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Next-generation TRK inhibitor demonstrates efficacy in tumors with emergent resistance mutations
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ATLANTA — BAY 2731954 appeared safe and demonstrated clinical activity among patients with solid tumors that harbored NTRK gene fusions and had become resistant to other TRK-targeted therapies, according to results from a phase 1 trial and an analysis of data from the FDA’s expanded access program presented at American Association for Cancer Research Annual Meeting.
Only 0.5% of all cancers diagnosed in the U.S. harbor NTRK fusions; however, these fusions occur in a wide variety of cancer types. Tumors with NTRK fusions respond well to treatment with TRK inhibitors such as larotrectinib (Vitrakvi; Bayer, Loxo Oncology), which received FDA approval in November.
BAY 2731954 (Bayer, Loxo Oncology) — previously known as LOXO-195 — is a next-generation TRK inhibitor that blocks TRK activity despite the presence of NTRK resistance mutations.
“Although the current generation of TRK inhibitors, led by larotrectinib, have been highly effective, we know that resistance will become a problem for some patients and additional treatments will be needed,” David Hyman, MD, chief of the early drug development service at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “BAY 2731954 offers the opportunity to potentially extend the total duration of benefit from TRK inhibition in these patients. Similar paradigms have transformed other oncogene-addicted tumors like HER2-positive breast cancer and EGFR-mutant and ALK fusion-positive non-small cell lung cancer.”
Hyman and colleagues evaluated data from 31 treated patients — seven children and 24 adults — with 11 cancer types. These included 20 patients treated with BAY 2731954 on a phase 1 clinical trial and 11 patients treated through an FDA expanded access single patient protocol.
All patients had previously received at least one first-generation TRK-targeted therapy (median duration, 9.5 months; range, 2-30).
In the phase 1 trial, patients received doses of BAY 2731954 ranging from 32 mg daily to 150 mg twice daily.
Ten of the 29 evaluable patients (34%) had a confirmed complete or partial response at the data cutoff.
Researchers then evaluated response according to mechanisms of underlying resistance. They found that nine of 20 patients (45%) with tumors that harbored a NTRK resistance mutation had a complete or partial response. Conversely, none of the three patients with TRK-independent resistance mechanisms responded to treatment with BAY 2731954.
“As we have seen with other oncogene-addicted cancers treated with targeted therapy, we believe that TRK fusion-positive cancers likely become resistant to existing TRK inhibitors by two main mechanisms,” Hyman told HemOnc Today. “So-called ‘on-target’ resistance is driven by the acquisition of new TRK mutations, and preliminary data suggests BAY 2731954 may be effective for these patients. Alternative ‘off-target’ or ‘bypass’ resistance occurs when tumors develop the ability to grow without TRK signaling.”
Hyman and colleagues hypothesized this is the case for some of the tumors without detectable TRK resistance mutations.
“That being said, I would caution it’s too early to reach any definitive conclusions about the utility of BAY 2731954 in these patients, and we are still enrolling these patients onto our study,” he added. “I would encourage any patient (or doctor treating one of these patients) who develops resistance to a current TRK inhibitor to identify a site participating in the BAY 2731954 study program.”
The most common adverse events associated with treatment in the phase 1 trial included dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia (20%), abdominal pain (20%), fatigue (20%) and lymphopenia (20%). Five adults experienced dose-limiting toxicities, including four with ataxia/dizziness and one with ataxia/vomiting.
One patient treated through the FDA expanded access program received a dose reduction for a treatment-related adverse event; no patient discontinued therapy.
Dose selection is ongoing, Hyman said.
“The main limiting factor at this point is gaining experience with BAY 2731954 in a larger number of patients,” he said. “This has been primarily limited by the amazing effectiveness of larotrectinib for current patients, which ultimately I view as a very positive thing. However, if drugs like larotrectinib eventually stop working, patients and doctors should know there is an alternative for these patients.” – by Alexandra Todak
Reference:
Hyman D, et al. Abstract CT127. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: Loxo Oncology and Bayer funded this study. Hyman reports consultant roles with and research funding from Bayer and Loxo Oncology. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Damon Reed, MD
These findings show both the tremendous promise and limits of precision medicine.
I agree patients should seek this agent [BAY 2731954] when progressing on LOXO-101 with specific resistance mutations. [The demonstration that] this fundamental driver of these cancers can be again successfully treated is the positive aspect of this abstract. That the other roughly half have adapted around this main driver should also be highlighted. Combinations or more adaptive schedules of targeted therapy — that is exposure and withdrawal of the agent to minimize emergence of resistance — should be explored in the future.
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