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

Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics Announce Primary Endpoint Met in Phase 2b Trial of Zipalertinib in Patients with Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations Who Have Received Prior Therapy (PRNewswire) - "Taiho Pharmaceutical...and Cullinan Therapeutics...announced today the REZILIENT1 trial, a Phase 1/2 clinical trial of zipalertinib...monotherapy in patients with non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) exon 20 insertion mutations who have received prior therapy, met its primary endpoint of overall response rate. The safety profile was generally consistent with previous data presentations. These results are based on the Phase 2b part of this study. Full results from REZILIENT1 will be submitted for presentation at an upcoming international medical conference. Pending discussions with the U.S. Food and Drug Administration (FDA), the companies plan to submit for U.S. regulatory approval in the second half of 2025."

EGFR exon 20 • FDA filing • P2b data • Non Small Cell Lung Cancer

Phase III study of zipalertinib plus first-line (1L) platinum-based chemotherapy in patients (pts) with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations (REZILIENT3): Safety lead-in results (ESMO Asia 2024) - P3 | "Methods The safety lead-in (Part A) was designed to confirm the use of zipalertinib 100 mg PO BID in combination with SoC chemotherapy (pemetrexed [500 mg/m 2 ]; carboplatin [AUC 5 mg/mL/min] or cisplatin [75 mg/m 2 ] up to 4 cycles; D1 of each 21-day cycle) for the randomized Part B of the trial. Conclusions The combination of zipalertinib 100 mg BID and SoC platinum-based chemotherapy was safe and tolerable with no new safety signals observed for each regimen. Based on these data, the randomized Part B of REZILIENT 3 is currently ongoing with zipalertinib 100 mg BID in combination with 1L SoC chemotherapy in pts with EGFR ex20ins-mutant NSCLC."

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

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=160 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Recruiting ➔ Active, not recruiting

EGFR exon 20 • Enrollment closed • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Cullinan Therapeutics Provides Corporate Update and Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "CLN-619 on-track for initial expansion cohort data in endometrial and cervical cancers in Q2 2025; Zipalertinib pivotal Phase 2b study enrollment completed ahead of schedule; results expected mid-year 2025."

P1 data • P2b data • Cervical Cancer • Endometrial Cancer • Non Small Cell Lung Cancer

Zipalertinib: “These results suggest the efficacy and safety of zipalertinib in patients with progression or after amivantamab”; Non-small cell lung cancer (Otsuka) - Q3 FY2024 Results

P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity. (PubMed, Proc Natl Acad Sci U S A) - "Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants."

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

ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, demonstrates best-in-class properties against Exon 20 insertions and other atypical EGFR mutations (EORTC-NCI-AACR 2024) - P1/2 | " ORIC-114 is exquisitely selective in kinome analysis, demonstrating superiority to all current clinical small molecule inhibitors tested, including firmonertinib, zipalertinib and BDTX-1535. ORIC-114 demonstrated best-in-class properties, including brain penetrance, superior selectivity across the kinome, potent activity across atypical mutations in EGFR, including PACC mutations and Exon 20 insertion mutations, and evidence of molecular response in patients. ORIC-114 is a promising therapy for NSCLC patients with atypical mutations in EGFR, including those with active CNS metastases, and is currently being evaluated in a global clinical trial (NCT05315700)."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

The prediction of treatment outcome in NSCLC patients harboring an EGFR exon 20 mutation using molecular modeling. (PubMed, Lung Cancer) - "In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses."

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

Modeling the Relationship of Clinical Safety Profile of EGFR Inhibitors with Wild-Type EGFR Inhibition in Cellular Model (IASLC-WCLC 2024) - "The EGFR inhibitors include commercially available proxy compounds of gefitinib, afatinib, osimertinib, mobocertinib, sunvozertinib, zipalertinib, BLU-945, BDTX-1535, etc. Clinical safety data are obtained from drug labels or publications, including all grades AEs and Grades ≥3 rash and diarrhea. The potency of inhibition of WT EGFR in a uniform nonclinical assay strongly correlated with overall rates and severity of rash and diarrhea observed in the clinical setting. These results may be useful in enhancing the understanding of the potential clinical safety profile of novel EGFR targeted therapies at the nonclinical development stage."

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

Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with NSCLC Harboring EGFR Exon 19 Insertions: A Report from the LC-SCRUM-Asia (IASLC-WCLC 2024) - "We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2B • EGFR • FGFR • PIK3CA • TP53

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. | Recruiting ➔ Active, not recruiting

EGFR exon 20 • Enrollment closed • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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

Cullinan Therapeutics Presents Positive Updated Data from Module C of Zipalertinib Pivotal Phase 2b Study at ESMO 2024 (GlobeNewswire) - P1/2b | N=284 | REZILIENT1 (NCT04036682) | Sponsor: Cullinan Therapeutics Inc. | "Cullinan Therapeutics, Inc...shared updated data in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations receiving zipalertinib after prior treatment with amivantamab enrolled in Module C of its pivotal Phase 2b REZILIENT1 clinical trial....Updated data show consistent objective response rate of 40% and manageable safety profile in patients with non-small cell lung cancer harboring epidermal growth factor receptor exon 20 insertion mutations treated with zipalertinib who progressed on or after prior amivantamab treatment."

P2b data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Cullinan Therapeutics Provides Corporate Update and Reports Second Quarter 2024 Financial Results (GlobeNewswire) - "Oncology: (i) CLN-619 (Anti-MICA/MICB monoclonal antibody):...Cullinan remains on track to report initial data from disease-specific dose expansion cohorts in endometrial and cervical cancers in the first half of 2025....(ii) Zipalertinib (EGFR ex20ins inhibitor):...An update to these initial REZILIENT1 results in patients with EGFR ex20ins NSCLC who have progressed after both prior chemotherapy and amivantamab will be presented in a mini oral presentation at the European Society for Medical Oncology (ESMO) meeting in September. Cullinan expects to complete enrollment in the pivotal Phase 2b portion of REZILIENT1 by year-end 2024."

Enrollment status • P1 data • P1/2 data • Cervical Cancer • Endometrial Cancer • Non Small Cell Lung Cancer

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations. (ASCOBT 2024) - P3 | "Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023."

Clinical • EGFR exon 20 • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. (PubMed, Int J Mol Sci) - "This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling."

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

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations. (ASCO 2024) - P3 | "Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 300 patients. Enrollment commenced in June 2023."

Clinical • EGFR exon 20 • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (EGFR) mutations. (ASCO 2024) - P2 | "Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Cullinan Therapeutics Announces Positive Initial Data from Pivotal Phase 2b REZILIENT1 Study of Zipalertinib (GlobeNewswire) - P1/2 | N=284 | REZILIENT1 (NCT04036682) | Sponsor: Cullinan Therapeutics Inc. | "Cullinan Therapeutics, Inc...announced positive initial data in patients receiving zipalertinib after prior treatment with amivantamab enrolled in its pivotal Phase 2b REZILIENT1 clinical trial....At data cut-off, 18 patients were evaluable for response and showed similar anti-tumor activity compared with those post prior chemotherapy in the previously reported Phase 1/2a part of the study....Zipalertinib demonstrated a manageable safety profile, similar to what has been previously reported. There were no grade 4 or grade 5 treatment-related adverse events​."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. (PubMed, J Med Chem) - "A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity."

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

REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov) - P3 | N=272 | Recruiting | Sponsor: Taiho Oncology, Inc. | Trial completion date: May 2026 ➔ Aug 2026 | Trial primary completion date: Jan 2026 ➔ Jul 2026

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

Cullinan Oncology Provides Corporate Update and Reports Fourth Quarter and Full Year 2023 Financial Results (GlobeNewswire) - "Zipalertinib: Cullinan expects to complete enrollment in the pivotal Phase 2b portion of the REZILIENT1 study in patients with EGFR ex20ins NSCLC who have progressed after prior systemic therapy, with or without exon 20 targeted therapy, by year-end 2024; CLN-049: Cullinan expects to provide a clinical data update from the ongoing Phase 1 multi-ascending dose study in r/r AML and MDS patients in the second half of 2024."

Enrollment status • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors. (PubMed, JTO Clin Res Rep) - "EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance."

EGFR exon 20 • Journal • Lung Cancer • Oncology • Solid Tumor • EGFR

Identification of Prognostic and Immune Characteristics of Two Lung Adenocarcinoma Subtypes Based on TRPV Channel Family Genes. (PubMed, J Membr Biol) - "Furthermore, we hypothesized that the expression patterns of feature genes in the LUAD model were related to the sensitivity to lung cancer therapeutic drugs TAS-6417 and Erlotinib. To sum up, our LUAD prognostic model possessed clinical applicability for prognosis and immunotherapy response prediction."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TRPV1

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=160 | Recruiting | Sponsor: Taiho Oncology, Inc. | Phase classification: P2b ➔ P2

Phase classification • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR