TAS6417/CLN-081 Is a Pan-Mutation–Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations

Abstract

Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced nonsmall cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of !1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wildtype EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors.Implications: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.

EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors

“…2 This negates a therapeutic window for these targeted therapies, and preclinical, and clinical development of novel EGFR TKIs for these mutants have thus been hampered; however, repurposed or newly developed TKIs are exhibiting a modestly favorable therapeutic window-EGFR exon 20 insertion mutations more readily inhibited than WT EGFR-in preclinical models (poziotinib, CLN-081) and early clinical studies (mobocertinib [previously known as TAK-788]) in both EGFRand ERBB2-mutated lung cancers. [3][4][5][6] However, the EGFR-A763_Y764insFQEA mutation (and the identical amino acid sequence of EGFR-D761_E762insEAFQ) sets itself apart from other exon 20 insertions as it stands at the transition of exon 19 and 20 of EGFR (Fig. 1A).…”

Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

“…Other EGFR-TKIs currently in clinical development-such as poziotinib and CLN-081-have also shown a reproducible therapeutic window in preclinical models [4,5,10]. The clinical trial of poziotinib for EGFR exon 20 insertion mutated NSCLC (ZENITH20, NCT03318939) has led to suboptimal initial efficacy results, with ORR below 15% and median PFS below 5 months (Table1)-results that may be explained by dose limiting skin and gastrointestinal adverse events at the 16 mg/day dosing [11].…”

“…Further development of alternative dosing schemes of poziotinib are ongoing (NCT03318939). The initial dose escalation of CLN-081 [5] is ongoing with some initial responses noted in the target cohort (NCT04036682). Another EGFR-TKI strategy based on our group's preclinical models [3] is the use of a higher than standard dose of osimertinib.…”

“…The majority of epidermal growth factor receptor (EGFR) and the structurally similar erb-b2 receptor tyrosine kinase 2 (ERBB2) exon 20 insertion mutations-representing 10% of all EGFR mutations-are unique among ErbB family members in that they activate the ATP binding pocket of these kinases without the typical conformational changes that enhance sensitivity to the majority of EGFR and/or ERBB2 tyrosine kinase inhibitors (TKIs) approved for clinical use in mid-2020 [1,2]. Over the last half a decade, novel EGFR-and/or ERBB2-TKIs or repurposed TKIs have been shown to have a slightly favorable therapeutic window for EGFR exon 20 insertion mutations in comparison to EGFR-wild type (WT) [3][4][5][6]. The ones that have reached clinical trial development for EGFR exon 20 insertion mutated non-small-cell lung cancer (NSCLC) include poziotinib, CLN-081, high dose osimertinib and mobocertinib; with differing levels of activity reported to date.…”

“…del19, -L858R, -L861Q, G719X, -S768I and -T790M. Off label use of approved EGFR TKIs is further supported for EGFR-exon 18 indels/E709X, -exon 19 insertions, -exon 20A763_Y764insFQEA, exon 18-25 kinase domain duplications and -rearrangements[1,2,5,9,10].…”