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.

Phase 2

Recruiting

• Conditions: Advanced or Metastatic NSCLC Harboring Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations
• Interventions: Drug: TAS6417

• Registration Number: NCT05967689
• Lead Sponsor: Taiho Oncology, Inc.

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of zipalertinib in participants with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring EGFR ex20ins mutations and other mutations.

Detailed Description

This study will evaluate the safety and efficacy of zipalertinib in participants with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations or other uncommon/single or compound Epidermal Growth Factor Receptor Proteins Mutations (EGFRmts).

Participants will be enrolled into 1 of the 4 following cohorts:

* Cohort A ("prior ex20ins treatment") will include participants harboring EGFR ex20ins who have progressed on or after initial treatment with standard platinum-based chemotherapy and prior treatment with an ex20ins agent for their advanced disease (administered together or separately).

* Cohort B ("first-line") will include participants harboring EGFR ex20ins who have not received prior treatment for advanced or metastatic disease and are not appropriate candidates for first-line doublet platinum-based chemotherapy or have refused first-line doublet platinum-based chemotherapy.

* Cohort C ("active brain mets") will include participants harboring EGFR ex20ins or other uncommon single or compound EGFRmts and active brain metastases and/or leptomeningeal disease (LMD). Participants may or may not have had prior treatment for advanced disease.

* Cohort D ("other uncommon EGFRmts") will include participants harboring other non-ex20ins, excluding C797S (uncommon single or compound) EGFRmts who have not received prior systemic therapy for their locally advanced or metastatic NSCLC disease.

Study Timeline

• Study First Submitted: 2023-07-11
• Study First Submitted QC: 2023-07-21
• Study Start: 2023-07-31
• Study First Posted: 2023-08-01
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-30
• Last Update Posted: 2025-06-03
• Primary Completion: 2026-02-28
• Study Completion: 2026-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 220

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 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).

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.

Exclusion Criteria

1. Patient 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. Patient has received Zipalertinib (TAS6417/CLN081) at any time
   2. Thoracic radiotherapy ≤28 days or palliative radiation (gamma knife radiotherapy is allowed) ≤14 days prior to the first dose of study treatment
   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. All prescribed medication, over-the-counter medication, vitamin preparations and other food supplements, or herbal medications that are strong or moderate CYP3A4 inducers or inhibitors within 7 days prior to first dose of study treatment

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 of the breast or cervix in situ
   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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A ("prior ex20ins treatment")	TAS6417	Cohort A ("prior ex20ins treatment") participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
Cohort B ("first-line treatment")	TAS6417	Cohort B participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
Cohort C ("active brain mets")	TAS6417	Cohort C participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
Cohort D ("other uncommon EGFRmts").	TAS6417	Cohort D participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.

Primary Outcome Measures

Name	Time	Method
All Cohorts: Objective Response Rate (ORR)	Up to approximately 2 years

Secondary Outcome Measures

Name	Time	Method
All Cohorts: Number of Participants with Clinically Significant Changes in Clinical Laboratory Parameters	Up to approximately 2 years
All Cohorts: Disease control rate (DCR)	Up to approximately 2 years
All Cohorts: Overall Survival (OS)	Up to approximately 2 years
All Cohorts: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)	Up to approximately 2 years
All Cohorts: Number of Participants with Clinically Significant Changes in Vital Signs	Up to approximately 2 years
All Cohorts: Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters	Up to approximately 2 years
All Cohorts: Number of participants With Change in Left Ventricular Ejection Fraction (LVEF) Evaluated Using Electrocardiography (ECHO) and Multigated Acquisition (MUGA) Scan	Up to approximately 2 years
All Cohorts: Duration of response (DoR)	Up to approximately 2 years
All Cohorts: Progression-free survival (PFS)	Up to approximately 2 years
Cohort C: Intracranial (i) Overall Response Rate (iORR)	Up to approximately 2 years
Cohort C: Intracranial Duration of Complete Response (iDCR)	Up to approximately 2 years
Cohort C: Intracranial Duration of Response (iDoR)	Up to approximately 2 years
All Cohorts: Minimum Plasma Concentration (Cmin) of Zipalertinib	Up to approximately 2 years

Trial Locations

Locations (99)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

City of Hope - Duarte; 🇺🇸 Duarte, California, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Memorial Sloan Kettering Cancer Center - Basking Ridge; 🇺🇸 Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Cancer Center - Monmouth; 🇺🇸 Middletown, New Jersey, United States

Memorial Sloan Kettering Cancer Center - Bergen; 🇺🇸 Montvale, New Jersey, United States

Memorial Sloan Kettering Cancer Center - Commack; 🇺🇸 Commack, New York, United States

Memorial Sloan Kettering Cancer Center - Westchester; 🇺🇸 Harrison, New York, United States

MSK Cancer Center; 🇺🇸 Long Island City, New York, United States

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