Understanding NTRK Fusion Actionability: An Overview of Targeted Therapy Options
Posted: Sunday, August 1, 2021
In a primer on the role of TRK inhibitors in the treatment of patients with NTRK fusion-positive cancers, Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, offered a historical look at the development, clinical activity, and safety of the first-generation TRK inhibitors, larotrectinib and entrectinib, in Annals of Oncology. In addition, with resistance to first-generation TRK inhibition a possibility for some patients, next-generation agents have emerged, including seltrectinib and repotrectinib. In this review, Dr. Drilon also clarified the utility of sequentially using TRK inhibitors for some patients—“a paradigm that parallels the use of targeted therapies in other oncogenic driver–positive cancers.”
In 2018, the first-generation TRK inhibitor larotrectinib received accelerated FDA approval to treat NTRK fusion–positive cancers, and it was joined by entrectinib in 2019. The rapid approval of larotrectinib was largely due to results from a registrational data set presenting an objective response rate of 81% among 55 patients, a partial and complete response in 63% and 17% of participants, respectively. There was also a median time-to-response of 1.8 months. Most notably, significant disease regression allowed limb-sparing surgery in early-stage disease.
Entrectinib underwent similar testing among 54 patients, yielding an objective response rate of 57% with a disease control duration of nearly 15 months. Both larotrectinib and entrectinib have demonstrated intracranial disease control.
According to Dr. Drilon, TRK inhibitors have a favorable overall safety profile. However, select on-target adverse events (such as weight gain, dizziness/ataxia, and paresthesias) occur occasionally and require monitoring in the clinic.
In the form of NTRK kinase domain mutations, resistance to first-generation TRK inhibition is a possibility for some patients; these mutations interfere with inhibitor binding and kinase domain conformation. Next-generation TRK inhibitors such as selitrectinib and repotrectinib are already in clinical trials and were created to tackle on-target resistance. These drugs abrogate kinase domain substitution resistance, allow re-engagement of the ATP-binding pocket, and even demonstrate increased activity against wild-type TRK compared with first-generation inhibitors. For off-target resistance, combination therapies (eg, TRK and MET inhibition) have achieved disease control and clinical proof of principle in selected patients.
Disclosure: For full disclosures of the study author, visit annalsofoncology.org.