Preliminary findings from a phase I study of LOXO-195 show that the investigational agent appears effective in patients with NTRK fusion–positive solid tumors that have become resistant to first-generation TRK inhibitors.

According to preliminary data from a phase I study of LOXO-195 (Loxo Oncology), the investigational agent appears effective in patients with NTRK fusionpositive solid tumors that have become resistant to first-generation TRK inhibitors (Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT127). The findings were presented by David Hyman, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, on April 1 at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA.

In November 2018, larotrectinib (Vitrakvi; Loxo Oncology) became the first TRK inhibitor to earn FDA approval, which also marked the agency's first tissue-agnostic nod for a targeted therapy. Larotrectinib is continuing to show remarkable efficacy in multiple tumor types harboring NTRK1/2/3 fusions, Hyman noted, “but as more patients were treated, we noticed resistance mutations emerge in a small but meaningful population.” These mutations can occur in three recurrent motifs—solvent front, xDFG, and gatekeeper—along the respective kinase domains of TRKA/B/C, “with the same end result, in that they interfere with the drug's ability to bind and inhibit constitutive, oncogenic protein activity,” he explained.

Enter LOXO-195, a next-generation TRK inhibitor “developed on the heels of larotrectinib, with a similar but more compact chemical structure,” Hyman said. The candidate drug was rapidly advanced into the clinic after demonstrating potent activity against TRK kinase domain mutations in enzyme- and cell-based assays, as well as in in vivo tumor models (Cancer Discov 2017;7:963–72).

To date, a total of 31 patients have received LOXO-195, 20 through the ongoing phase I trial and another 11 through the FDA's expanded access (compassionate use) protocol. All had disease progression on a prior TRK inhibitor—chiefly larotrectinib, but also entrectinib (Ignyta) and PLX7486 (Plexxikon). Hyman reported that of 29 evaluable patients, the objective response rate (ORR) to LOXO-195 was 34%. In a subanalysis of 20 patients who were found, via tissue and plasma sequencing, to have acquired TRK kinase domain mutations—mainly in the solvent-front motif—the ORR was 45%. Meanwhile, of 3 patients identified with bypass, or TRK-independent, mutations, none responded to treatment.

“Pretty much all of LOXO-195's activity is in this subset [with known TRK resistance mutations], which is consistent with our biological understanding of its mechanism,” Hyman said. The ORR of 45% is “about what we expected here, and considered promising,” he added. “That said, it's very much an initial estimate and will require confirmation with expanded experience [with the drug].”

Alexander Drilon, MD, also of MSKCC and a trial author, is similarly encouraged by the data, “as it highlights our ability to reestablish disease control in select patients after a first-generation TRK inhibitor fails,” he said. “This paradigm is not unlike what we've seen in lung cancers with sensitizing ALK, ROS1, or EGFR mutations.”

Not unlike the trajectory of other multikinase-targeted therapies, newer TRK inhibitor iterations will probably be needed to keep one jump ahead of resistance, Hyman said. “As well, the benefit is additive over time; by stringing together multiple agents, we can have a greater impact on patients' lives.” He highlighted one patient with NTRK1 fusion–positive colorectal cancer who “got 6 months out of larotrectinib and has now been on LOXO-195 for 22 months.”

“Because resistance almost invariably occurs, any new treatments that we can switch patients to down the line are welcome,” Drilon agreed. “At least right now, I don't see a clearly superior approach to this [sequential strategy].”

Within the landscape of TRK inhibitor development, larotrectinib's first-generation counterpart, entrectinib, is currently under priority review by the FDA, with a decision expected later this year. San Diego, CA–based TP Therapeutics has another candidate specifically aimed at combating resistance, repotrectinib, in the pipeline. Following the first disclosure of LOXO-195 at AACR, “we'll now have to see what bar the FDA sets for its approval,” Hyman said. –Alissa Poh


Lecia Sequist, MD, MPH, presented findings of the TATTON trial.

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