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 Criteria55

• Written informed consent.
• ≥18 years of age (or meets the country's regulatory definition of legal adult age, whichever is greater.
• Pathologically confirmed, locally advanced or metastatic NSCLC meeting all the following criteria:
• Cohort A participants:
• Documented EGFR ex20ins status, as determined by local testing performed at a Clinical 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, either alone or in combination with standard platinum-based chemotherapy for the treatment of advanced disease. Participants who discontinued previous treatment due to unacceptable toxicity are eligible.
• i. Permitted prior ex20ins therapies include: amivantamab, sunvozertinib (DZD9008), and BLU451. Other prior ex20ins--directed treatment may be discussed with the Sponsor for eligibility assessment.
• Participants with brain metastasis must be neurologically stable. Participants must have received central nervous system (CNS)-directed therapy and have no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or computed tomography \[CT\] scan) during the Screening Period. Additionally, they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Participants with a history of uncontrolled seizures or LMD are not eligible.
• 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.
• Participants with brain metastasis must be neurologically stable. Participants must have received CNS-directed therapy and have no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the Screening Period, and they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Participants with history of uncontrolled seizures or LMD are not eligible.
• 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 with brain metastasis must be neurologically stable. Participants must have received CNS-directed therapy and have no evidence of progression for at least 4 weeks after CNS- directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the Screening Period, and they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Participants with history of uncontrolled seizures or LMD are not eligible.
• 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).
• Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• 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.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 17.
• Adequate organ function, as defined by the hematologic, renal and hepatic laboratory values.
• 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).
• 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:
• 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)
• 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).
• Participants with brain metastasis are eligible if they fulfill all of the criteria below:
• Have received CNS-directed therapy and have no evidence of progression for at least 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-convulsant medications for at least 2 weeks prior to the first dose of study treatment,
• Are neurologically stable with no history of uncontrolled seizures.
• ECOG PS of 0 or 1.
• Dose Optimization Substudy:
• Has pathologically confirmed, locally advanced or metastatic NSCLC meeting all the following criteria:
• Documented EGFR ex20ins status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US)
• Progressed on or after systemic therapy standard platinum-based chemotherapy for the treatment of advanced disease. Participants who discontinued previous treatment 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).
• Participants with CNS metastases are eligible if both of the following criteria are met:
• i. Measurable lesions according to RANO-BM defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension, with a minimum size of 10 millimeters (mm), or at least 5 mm if MRI slice thickness is ≤ 1.5 mm ii. Previously received definitive local treatment and have stable CNS disease (defined as being neurologically stable and off corticosteroid for at least 2 weeks prior to enrollment) OR Asymptomatic CNS metastases ≤ 2 cm in size if, in the opinion of the investigator, immediate definitive treatment is not indicated.
• Measurable disease per RECIST 1.1.
• Has archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers
• ECOG PS of 0 or 1.
• Has adequate organ function.