Getting Ready for Resistance to First-Gen NTRK Inhibitors

Alexander M. Castellino, PhD

April 08, 2019

ATLANTA — Larotrectinib (Vitrakvi, Loxo Oncology Inc/Bayer), the first tumor agnostic drug to target fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene, was approved only months ago, but already studies are in place to address mutations that emerge with first-generation TRK-targeted agents.

Several presentations here at the American Association for Cancer Research (AACR) 2019 provided insights from investigational agents that address on-target and off-target mutations that emerge as resistance mechanisms to larotrectinib or to the next NTRK inhibitor that is nearing approval, entrectinib.

One of the new investigational drugs, LOXO-195 (Loxo Oncology), a follow-on to larotrectinib, is described as a next-generation TRK-targeted agent. It was shown to achieve responses in patients who acquired on-target resistance while taking NTRK inhibitors (abstract CT127).

Presenter David Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News that some patients who are receiving the current TRK inhibitors acquire on-target mutations, namely, mutations in the TRK kinase domain. These mutations occur in three recurrent motifs and are designated solvent front mutations, xDFG, and gatekeeper mutations. "Conceptually, they are all gatekeeper mutations," Hyman said.

"There are a proportion of patients who are likely to benefit from the second-generation TRK inhibitor," Hyman told Medscape Medical News.

"Given how promising our early data are, I would encourage patients who have disease progression after treatment with a first-generation TRK inhibitor to seek out a clinical trial testing a next-generation TRK-inhibitor," Hyman said.

Study Details for LOXO-195

Hyman presented data from a phase 1 study in children (<12 years of age) and in children, adolescents, and adults (≥12 years of age) who experienced disease progression while taking or who were intolerant to a prior TRK inhibitor. LOXO-195 was tested in cohorts at 50 mg once daily and up to 150 mg twice daily.

In a second single-patient protocol study, patients who had no other access to treatment were provided LOXO-195 in a compassionate use program.

Of 31 patients in the study, 22 were females (71%; median age, 37 years), 23% were aged ≤18 years, and 97% had acquired resistance to first-generation TRK inhibitors (larotrectinib, 69%; entrectinib, 28%). Of 31 patients, 20 were from the phase 1 study (65%), and 11 were from the compassionate use study (35%). Among the patient population, mutations were acquired across 15 tumor types.

TRK resistance mechanisms were identified from testing plasma samples (carried out centrally using Guardant 360) and/or testing tissue samples (per local, institutional standards).

On-target dose-limiting toxicities seen at the higher doses of LOXO-195 in the phase 1 study included only ataxia, dizziness, and vomiting and were reversible with dose interruptions or reductions.

Most of the mutations were solvent front mutations (n = 14); other mutations included gatekeeper (n = 4), xDFG (n = 2), bypass (n = 3), and other/unknown (n = 8) mutations. Bypass mutations are off-target new activation mutations in the MAP kinase pathway (eg, KRAS, BRAF, MET).

Objective responses were reported in 50% (7 of 14 patients), 25% (1 of 4 patients), and 50% (1 of 2 patients) with solvent front, gatekeeper, and xDFG mutations, respectively.

Hyman commented: "We need to better understand why some patients who develop on-target mutations respond to therapy with second-generation TRK inhibitors and why others do not."

The study is enrolling additional patients to identify those who will achieve clinically meaningful responses, Hyman said.

Off-Target Mutational Study

Also presented at the meeting were early data with another next-generation TRK inhibitor, repotrectinib (TP Therapeutics). It was shown to be tenfold to 100-fold more potent than LOXO-195, larotrectinib, and entrectinib against TRK fusion, solvent front mutations, and gatekeeper mutations (abstract 442). The drug is currently being tested in the TRIDENT-1 study, which is enrolling patients with TRK mutations across all solid tumors.

In another presentation, Memorial Sloan Kettering Cancer Center researchers presented data from patients who had developed off-target mutations to the first-generation TRK inhibitors (abstract LB-118).

Paired tumor biopsy specimens and serial cell-free DNA were prospectively collected and sequenced from patients with TRK fusion–positive cancers before they were treated with first- and next-generation TRK inhibitors and at progression.

Six of eight patients with gastrointestinal tumors were shown to develop off-target mutations in KRAS, MET, BRAF, MAPK, or ERBB, with some patients showing multiple resistance mechanisms.

Preclinical evidence suggests that these emerging resistance mechanisms may be successfully managed with simultaneous TRK and MEK inhibition. "Upfront treatment with the combination may confer more durable responses," the investigators suggest.

The study with LOXO-195 was funded by Loxo Oncology and Bayer. Hyman has received compensation from Bayer for consultancy work and research funding from Loxo Oncology and Bayer. Disclosures for all investigators involved in the study are available in the AACR abstracts.

American Association for Cancer Research (AACR) 2019: Abstract CT127. Presented April 1, 2019.

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