in the opinion of theinvestigator, immediate definitive treatment is not indicated.

3. Measurable disease per RECIST 1.1.

4. Has archival tumor tissue available for submission, with minimum quantity sufficientto evaluate EGFRmt status and, where possible, other biomarkers

5. ECOG PS of 0 or 1.

6. Has adequate organ function.

Exclusion Criteria:

1. Participant is currently receiving an investigational drug in a clinical trial orparticipating in any other type of medical research judged to be scientifically ormedically incompatible with this study.

2. Has received any of the following within the specific time frame specified:

3. Participant has received Zipalertinib (TAS6417/CLN081) at any time

4. CNS radiotherapy (gamma knife radiotherapy is allowed) ≤ 12 weeks, thoracicradiotherapy ≤ 28 days, or other palliative radiation ≤ 14 days prior to thefirst dose of study

5. Anticancer immunotherapy ≤28 days prior to the first dose of study treatment

6. Major surgery (excluding placement of vascular access) ≤28 days prior to thefirst dose of study treatment.

7. Any prior treatment with an EGFR exon20ins- targeted TKI

8. Participants with leptomeningeal CNS disease.

9. Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment, exceptfor Grade 2 alopecia or skin pigmentation. Participants with other chronic butstable Grade 2 toxicities may be allowed to enroll after agreement between theInvestigator and Sponsor.

10. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or evidence of clinically active interstitial lung disease.

11. Impaired cardiac function or clinically significant cardiac disease including any ofthe following:

12. History of congestive heart failure (CHF) Class III/IV according to the NewYork Heart Association (NYHA) Functional Classification.

13. Serious cardiac arrhythmias requiring treatment.

14. Resting corrected QT interval (QTc) >470 msec using Fridericia's formula (QTcF).

15. Is unable to swallow tablets or has any disease or condition that may significantlyaffect gastrointestinal absorption of zipalertinib (eg, inflammatory bowel disease,malabsorption syndrome, or prior gastric/bowel resection).

16. History of another primary malignancy ≤2 years prior to the date of first dose ofstudy treatment unless at least one of the following criteria are met:

17. Adequately treated basal or squamous cell carcinoma of the skin

18. Cancer in situ of the breast or cervix

19. Participants with previously treated malignancy if all treatment for thatmalignancy was completed at least 2 years prior to first dose and no evidenceof disease

20. Participants with concurrent malignancy clinically stable and not requiringtumor-directed treatment

21. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)that is not controlled with treatment.

22. History of Coronavirus disease 2019 (COVID-19) infection within 4 weeks prior toenrollment and/or has persistent clinically significant pulmonary symptoms relatedto prior COVID-19 infection.

23. Active bleeding disorders.

24. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar instructure or class.

25. Is pregnant, lactating, or planning to become pregnant.

26. The participant is, in the Investigator's opinion, unable or unwilling to complywith the trial procedures.