Comparing 8 approaches for advanced or metastatic NSCLC harboring epidermal growth

Inclusion

• +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 PeriodScreeningThe checks done before joining, to see whether a study fits.Read more →. 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.
• +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.
• +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
• +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 with brain metastasis are eligible if they fulfill all of the criteria below:
• +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 enrollmentEnrolmentThe number of participants a study plans to include, or has included.Read more →) OR Asymptomatic CNS metastases ≤ 2 cm in size if, in the opinion of the investigatorPrincipal investigatorThe doctor or researcher responsible for running the study at a site.Read more →, immediate definitive treatment is not indicated.
• +Written informed consentInformed consentThe process of being told what taking part involves, then choosing freely.Read more →.
• +≥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:
• +CohortCohortA group of participants sharing a characteristic, followed together.Read more → 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).
• +i. Permitted prior ex20ins therapies include: amivantamab, sunvozertinib (DZD9008), and BLU451. Other prior ex20ins--directed treatment may be discussed with the SponsorSponsorThe organisation responsible for the study overall.Read more → for eligibilityEligibility criteriaThe full list of requirements for taking part in a study.Read more → assessment.
• +Cohort B participants:
• +Documented EGFR ex20instatus, as determined by local testing performed at a CLIA-certified (US) or locally certified laboratory (outside the US).
• +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).
• +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).
• +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 biomarkersBiomarkerSomething measurable in the body used as a signal of what is happening.Read more → (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.
• +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 careStandard of careThe treatment normally given for a condition outside a study.Read more → (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).
• +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)
• +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.
• +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 controlControl groupThe group a new treatment is measured against.Read more → during the study prior to the first dose of study drug and for 1 month after the last dose of study treatment.
• +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.
• +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.
• +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).