Foretinib Shows Promise as Second-Line Therapy for MET Exon 14 Skipping NSCLC

After failure of type 1b MET tyrosine kinase inhibitors (TKIs), foretinib, a type 2 MET TKI, shows potent activity against secondary mutations among patients with MET exon 14 skipping NSCLC, according to findings from a recent study.

Capmatinib and tepotinib are type 1b MET TKIs that are guideline-recommended front-line treatments for patients with NSCLC and MET exon 14 skipping mutations (METex14). While these agents generated progression-free survival  (PFS) of 5.4 to 12.4 months in clinical trials, the emergence of acquired resistance is almost unavoidable due to D1228X or Y1230X secondary mutations of the MET.

In a study, Toshio Fujino, MD, Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Japan, and colleagues explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.

Researchers analyzed the inhibitory effects of 300 drugs, including 33 MET TKIs in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen discovered 4 type 2 MET TKIs: altiratinib, CEP-40783, foretinib and sitravatinib.

As a result, Dr Fujino and colleagues performed further growth inhibitory assays using these 4 MET TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. They also conducted evaluations utilizing Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to validate the findings. Furthermore, molecular dynamics simulations were carried out to assess differences in binding between type 2 MET TKIs.

The study findings show that all 6 type 2 MET TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib demonstrated potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model. CEP-40783 and altiratinib demonstrated some activity.

Findings from the molecular dynamics analysis indicated that the long tail of foretinib plays an essential role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Moreover, tertiary G1163X mutations, collectively with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.

“The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230,” concluded Dr Fujino and colleagues.

Source:

Fujino T, Suda K, Koga T, et al. Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol. 2022;15(1):79. Published 2022 Jun 11. doi:10.1186/s13045-022-01299-z