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    DRUG:

    zipalertinib (CLN-081)

    i
    Other names: CLN-081, TAS6417, TPC-064, CLN 081, CLN081, TAS 6417, TAS-6417, TPC064, TPC 064
    Company:
    Cullinan Therap, Otsuka, Taiho Pharma, ZAI Lab
    Drug class:
    EGFR inhibitor, Tyrosine kinase inhibitor
    Related drugs:
    19d
    An EAP Treatment Protocol of Zipalertinib (clinicaltrials.gov)
    P=N/A, N=0, Available, Taiho Oncology, Inc.
    New trial
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation
    |
    zipalertinib (CLN-081)
    29d
    Therapeutic Advances in Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations: From Molecular Biology to Targeted Therapy. (PubMed, Int J Mol Sci)
    Sunvozertinib, an oral, selective EGFR inhibitor, received U.S. Food and Drug Administration (FDA) accelerated approval in 2025, with an ORR of 46% and a median duration of response (DOR) of 11.1 months in platinum-pretreated patients. Emerging therapies, including zipalertinib and furmonertinib, have shown promising results in early-phase trials, with zipalertinib demonstrating activity in patients pretreated with amivantamab (ORR 31.5%) and furmonertinib achieving remarkable responses in treatment-naive patients (ORR 78.6% at 240 mg). This comprehensive review analyzes the molecular biology, structural mechanisms, current therapeutic options, and novel investigational agents for EGFR ex20ins-mutated NSCLC.
    Review • Journal
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Ivesa (firmonertinib) • Zegfrovy (sunvozertinib) • zipalertinib (CLN-081)
    2ms
    REZILIENT4: 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 (clinicaltrials.gov)
    P3, N=360, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    EGFR L861Q • EGFR G719X • EGFR S768I
    |
    cisplatin • carboplatin • pemetrexed • zipalertinib (CLN-081)
    2ms
    REZILIENT4: 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 (clinicaltrials.gov)
    P3, N=360, Recruiting, Taiho Oncology, Inc. | N=141 --> 360
    Enrollment change • Trial initiation date
    |
    EGFR L861Q • EGFR G719X • EGFR S768I
    |
    cisplatin • carboplatin • pemetrexed • zipalertinib (CLN-081)
    3ms
    REZILIENT2: 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. (clinicaltrials.gov)
    P2, N=220, Recruiting, Taiho Oncology, Inc. | N=324 --> 220
    Enrollment change
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR L858R • EGFR exon 19 deletion • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    zipalertinib (CLN-081)
    3ms
    REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov)
    P3, N=285, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    EGFR mutation • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    carboplatin • zipalertinib (CLN-081)
    4ms
    TAS6417-302: Study Evaluating Zipalertinib with Chemotherapy for Lung Cancer Patients with Uncommon EGFR Mutations After Surgery (2025-521775-31-00)
    P2/3, N=131, Recruiting, Taiho Oncology Inc.
    New P2/3 trial
    |
    EGFR mutation • EGFR exon 20 insertion • EGFR L861Q • EGFR G719X • EGFR S768I • EGFR exon 20 mutation
    |
    cisplatin • carboplatin • pemetrexed • zipalertinib (CLN-081)
    4ms
    REZILIENT2: 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. (clinicaltrials.gov)
    P2, N=324, Recruiting, Taiho Oncology, Inc. | N=224 --> 324 | Trial completion date: Aug 2026 --> Dec 2028 | Trial primary completion date: Feb 2026 --> Aug 2028
    Enrollment change • Trial completion date • Trial primary completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR L858R • EGFR exon 19 deletion • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    zipalertinib (CLN-081)
    4ms
    Zipalertinib With Carboplatin and Pemetrexed for the Treatment of Resectable, Stage II-IIIB, Non-Small Cell Lung Cancer (clinicaltrials.gov)
    P2, N=16, Not yet recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Dec 2029 --> Jun 2030 | Initiation date: Jan 2026 --> Jun 2027 | Trial primary completion date: Dec 2028 --> Jun 2029
    Trial completion date • Trial initiation date • Trial primary completion date
    |
    EGFR mutation • EGFR L861Q • EGFR G719X
    |
    carboplatin • pemetrexed • zipalertinib (CLN-081)
    4ms
    Zipalertinib-A Novel Treatment Opportunity for Non-Small Cell Lung Cancers with Exon 20 Insertions and Uncommon EGFR Mutations. (PubMed, Cancers (Basel))
    The role and the integration of therapies targeting exon20ins or uncommon mutations into the first- and second-line treatment armamentarium for NSCLC patients is not yet fully established, and the therapeutic impact of monotherapies (e.g., sunvozertinib, firmonertinib) versus combinations with standard platinum-based chemotherapy (e.g., zipalertinib, amivantamab) currently still lacks robust evidence to further change the therapeutic landscape for these patients. Therefore, results from the ongoing trials are eagerly awaited and are expected to shed some light on these open questions.
    Review • Journal
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR T790M • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    Ivesa (firmonertinib) • Zegfrovy (sunvozertinib) • zipalertinib (CLN-081)
    7ms
    Zipalertinib With Carboplatin and Pemetrexed for the Treatment of Resectable, Stage II-IIIB, Non-Small Cell Lung Cancer (clinicaltrials.gov)
    P2, N=16, Not yet recruiting, Jonsson Comprehensive Cancer Center
    New P2 trial
    |
    carboplatin • pemetrexed • zipalertinib (CLN-081)
    7ms
    REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov)
    P3, N=272, Recruiting, Taiho Oncology, Inc. | Trial completion date: Aug 2026 --> May 2027 | Trial primary completion date: Jul 2026 --> Oct 2026
    Trial completion date • Trial primary completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation
    |
    carboplatin • zipalertinib (CLN-081)