zipalertinib (CLN-081) / Cullinan Therap, Otsuka, ZAI Lab, Taiho - LARVOL DELTA

Zipalertinib Plus Chemotherapy for 1 st Line NSCLC with EGFR Exon 20 Insertions: Results From the Phase 3 Trial (REZILIENT 3) (IASLC-WCLC 2026) - P3 | "Methods : In this international, randomized-controlled, open-label phase 3 trial, advanced NSCLC patients with EGFR ex20ins and no prior treatment for advanced disease were randomized 1:1 to platinum-pemetrexed chemotherapy with or without zipalertinib 100mg BID. Conclusions : The addition of zipalertinib to platinum-based chemotherapy provided a statistically significant and clinically meaningful 6.0 months PFS improvement as first-line treatment for advanced NSCLC patients with EGFR ex20ins. No new safety signals were observed and continued follow-up of REZILIENT 3 is ongoing to further characterize the OS benefit and exploratory endpoints (ClinicalTrials.gov number NCT05973773)."

EGFR exon 20 • Late-breaking abstract • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR

Phase III Trials Test First-Line Options in Advanced NSCLC. (PubMed, Cancer Discov) - "Presented at the 2026 World Conference on Lung Cancer, two phase III trials-PAPILLON and REZILIENT3-established amivantamab and zipalertinib combination therapies as effective first-line strategies for advanced NSCLC with EGFR exon 20 insertions, with significantly improved progression-free survival, although high crossover rates prevented them demonstrating an overall survival benefit. Separately, HARMONi-2 showed that the bispecific antibody ivonescimab improved overall survival versus pembrolizumab in PD-L1-positive NSCLC, supporting its use as standard of care in China while larger global trials continue."

Journal • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • PD-L1

P-Loop/αC-Helix Compressing Mutations and Exon 20 Insertions in EGFR-Mutant NSCLC: A Rapidly Evolving Therapeutic Landscape. (PubMed, J Clin Oncol) - "EGFR PACC and ex20ins are established subgroups of kinase domain mutations, distinct from classical mutations, due to structure and responsiveness to available TKIs."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Central Nervous System (CNS) Activity of Zipalertinib in Non-Small Cell Lung Cancer (NSCLC) Patients with Uncommon EGFR Mutations (EGFRmt) (ESMO 2026) - No abstract available

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zipalertinib Plus Chemotherapy Meets Primary Endpoint of Progression-Free Survival in Planned Interim Analysis of Phase 3 REZILIENT3 Trial in First-Line EGFR Exon 20 Insertion Mutation Non-Small Cell Lung Cancer (Businesswire) - "In this analysis, the study demonstrated a statistically significant and clinically meaningful improvement in PFS in the zipalertinib containing arm. Observed safety for the zipalertinib containing arm was manageable. Based on these data, the Independent Data Monitoring Committee recommended unblinding the study. The trial will continue to monitor efficacy and safety. Full results from REZILIENT3 will be submitted for presentation at an upcoming international medical conference. Based on these results, pending discussions with the U.S. Food and Drug Administration (FDA), Taiho Oncology, Taiho Pharmaceutical and Cullinan Therapeutics plan to pursue U.S. regulatory approval for this combination regimen in the first-line setting."

EGFR exon 20 • FDA filing • P3 data: top line • Trial status • Non Small Cell Lung Cancer

Zipalertinib in NSCLC Patients (Pts) With EGFR Exon 20 Insertion (Ex20Ins) Mutations Who Received Prior Amivantamab (IASLC-WCLC 2025) - "Mature efficacy data, including at least 9 months follow up for all 83 pts will be presented. Conclusions : Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in pts with exon20ins NSCLC who have received prior chemotherapy and prior amivantamab, reflecting a clinically-relevant patient population for which there are currently no approved therapies."

Clinical • EGFR exon 20 • Anemia • Dental Disorders • Dermatitis • Dermatology • Hematological Disorders • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Pneumonia • Pruritus • Solid Tumor • Stomatitis • EGFR

Phase (Ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (Ins20). (ASCO 2022) - P1/2 | "In pts with heavily-pretreated advanced EGFR ins20 NSCLC, CLN-081 has a manageable safety profile, with anti-tumor activity across the range of doses tested. Further, CLN-081 has demonstrated a favorable clinical profile at the dose of 100 mg BID, with an encouraging objective response rate, response durability, and no Gr 3 rash or diarrhea."

Clinical • EGFR exon 20 • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Phase 2 Interim Results of Zipalertinib in Patients With NSCLC Harboring Uncommon Non-Exon 20 Insertion EGFR Mutations (IASLC-WCLC 2025) - P2 | "The safety profile of zipalertinib was manageable, with no new safety signals. Enrollment in this study is ongoing, focusing on previously untreated patients to confirm the observed preliminary clinical efficacy."

Clinical • P2 data • Anemia • Dental Disorders • Dermatitis • Dermatology • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Stomatitis • EGFR

Adjuvant ctDNA-Adapted Treatment With Zipalertinib in Early-Stage Atypical EGFR-Mutant NSCLC (clinicaltrials.gov) - P2 | N=42 | Not yet recruiting | Sponsor: Stanford University

Circulating tumor DNA • New P2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • PD-L1

Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. (ASCO 2025) - P1/2 | "Of the 51 pts with prior ami, 30 had no other ex20ins-directed therapy, while 21 had also received other ex20ins drugs (such as mobocertinib, sunvozertinib, BLU-451, or poziotinib), the cORR was 30.0% and 14.3%, respectively. Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in pts with exon20ins NSCLC who have received prior platinum-based chemotherapy and for those who received prior amivantamab, a significant and growing unmet need. BICR assessed tumor responses per RECIST v1.1.CR=complete response, PR=partial response, SD=stable disease."

Clinical • EGFR exon 20 • IO biomarker • Anemia • Dental Disorders • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • EGFR

Safety and anti-tumour activity of zipalertinib in NSCLC patients (pts) with EGFR exon 20 insertion (ex20ins) mutations who received prior amivantamab (ESMO 2024) - P1/2 | "This is the first report to systematically characterize the anti-tumor activity of a new irreversible and selective EGFR ex20ins TKI, in heavily treated pts with NSCLC harboring EGFR ex20ins mutations who have received prior amivantamab. In this amivantamab resistant setting, zipalertinib demonstrated promising efficacy, similar to pts that progressed after platinum-based chemotherapy alone and had a manageable safety profile."

Clinical • EGFR exon 20 • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zipalertinib Plus Chemotherapy Demonstrates 6-Month Median Progression-Free Survival Benefit in REZILIENT3 Phase 3 Trial in First-Line EGFR Exon 20 Insertion Mutation Non-Small Cell Lung Cancer (Businesswire) - "These late-breaking results from the planned interim analysis of REZILIENT3 were selected for presentation in the Presidential Symposium 2 at IASLC 2026 WCLC....At the pre-planned interim efficacy analysis after 122 PFS events, treatment with zipalertinib plus chemotherapy led to significantly longer median PFS than chemotherapy alone (14.5 vs. 8.5 months; HR: 0.50; 95% CI 0.34-0.73; P=0.00015). This PFS benefit was consistent across subgroups, including patients with brain metastases (HR: 0.38). Objective response rate was higher with the combination therapy (65.0% vs. 40.3%), P<0.0001, with a longer median duration of response (14.2 vs. 9.9 months). At the interim overall survival (OS) analysis (30% maturity), the hazard ratio for death for zipalertinib plus chemotherapy as compared with chemotherapy was 0.72 (95% CI, 0.42-1.23)."

EGFR exon 20 • Late-breaking abstract • P3 data • Non Small Cell Lung Cancer

Taiho Oncology, Inc. and Cullinan Therapeutics…announced that results from the planned interim analysis of the Phase 3 REZILIENT3 trial have been selected for presentation in the Presidential Symposium 2 at the International Association for the Study of Lung Cancer's (IASLC) 2026 World Conference on Lung Cancer (WCLC)… (Businesswire) - "REZILIENT3 evaluates zipalertinib plus chemotherapy versus chemotherapy alone in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC)."

EGFR exon 20 • P3 data • Non Small Cell Lung Cancer

Activity of zipalertinib against active central nervous system (CNS) metastases in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins)/other uncommon mutations (ESMO 2025) - P2 | "Conclusions In summary, zipalertinib demonstrated clinically meaningful intracranial antitumor activity in patients with NSCLC harboring ex20ins/other uncommon EGFR mt, similar to the overall systemic anticancer activity in this population, with no new safety signals observed. Cohort enrollment is ongoing to better characterize clinical activity of zipalertinib against CNS lesions."

Clinical • EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Emergence of EGFR C797S as a resistance mechanism to CLN081 in EGFR exon 20-mutant NSCLC: case report. (PubMed, Front Oncol) - "Although C797S-mediated resistance has been hypothesized and demonstrated in preclinical models of CLN081 exposure, this represents, to our knowledge, the first reported in vivo identification of an EGFR C797S resistance mutation following CLN081 therapy. This case provides clinically relevant insight into resistance mechanisms associated with emerging EGFR exon 20-targeted therapies."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zipalertinib in Patients With EGFR Exon 20 Insertion-Positive NSCLC Previously Treated With Platinum-Based Chemotherapy With or Without Amivantamab. (PubMed, J Clin Oncol) - P1/2 | "Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC who received prior platinum-based chemotherapy with or without amivantamab."

Journal • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • EGFR

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions. (PubMed, J Clin Oncol) - "Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash."

EGFR exon 20 • Journal • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Erratum: Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions. (PubMed, J Clin Oncol) - No abstract available

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Portfolio Highlights and 2026 Milestones: Zipalertinib (EGFR ex20ins inhibitor) (GlobeNewswire) - "In April, the U.S. FDA accepted an NDA for zipalertinib for the treatment of patients with locally advanced or metastatic EGFR ex20ins NSCLC whose disease has progressed on or after platinum-based chemotherapy, with or without amivantamab. The Prescription Drug User Fee Act (PDUFA) target action date is February 27, 2027. In February, Taiho completed enrollment of the pivotal study REZILIENT3 in 1L EGFR ex20ins NSCLC. Taiho expects to obtain top-line results by the end of 2026."

EGFR exon 20 • P3 data: top line • PDUFA • Non Small Cell Lung Cancer

REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov) - P3 | N=285 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Trial primary completion date: Oct 2026 ➔ May 2027

Trial primary completion date • Breast Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

CLN-081-001: A Phase 1/2a Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=80; Recruiting; Sponsor: Cullinan Pearl; Trial primary completion date: Sep 2021 ➔ Mar 2022

Clinical • EGFR exon 20 • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

CLN-081-001: A Phase 1/2a Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=284 | Recruiting | Sponsor: Cullinan Oncology, LLC | N=80 ➔ 284 | Trial completion date: Mar 2022 ➔ Dec 2023 | Trial primary completion date: Mar 2022 ➔ Dec 2023

EGFR exon 20 • Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

CLN-081-001: A Phase 1/2 Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=284 | Recruiting | Sponsor: Cullinan Oncology, LLC | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

EGFR exon 20 • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

REZILIENT1: A Phase 1/2 Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=284 | Active, not recruiting | Sponsor: Cullinan Therapeutics Inc. | Trial completion date: Mar 2026 ➔ Mar 2028 | Trial primary completion date: Jan 2026 ➔ Oct 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

WITHDRAWN: Phase 3 study of zipalertinib plus adjuvant chemotherapy in early-stage NSCLC harboring EGFR exon 20 insertion or other uncommon EGFR mutations (REZILIENT4). (ASCO 2026) - P3 | "Funded by Taiho Oncology, Inc. Clinical Trial Registration Number: NCT07128199 Abstract withdrawn."

Clinical • EGFR exon 20 • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR