LOXO-195 Active After Initial Anti-TRK Failure in Multiple Tumor Types

David Hyman, MD

A third of patients with advanced TRK fusion tumors had objective responses to the second-generation TRK inhibitor LOXO-195 after failure of initial anti-TRK therapy, data from an ongoing trial showed.

Ten of 29 patients had complete or partial responses, and 9 others had stable disease. Responses occurred in tumors harboring the 3 most common acquired TRK kinase domain resistance mutations.

No “off-target” dose-limiting toxicity (DLT) occurred, and all DLTs were reversible with dose interruption or reduction, David Hyman, MD, of Memorial Sloan Kettering Cancer Center, reported at the 2019 AACR Annual Meeting.

“LOXO-195 was well tolerated at doses less than or equal to 100 mg BID; the optimal dose and schedule are still being explored,” said Hyman. “We observed preliminary efficacy in TRK fusion—positive patients with acquired TRK kinase domain resistance mutations. Additional data are needed to define the activity in each specific kinase mutation.

“These data suggest LOXO-195 may help provide a continuum of care for patients with TRK fusion cancer that progresses on first-generation TRK inhibitors.”

After embryonal development, TRK expression occurs primarily in the nervous system. Three TRK receptors are encoded by distinct genes (NTRK1, 2, and 3 or TRKA, B, and C). TRK fusions are rare but occur across diverse tumor types in pediatric and adult patient populations.

Larotrectinib (Vitrakvi), the first FDA-approved TRK inhibitor, achieved an objective response rate of 81% in 109 patients with various TRK fusion tumors, and median response duration had yet to be reached after a median follow-up of 17.6 months.²

The effectiveness of TRK inhibition is limited by development of acquired resistance, most often from emergence of the solvent front (SF), gatekeeper (GK), and xDFG TRK kinase mutations. Patients whose tumors develop acquired resistance to TRK inhibition have few treatment options and a poor prognosis.

LOXO-195 is highly selective for all three TRK kinases and exhibits potent inhibition of all three. Studies involving enzyme- and cell-based assays as well as in vivo tumor models demonstrated against SF, GK, xDFG, and other TRK mutations, said Hyman.

LOXO-195 was evaluated in a phase I dose-escalation study, as well as a single-patient population (SPP), comprising individuals who would not have had access to the drug but had characteristics similar to the patients enrolled in the phase I trial. The SPP patients received LOXO-195 through an FDA-administered standard access program with cooperation from Loxo Oncology and Bayer, said Hyman. Patients with resistance or intolerance to prior anti-TRK therapy were eligible.

Data analysis included 31 patients, 20 enrolled in the phase I trial and 11 in the SPP. The patients had a median age of 37 and an age range of 1 to 72. Seven patients were younger than 18 (pediatric). Fifteen types of tumors were represented, the most common being sarcoma (16%), gastrointestinal stromal tumors (13%), pancreas (12%), and breast and mammary analog secretory carcinoma (10% each).

All the patients had prior exposure to a TRK inhibitor, which was larotrectinib in 21 cases, entrectinib in 9, and PLX7486 in 1. Median duration of anti-TRK treatment was 11 months.

Doses of LOXO-195 evaluated ranged from 50 mg QD to 150 mg BID. Five patients had dose-limiting toxicity (DLT, dizziness, ataxia, vomiting). Patients in SPP received LOXO-195 at doses ranging from 20 mg BID to 300 mg QD, and no DLTs occurred.

The safety analysis included only the patients from the phase I trial. The most common treatment-emergent adverse events (TEAEs, all grades) were dizziness (65%), ataxia (60%), nausea (50%), vomiting (40%), anemia (30%), gait disturbance (30%), myalgia (25%), abdominal pain (25%), fatigue (20%), and decreased lymphocyte count (20%). There were no grade 4 TEAEs, and the most common grade 3 TEAEs included ataxia (20%), dizziness (15%), vomiting (10%), and anemia (10%).

Pharmacokinetic data showed that plasma levels of LOXO-195 after the first 50-mg dose led to unbound concentrations exceeding IC50 for both wild-type and mutant TRK. Mean plasma half-life was 3 hours, and moderate to high intra- and interpatient variability was observed. Collectively, the data provided support for potential inhibition of TRK resistance mutation.

The mechanism of TRK resistance to prior therapy was SF in 14 patients, GK in 4, xDGF in 2, bypass in 3, and other/unknown in 8. The 10 objective responses during LOXO-195 treatment consisted of 7 patients with SF mutation, 1 each with GK and xDFG, and 1 unknown (a patient intolerant but not resistant to prior TRK inhibition).

References

1. Hyman D, Kummar S, Farago A, et al. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT127.
2. Lassen U, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 409O.

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