Abstract
Background Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).
Methods We used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.
Results Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.
Conclusions This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.
Competing Interest Statement
DBC reports personal fees (consulting fees and honoraria) and nonfinancial support (institutional research support) from Takeda/Millennium Pharmaceuticals, AstraZeneca, Pfizer and BluePrint Medicine, as well as nonfinancial support (institutional research support) from Merck Sharp and Dohme Corporation, Merrimack Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Spectrum Pharmaceuticals, Tesaro, all outside the submitted work. SSK reports research support from Boehringer Ingelheim, MiNA Therapeutics, and Taiho Therapeutics, as well as personal fees (honoraria) from Boehringer Ingelheim, Bristol Meyers Squibb, and Takeda Pharmaceuticals; outside the submitted work. No other conflict of interest is reported.
Footnotes
Disclosure of Potential Conflicts of interest: DBC reports personal fees (consulting fees and honoraria) and nonfinancial support (institutional research support) from Takeda/Millennium Pharmaceuticals, AstraZeneca, Pfizer and BluePrint Medicine, as well as nonfinancial support (institutional research support) from Merck Sharp and Dohme Corporation, Merrimack Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Spectrum Pharmaceuticals, Tesaro, all outside the submitted work. SSK reports research support from Boehringer Ingelheim, MiNA Therapeutics, and Taiho Therapeutics, as well as personal fees (honoraria) from Boehringer Ingelheim, Bristol Meyers Squibb, and Takeda Pharmaceuticals; outside the submitted work. No other conflict of interest is reported.