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First- Versus Second-Generation TRK Inhibitors for NTRK Fusion–Positive Cancers

By: Justine Landin, PhD
Posted: Friday, January 14, 2022

Second-generation TRK inhibitors may be more beneficial than first-generation TRK inhibitors for the treatment of NTRK fusion–positive cancers, according to Prabhjot S. Mundi, MD, of Columbia University Irving Medical Center, and colleagues. In particular, the second-generation TRK inhibitors selitrectinib and repotrectinib demonstrate promising antitumor activity while avoiding the clinical resistance observed with larotrectinib and entrectinib. The findings of this review were published in Critical Reviews in Oncology/Hematology.

“Clinical trials of [larotrectinib and entrectinib] demonstrated significant and durable responses in patients with tumors harboring NTRK alterations. Unfortunately, acquired resistance inevitably develops. The second-generation TRK inhibitors selitrectinib and repotrectinib are designed to overcome known mechanisms of resistance,” stated the study authors.

Larotrectinib and entrectinib are potent inhibitors of the ATP-binding site of the kinase domain of TrkA, TrkB, and TrkC, with IC50 levels in the low (1–5 nM) range. However, tumors harboring the kinase domain mutation G2032R tend to be associated with clinical resistance following crizotinib, lorlatinib, and entrectinib treatment. Clinical resistance appears likely to occur in patients with NTRK fusion–positive cancers treated with first-generation TRK inhibitors, with a median duration of response to larotrectinib and entrectinib of 8.3 and 10.5 months, respectively. Of these patients, up to 90% harbor secondary mutations in the kinase domain associated with drug resistance.

Next-generation TRK inhibitors such as taletrectinib, selitrectinib, and repotrectinib have similarly demonstrated potent growth inhibition of NTRK fusion–positive tumors, with near-complete growth inhibition at select doses (> 50 mg/kg). Selitrectinib and repotrectinib are lower-weight compounds than first-generation inhibitors, allowing the drugs to interact with the ATP-binding site without steric clash with solvent-front and xDFG motif mutations. Thus, the authors suggest that these second-generation TRK inhibitors are potent antitumor agents and may avoid clinical resistance due to secondary solvent-front mutations.

Disclosure: The study authors reported no conflicts of interest.


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