Sponsor: Taiho Oncology, Inc. (industry)
Phase: 3
Start date: June 30, 2023
Planned enrollment: 272
Last updated in HealthScout: Nov 2024
Zipalertinib, also known as CLN-081 or TAS6417, is an investigational oral tyrosine kinase inhibitor (TKI) targeting non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. These mutations are associated with resistance to conventional EGFR TKIs, presenting a significant therapeutic challenge.
Zipalertinib is designed to selectively inhibit EGFR exon 20 insertion mutations while sparing wild-type EGFR. This selectivity aims to reduce off-target effects commonly associated with EGFR inhibition, such as rash and diarrhea. The drug's novel pyrrolopyrimidine scaffold enhances its binding affinity to mutant EGFR, leading to potent inhibition of tumor cell growth in preclinical models. (pubmed.ncbi.nlm.nih.gov)
In a phase 1/2a clinical trial involving 73 heavily pretreated patients with recurrent or metastatic NSCLC harboring EGFR exon 20 insertions, zipalertinib demonstrated promising antitumor activity. The confirmed objective response rate (ORR) across all dose levels was 38.4%, with all responses being partial. Specifically, at the 100 mg twice-daily dose, the ORR was 41%. The median progression-free survival (PFS) for all patients was 10 months, with a median duration of response (DOR) of 10 months. (pubmed.ncbi.nlm.nih.gov)
In a subsequent phase 2b study (REZILIENT1), zipalertinib continued to show efficacy in patients who had progressed after prior treatments, including amivantamab. Among 30 evaluable patients, the confirmed ORR was 40%, with a disease control rate (DCR) of 90%. The median PFS was 9.7 months, and the median DOR was not yet estimable at the time of reporting. (dnews.com)
Zipalertinib has demonstrated a manageable safety profile. In the phase 1/2a study, the most common treatment-related adverse events (TRAEs) were rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). Notably, no grade 3 or higher rash or diarrhea occurred at doses of 100 mg twice daily or below. Grade 3 or higher TRAEs were observed in 23% of patients, with anemia being the most common (10%). (pubmed.ncbi.nlm.nih.gov)
In the phase 2b study, the safety profile remained consistent. The most common TRAEs (≥10%) included rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%), with the majority being grade 1 or 2. No grade 4 or 5 TRAEs were reported. (dnews.com)
Last updated: Apr 2025
As of mid-2024, there are no clinical results or independent published analyses available for the Phase 3 clinical trial NCT05973773 studying zipalertinib plus chemotherapy compared to chemotherapy alone in untreated, locally advanced or metastatic nonsquamous NSCLC with EGFR exon 20 insertion mutations. Existing online news coverage mainly addresses the trial’s initiation, emphasizing the unmet need for new therapies in this mutation subtype.
Media and press releases highlight that this trial is significant due to the lack of treatment options and poor prognosis associated with EGFR exon 20 insertion mutations in non-small cell lung cancer. The launch of this study is described as important for expanding potential treatment options for these patients, an area where current standard-of-care therapies have limited efficacy. Comments from company leadership in press announcements reinforce the belief that targeting EGFR exon 20 insertions remains a clinical priority.
No reports of interim results, patient perspectives, or expert oncology community commentary specific to NCT05973773 are available as of the latest web search. There is also no discussion of trial enrollment progress or safety signals.
No relevant information found beyond the initial press and company announcements.
Last updated: Apr 2025
Goal: The trial's goal is to evaluate and compare the safety and efficacy of the investigational drug zipalertinib, combined with standard first-line chemotherapy, against chemotherapy alone in patients with advanced NSCLC who have EGFR exon 20 insertion mutations.
Patients: This trial involves patients aged 18 years or older, diagnosed with locally advanced or metastatic nonsquamous non-small cell lung cancer with confirmed EGFR exon 20 insertion mutations. Eligible participants have not received prior systemic treatment for advanced or metastatic disease, and those with stable CNS metastases may participate.
Design: The study follows a randomized, controlled, open-label, multinational Phase 3 design comprised of two main parts. Part A is a safety lead-in to establish the safe dose for zipalertinib. Part B is a 1:1 randomized, open-label comparison between the zipalertinib plus chemotherapy regimen and chemotherapy alone.
Treatments: The study investigates zipalertinib (TAS6417), an oral, irreversible tyrosine kinase inhibitor targeting EGFR exon 20 insertion mutations, distinguished by its selective action on mutant EGFR. Previous trials have shown it offers a partial response rate of 38.4% in pretreated patients, with a median progression-free survival of 10 months and a favorable safety profile. Standard chemotherapy protocols involve pemetrexed and a platinum agent (carboplatin or cisplatin) administered over a 21-day cycle.
Outcomes: The primary outcomes comprise the rate and severity of treatment-emergent adverse events, and progression-free survival (PFS). Secondary outcomes include overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), intracranial responses, quality of life assessments, and pharmacokinetic parameters.
Burden on patient: The overall burden on patients is moderate. Participation involves regular 21-day cycles of chemotherapy with zipalertinib in the experimental arm. Patients will undergo scans and blood draws consistent with standard oncology practice but may be more frequent due to the trial's requirements for pharmacokinetics and close monitoring. Frequent travel for treatment administrations and monitoring visits may increase the burden compared to oral regimen studies.
Inclusion-
1. Provide written informed consent.
2. ≥18 years of age (or meets the country's regulatory definition for legal adult age, whichever is greater).
3. Pathologically confirmed, locally advanced or metastatic nonsquamous NSCLC
4. Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment received \>6 months prior to first dose of study treatment is allowed for early-stage
NSCLC. Prior monotherapy with an approved EGFR TKI (ie, gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib) as nonstandard first-line therapy for the treatment of locally advanced or metastatic disease is allowed if all of the following criteria are met:
1. Treatment duration did not exceed 8 weeks;
2. Lack of disease response was documented (radiographically) by an increase in tumor burden (a copy of the computerized tomography \[CT\] report showing increase in tumor burden from baseline should be submitted);
3. Associated toxicities have resolved to baseline; and
4. The EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to randomization, whichever is longer.
Prior therapy with EGFR TKI agents targeting exon20ins mutations including amivantamab, mobocertinib, sunvozertinib, furmonertinib, and poziotinib is not allowed.
5. Documented EGFR mutation status, as determined by local testing performed at a CLIA certified (US) or accredited (outside of the US) local laboratory, defined as follows:
1. Part A: EGFR ex20ins or other uncommon single or compound EGFR mutation
2. Part B: EGFR ex20ins mutation
6. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFR mutation status and, where possible, other biomarkers. Patients with insufficient tissue (details provided in laboratory manual) may be eligible following discussion with the sponsor; a fresh biopsy will not be required.
7. Patients with brain metastasis(es) who have previously received definitive local treatment and have stable central nervous system (CNS) disease (defined as being neurologically stable and off corticosteroid for at least 2 weeks prior to enrollment) are eligible. If brain metastases are diagnosed on screening imaging, the patient may be rescreened for eligibility after definitive treatment.
b. Asymptomatic brain metastases ≤2 cm in size can be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated.
8. At least one measurable lesion as determined per RECIST 1.1 for patients enrolling to Part B. Patients enrolling to Part A may be enrolled without measurable disease.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
10. Adequate organ function, as defined by the laboratory value
11. Have a life expectancy of at least 3 months as assessed by the investigator.
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of childbearing potential if they are postmenopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
13. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 6 months after the last dose of study treatment or longer, based on local requirements.
Exclusion -
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. Prior treatment with any of the following within the specific time frame specified:
1. Zipalertinib (TAS6417/CLN-081) at any time.
2. Thoracic radiotherapy ≤28 days, palliative radiation of nonthoracic disease ≤14 days, or palliative radiation of a single lesion ≤7 days prior to first dose of study treatment.
3. Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment.
4. 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.
3. Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment in the neoadjuvant or adjuvant setting, except for Grade 2 alopecia or skin pigmentation. Patients 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 any 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 calculated using Fridericia's formula (QTcF).
6. 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 GI 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. Previously treated malignancy, if all treatment for that malignancy was completed at least 2 years prior to first dose of study treatment, and no current evidence of disease
4. Concurrent malignancy determined to be clinically stable and not requiring tumor directed treatment
8. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment.
9. History of COVID-19 infection within 4 weeks prior to enrolment and/or have 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. To platinum-containing drugs (ie, cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications toning drugs (ie, cisplatin, carboplatin) or pemetrexed according to the respective local labels.
12. History of leptomeningeal disease and spinal cord compression.
13. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.
14. Is pregnant or lactating or planning to become pregnant
15. The patient is, in the investigator's opinion, unable or unwilling to comply with the trial procedures.
Leuven, Flemish Brabant, 3000, Belgium
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Status: Recruiting
Gent, Oost-Vlaaderen, 9000, Belgium
No email / No phone
Status: Recruiting
Menen, West Flanders, 8930, Belgium
No email / No phone
Status: Recruiting
Rosières, West-Vlaanderen, 8800, Belgium
No email / No phone
Status: Recruiting
Fortaleza, Ceará, 60335-480, Brazil
No email / No phone
Status: Recruiting
Porto Alegre, Rio Grande Do Sul, 90610-000, Brazil
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Status: Recruiting
Itajaí, Santa Catatina, 88301, Brazil
No email / No phone
Status: Recruiting
Jaú, São Paulo, 17210-180, Brazil
No email / No phone
Status: Recruiting
Panagyurishte, Pazardzhik, 1527, Bulgaria
No email / No phone
Status: Recruiting
Sofia, 4500, Bulgaria
No email / No phone
Status: Recruiting
Brampton, Ontario, L6R 3J7, Canada
No email / No phone
Status: Recruiting
Toronto, Ontario, M5G 2M9, Canada
No email / No phone
Status: Not yet recruiting
Strasbourg cedex, Alsace, 67091, France
No email / No phone
Status: Recruiting
Caen cedex 9, Basse-Normandie, 14033, France
No email / No phone
Status: Recruiting
Paris cedex, Ile-de-France, 75248, France
No email / No phone
Status: Recruiting
Boulogne-Billancourt, Île-de-France, 92100, France
No email / No phone
Status: Recruiting
Limoges, Limousin, 87042, France
No email / No phone
Status: Recruiting
Pessac, Nouvelle-Aquitaine, 33604, France
No email / No phone
Status: Recruiting
Le Mans cedex 9, Pays De La Loire, 72037, France
No email / No phone
Status: Recruiting
Villejuif, Val-de-Marne, 94805, France
No email / No phone
Status: Recruiting
Hamburg, Hamburg (Hansestadt), 22763, Germany
No email / No phone
Status: Recruiting
Gießen, Hessen, 35392, Germany
No email / No phone
Status: Recruiting
Regensburg, 93053, Germany
No email / No phone
Status: Recruiting
München, 80337, Germany
No email / No phone
Status: Not yet recruiting
Piraeus, Attica, 18547, Greece
No email / No phone
Status: Recruiting
Athens, Attica, 11527, Greece
No email / No phone
Status: Recruiting
Patra, Peloponnese, 26504, Greece
No email / No phone
Status: Recruiting
Peiraias, Pireas, 185 47, Greece
No email / No phone
Status: Recruiting
Larissa, Thessaly, 41110, Greece
No email / No phone
Status: Recruiting
Thessaloniki, 54622, Greece
No email / No phone
Status: Recruiting
Jerusalem, 9103102, Israel
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Status: Recruiting
Afula, 18101, Israel
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Status: Recruiting
Jerusalem, 9112001, Israel
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Status: Recruiting
Tel Aviv, 6423906, Israel
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Status: Recruiting
Tel aviv, 69710, Israel
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Status: Recruiting
Meldola, Forlì-Cesena, 47014, Italy
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Status: Recruiting
Modena, 41224, Italy
No email / No phone
Status: Recruiting
Verona, 37126, Italy
No email / No phone
Status: Recruiting
Ravenna, 48121, Italy
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Status: Recruiting
Pavia, 27100, Italy
No email / No phone
Status: Recruiting
Milan, 20132, Italy
No email / No phone
Status: Recruiting
Nagoya, Aiti [Aichi], 464-8681, Japan
No email / No phone
Status: Recruiting
Hirosaki-Shi, Aomori, 036-8563, Japan
No email / No phone
Status: Recruiting
Fukuoka-shi, Hukuoka, 811-1395, Japan
No email / No phone
Status: Recruiting
Yokohama, Kanagawa, 236-0051, Japan
No email / No phone
Status: Recruiting
Sagamihara, Kanagawa, 252-0375, Japan
No email / No phone
Status: Recruiting
Kumamoto-Shi, Kumamoto, 861-4163, Japan
No email / No phone
Status: Recruiting
Sendai, Miyagi, 980-0873, Japan
No email / No phone
Status: Recruiting
Okayamashi, Okayama, 700-8558, Japan
No email / No phone
Status: Recruiting
Sakai-Shi, Osaka, 591-8555, Japan
No email / No phone
Status: Recruiting
Hirakata, Osaka, 573-1191, Japan
No email / No phone
Status: Recruiting
Shinjuku-Ku, Tokyo, 160-8582, Japan
No email / No phone
Status: Not yet recruiting
Koto, Tokyo, 135-8550, Japan
No email / No phone
Status: Recruiting
Osaka, 534-0021, Japan
No email / No phone
Status: Recruiting
Osaka, 541-8567, Japan
No email / No phone
Status: Recruiting
Kanazawa, 920-8641, Japan
No email / No phone
Status: Recruiting
Suwon-si, Gyeonggi-do, 16247, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Suwon-si, Gyeonggi-do, 16499, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Jinju, Gyeongsangnamdo [Kyongsangnam-do], 52727, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Incheon, Incheon Gwang'yeogsi [Inch'on-Kwangyokshi], 22332, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], 02841, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Seoul, Seoul Teugbyeolsi [Seoul-T'ukpyolshi], 08308, Korea, Republic of
No email / No phone
Status: Not yet recruiting
Mirador, Puebla, 72530, Mexico
No email / No phone
Status: Recruiting
Veracruz, 91900, Mexico
No email / No phone
Status: Recruiting
Nijmegen, Gelderland, 6525 GA, Netherlands
No email / No phone
Status: Recruiting
Amsterdam, Noord-Holland, 1081 HV, Netherlands
No email / No phone
Status: Recruiting
Quezon City, Metropolitan Manila, 1112, Philippines
No email / No phone
Status: Not yet recruiting
Muntinlupa, 1780, Philippines
No email / No phone
Status: Recruiting
Łódź, Lódzkie, 90-302, Poland
No email / No phone
Status: Not yet recruiting
Lublin, Lubelskie, 20-954, Poland
No email / No phone
Status: Not yet recruiting
Pozna?, Wielkopolskie, 60-569, Poland
No email / No phone
Status: Not yet recruiting
Cluj-Napoca, Cluj, 400641, Romania
No email / No phone
Status: Recruiting
Craiova, Dolj, 200746, Romania
No email / No phone
Status: Recruiting
Timişoara, Timis, 300166, Romania
No email / No phone
Status: Recruiting
Suceava, 720214, Romania
No email / No phone
Status: Recruiting
Singapore, 30433, Singapore
No email / No phone
Status: Not yet recruiting
Singapore, 228510, Singapore
No email / No phone
Status: Recruiting
Singapore, 308900, Singapore
No email / No phone
Status: Recruiting
Singapore, 574623, Singapore
No email / No phone
Status: Recruiting
A Coruña, La Coruña, 15006, Spain
No email / No phone
Status: Not yet recruiting
Madrid, 28046, Spain
No email / No phone
Status: Recruiting
Málaga, 29010, Spain
No email / No phone
Status: Not yet recruiting
Madrid, 28040, Spain
No email / No phone
Status: Not yet recruiting
Jaén, 23007, Spain
No email / No phone
Status: Recruiting
Madrid, 28033, Spain
No email / No phone
Status: Not yet recruiting
Madrid, 28041, Spain
No email / No phone
Status: Not yet recruiting
Barcelona, 08036, Spain
No email / No phone
Status: Not yet recruiting
Barcelona, 08017, Spain
No email / No phone
Status: Recruiting
Barcelona, 08023, Spain
No email / No phone
Status: Recruiting
Pathum Wan, Bangkok, 10330, Thailand
No email / No phone
Status: Recruiting
Bang Phlat, Bangkok, 10700, Thailand
No email / No phone
Status: Recruiting
Krung Thep Maha Nakhon, Khet Dusit, 10300, Thailand
No email / No phone
Status: Recruiting
Ankara, 6520, Turkey
No email / No phone
Status: Recruiting
Adana, 01060, Turkey
No email / No phone
Status: Not yet recruiting
Adana, 01120, Turkey
No email / No phone
Status: Recruiting
Ankara, 06010, Turkey
No email / No phone
Status: Not yet recruiting
Edirne, 22130, Turkey
No email / No phone
Status: Not yet recruiting
Etlik, 06010, Turkey
No email / No phone
Status: Not yet recruiting
Istanbul, 34214, Turkey
No email / No phone
Status: Recruiting
Istanbul, 34722, Turkey
No email / No phone
Status: Recruiting
Çankaya, 06800, Turkey
No email / No phone
Status: Not yet recruiting
Nottingham, England, NG5 1PB, United Kingdom
No email / No phone
Status: Recruiting
Torquay, England, TQ2 7AA, United Kingdom
No email / No phone
Status: Not yet recruiting
London, England, NW3 2QG, United Kingdom
No email / No phone
Status: Recruiting
Henderson, Nevada, 89052, United States
No email / No phone
Status: Recruiting
Henderson, Nevada, 89074, United States
No email / No phone
Status: Recruiting
Las Vegas, Nevada, 89144, United States
No email / No phone
Status: Recruiting
Las Vegas, Nevada, 89169, United States
No email / No phone
Status: Recruiting
Las Vegas, Nevada, 89148, United States
No email / No phone
Status: Recruiting
Las Vegas, Nevada, 89218, United States
No email / No phone
Status: Recruiting
Henderson, Nevada, 89052, United States
No email / No phone
Status: Recruiting
Canton, Ohio, 44718, United States
No email / No phone
Status: Recruiting
Toledo, Ohio, 43623, United States
No email / No phone
Status: Withdrawn
Houston, Texas, 77030, United States
No email / No phone
Status: Recruiting