zipalertinib (CLN-081) / Cullinan Therap, Otsuka 
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  • ||||||||||  zipalertinib (CLN-081) / Cullinan Therap, Otsuka
    Enrollment closed, EGFR exon 20, Metastases:  REZILIENT1: A Phase 1/2 Trial of CLN-081 in Patients with Non-Small Cell Lung Cancer (clinicaltrials.gov) -  Sep 19, 2024   
    P1/2,  N=284, Active, not recruiting, 
    However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants. Recruiting --> Active, not recruiting
  • ||||||||||  Review, Journal, EGFR exon 20:  Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. (Pubmed Central) -  Jun 19, 2024   
    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.
  • ||||||||||  zipalertinib (CLN-081) / Cullinan Oncology, Otsuka
    Journal, EGFR exon 20:  Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. (Pubmed Central) -  May 21, 2024   
    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.
  • ||||||||||  zipalertinib (CLN-081) / Cullinan Therap, Otsuka
    Trial completion date, Trial primary completion date, EGFR exon 20, Metastases:  REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov) -  May 3, 2024   
    P3,  N=272, Recruiting, 
    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. Trial completion date: May 2026 --> Aug 2026 | Trial primary completion date: Jan 2026 --> Jul 2026
  • ||||||||||  Journal, EGFR exon 20:  The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors. (Pubmed Central) -  Jan 17, 2024   
    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.
  • ||||||||||  zipalertinib (CLN-081) / Cullinan Therap, Otsuka
    Trial completion date, Trial primary completion date, EGFR exon 20, Metastases:  REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (clinicaltrials.gov) -  Aug 25, 2023   
    P3,  N=312, Recruiting, 
    Phase classification: P2b --> P2 Trial completion date: Apr 2027 --> May 2026 | Trial primary completion date: Dec 2026 --> Jan 2026
  • ||||||||||  Journal:  Targeting exon 20 insertion mutations in lung cancer. (Pubmed Central) -  Nov 19, 2022   
    Recent clinical evidence indicates that targeted therapies could improve survival benefits to some extent. More efforts on drug development are underway to bring higher response rates both extracranial and intracranial, sustained clinical remission, and better survival benefits.
  • ||||||||||  zipalertinib (CLN-081) / Cullinan Therap, Otsuka
    Trial completion date, Trial primary completion date, EGFR exon 20, Metastases:  REZILIENT1: A Phase 1/2 Trial of CLN-081 in Patients with Non-Small Cell Lung Cancer (clinicaltrials.gov) -  Nov 15, 2022   
    P1/2,  N=284, Recruiting, 
    More efforts on drug development are underway to bring higher response rates both extracranial and intracranial, sustained clinical remission, and better survival benefits. Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
  • ||||||||||  zipalertinib (CLN-081) / Cullinan Therap, Otsuka
    Enrollment change, Trial completion date, Trial primary completion date, EGFR exon 20, Metastases:  REZILIENT1: A Phase 1/2 Trial of CLN-081 in Patients with Non-Small Cell Lung Cancer (clinicaltrials.gov) -  Oct 18, 2022   
    P1/2,  N=284, Recruiting, 
    We also found a novel secondary mutation (F856V) that may confer acquired resistance to mobocertinib. N=80 --> 284 | Trial completion date: Mar 2022 --> Dec 2023 | Trial primary completion date: Mar 2022 --> Dec 2023
  • ||||||||||  Exkivity (mobocertinib) / Takeda
    Mechanisms of resistance to mobocertinib in EGFR exon 20 insertion-mutant non-small cell lung cancer (NSCLC) (Exhibition Hall) -  Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_446;    
    Conclusions EGFR C797S mutation and EGFR amplification were identified as resistance mechanisms to mobocertinib in EGFR exon 20 insertion-mutant NSCLC models. Combined treatment of brigatinib plus cetuximab or amivantamab may be an effective therapeutic strategy for EGFR exon 20 insertion/C797S-mutant NSCLC in preclinical models.
  • ||||||||||  Retrospective data, Review, Journal, IO biomarker, EGFR exon 20:  Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and pooled analysis of patient outcomes. (Pubmed Central) -  Aug 6, 2022   
    Conventional treatments used in patients with EGFR exon 20 insertion mutation-positive NSCLC have limited efficacy, though chemotherapy appeared to be associated with better response and survival outcomes than non-exon 20 targeting EGFR-TKIs and IO agents. This supports the need to identify EGFR exon 20 insertion mutations as the availability of new targeted treatments may offer additional therapeutic options to these patients.