2. Academic Validation
  3. Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer

Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer

  • Cancer Discov. 2021 Jul;11(7):1672-1687. doi: 10.1158/2159-8290.CD-20-1683.
Francois Gonzalvez 1,  Sylvie Vincent 2,  Theresa E Baker 1,  Alexandra E Gould 2,  Shuai Li 3,  Scott D Wardwell 1,  Sara Nadworny 1,  Yaoyu Ning 1,  Sen Zhang 1,  Wei-Sheng Huang 1,  Yongbo Hu 2,  Feng Li 1,  Matthew T Greenfield 1,  Stephan G Zech 1,  Biplab Das 1,  Narayana I Narasimhan 1,  Tim Clackson 1,  David Dalgarno 1,  William C Shakespeare 1,  Michael Fitzgerald 2,  Johara Chouitar 2,  Robert J Griffin 2,  Shengwu Liu 4,  Kwok-Kin Wong 3,  Xiaotian Zhu 1,  Victor M Rivera 5
Affiliations

Affiliations

  • 1 ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
  • 2 Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
  • 3 Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 5 ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Victor.Rivera@TheseusPharma.com.
PMID: 33632773 DOI: 10.1158/2159-8290.CD-20-1683
Abstract

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung Cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

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