A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Phase 3 Study of Zipalertinib Plus Adjuvant Chemotherapy Versus Placebo Plus Adjuvant Chemotherapy in Stage IB-IIIA NSCLC Patients With Uncommon EGFR Mutations Following Complete Tumor Resection (REZILIENT4)

Plain English Summary

A Study to Assess the Efficacy and Safety of Zipalertinib Versus Placebo for Adjuvant Treatment in Participants With Stage IB-IIIA NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection is a Phase 3 clinical trial sponsored by Taiho Oncology, Inc. studying NSCLC, Stage IB-IIIA, Lung Cancer, Adjuvant, Post-surgical, EGFR, Exon 20, Early Stage Lung Cancer, Uncommon EGFR Mutations. Tests zipalertinib plus chemotherapy vs. placebo plus chemotherapy for early stage lung cancer with uncommon EGFR mutations. For patients who have had their lung cancer surgically removed and have certain EGFR mutations. Participation involves taking study drugs or placebo for up to 5 years and regular check-ups. Alternative treatments include standard chemotherapy and targeted therapies. The trial aims to enroll 360 participants.

Official Summary

The purpose of this study is to compare the efficacy of zipalertinib combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in participants with early stage (stage IB-IIIA) resected non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor mutation (EGFRmt).

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if diagnosed with early stage (IB-IIIA) non-small cell lung cancer with uncommon EGFR mutations. Not eligible if currently receiving other investigational drugs or have had prior systemic anticancer therapy. Age: 18+ years. Health: Good general health, no active bleeding disorders, no history of other cancers. Must have undergone complete tumor resection with negative margins and no brain metastasis. This trial is studying NSCLC, Stage IB-IIIA, Lung Cancer, Adjuvant, Post-surgical, EGFR, Exon 20, Early Stage Lung Cancer, Uncommon EGFR Mutations, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

Primary outcome measures include disease-free survival, which means how long patients stay free from cancer recurrence. The specific primary outcome measures are: Disease-free Survival (DFS) as Assessed by the Investigator (Up to 5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a treatment gap for early stage lung cancer patients with uncommon EGFR mutations, offering a new potential therapy. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets NSCLC, Stage IB-IIIA, Lung Cancer, Adjuvant, Post-surgical, EGFR, Exon 20, Early Stage Lung Cancer, Uncommon EGFR Mutations, where improved treatment options are needed.

Investor Insight

Market size is significant, with a growing need for effective treatments for early stage lung cancer with uncommon EGFR mutations. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have any of the uncommon EGFR mutations and if you are a candidate for this study. Participation involves taking study drugs or placebo and regular check-ups at the clinic. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 360 participants

Interventions

• DRUG: Cisplatin — IV infusion.
• DRUG: Carboplatin — IV infusion.
• DRUG: Pemetrexed — IV infusion.
• DRUG: TAS6417 — Oral tablets.
• DRUG: Zipalertinib Matching-placebo — Oral tablets.

Primary Outcomes

• Disease-free Survival (DFS) as Assessed by the Investigator (Up to 5 years)

Secondary Outcomes

• Disease-free Survival Rate (At 2, 3 and 5 years)
• Overall Survival (OS) (Up to 5 years)
• Overall Survival Rate (At 2, 3 and 5 years)
• DFS of Central Nervous System (cDFS) (Up to 5 years)
• 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 5 years)

Full Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed diagnosis of primary NSCLC on predominantly non-squamous histology.
2. Documented EGFRmt status as determined by local testing performed at a clinical laboratory improvement amendment (CLIA) certified (United States \[US\]) or accredited (outside of the US) local laboratory, defined as either one of the following EGFRmt:

   1. exon20 insertion mutations (ex20ins) or
   2. other uncommon, non-ex20ins EGFRmt (eg, G719X, L861Q, or S768I)
3. Baseline imaging assessment of the brain (MRI or CT scan) performed within 8 weeks prior to randomization must show no evidence of brain metastasis
4. Complete surgical resection of the primary NSCLC is mandatory with negative surgical margins and systematic lymph node sampling or dissection.
5. Complete recovery from surgery, including post-operative wound healing at the time of randomization. Randomization must occur between 4 weeks and 12 weeks following surgery.
6. Eastern cooperative oncology group performance status (ECOG PS) of 0 or 1.
7. Pathologic (post-operative) Stage IB, IIA, IIB, or IIIA according to the tumor nodes metastasis (TNM) staging system for lung cancer. In addition, participants with stage IIIB are eligible when regional lymph node involvement is N2.

   \- Participants with Stage IB NSCLC should be considered when disease has high-risk features (eg, visceral pleural invasion, lymphovascular invasion or high-grade histology) and participants are suitable for adjuvant chemotherapy according to international guidelines such as the 2025 European Society for Medical Oncology guideline.
8. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers.

   .

Exclusion Criteria:

1. Is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study.
2. Treatment with any of the following within the time frame specified:

   1. Zipalertinib (TAS6417/CLN-081) or any other EGFR inhibitor at any time.
   2. Pre-operative or post-operative or planned radiation therapy for the current lung cancer.
   3. Any prior systemic anticancer therapy (e.g., neoadjuvant chemotherapy), including investigational therapy, for treatment of NSCLC.
   4. Major surgery (including primary tumor surgery, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
   5. Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known.
3. Has received only wedge resections (complete anatomic segmentectomy is acceptable).
4. Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-induced ILD/pneumonitis or any evidence of clinically active ILD/pneumonitis.
5. Unable to swallow tablets or has any disease or condition that may significantly affect gastrointestinal (GI) absorption of zipalertinib (such as inflammatory bowel disease, malabsorption syndrome, or prior significant bowel resection).
6. Has a history of any other cancer except for any of the following:

   1. Non-melanoma skin cancer treated with curative intent
   2. Carcinoma in situ treated with curative intent
   3. Other curatively treated cancer, with no evidence of disease for \>3 years following the end of treatment and, in the opinion of the treating physician, has no substantial risk of recurrence.
7. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment. Screening not required.
8. Active bleeding disorders.
9. Known:

   a. Hypersensitivity: i. To the ingredients in zipalertinib/placebo or any drugs similar in structure or class. ii. To platinum-containing drugs (i.e., cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications to platinum-containing drugs (i.e., cisplatin, carboplatin) or pemetrexed according to the respective local labels.
10. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.

Trial Locations

• Alaska Oncology and Hematology, Anchorage, Alaska, United States
• City of Hope Comprehensive Cancer Center - Duarte, Duarte, California, United States
• City of Hope Comprehensive Cancer Center Orange County Lennar Foundation Cancer Center, Irvine, California, United States
• Scripps Clinic Torrey Pines, La Jolla, California, United States
• Kaiser Permanente - Vallejo Medical Center, Vallejo, California, United States
• Georgetown University School of Medicine, Washington D.C., District of Columbia, United States
• D&H Cancer Research Center - Margate, Margate, Florida, United States
• Alpha Oncology Research, Orange City, Florida, United States
• City of Hope - Atlanta, Newnan, Georgia, United States
• University of Illinois Medical Center, Chicago, Illinois, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Related conditions include other types of lung cancer, early stage lung cancer, and uncommon EGFR mutations.
• Therapeutic areas include non-small cell lung cancer, adjuvant therapy, and targeted therapies.

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