Abstract
Presenting data on 50 of 55 patients with advanced TRK fusion–positive tumors, researchers reported that 76% of patients responded to the selective pan-TRK inhibitor larotrectinib, and 12% of patients experienced complete responses; 93% of responders remain on therapy. The targeted therapy was well tolerated, with just 13% of patients requiring a dose modification. None of the patients discontinued treatment due to adverse events.
The only selective pan-TRK inhibitor currently in clinical development, larotrectinib (LOXO-101; Loxo Oncology), shows striking and lasting efficacy against a variety of tumors—and in both adult and pediatric patients. Data were presented on June 3 at the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL.
Researchers reported response data for 50 of 55 patients enrolled in three trials: eight adults from a phase I trial, 12 from the pediatric phase I/II SCOUT trial, and 35 adults and adolescents from the phase II NAVIGATE basket trial. All had advanced, TRK fusion–positive solid tumors, representing 17 different types of cancer; some were rare cancers, such as infantile fibrosarcoma and salivary gland cancer, whereas others, such as melanoma and lung cancer, were common. (TRK fusions occur in about 90% of certain rare cancers, but in only about 0.5% to 1% of common cancers.)
Among the 50 patients who had been on the study long enough to have had at least two scans, 76% responded to larotrectinib. “You'd be hard-pressed to find a targeted therapy, even within a single disease context, that has results like this,” said David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who presented the findings. The median time to response was 1.8 months.
In addition, 12% of patients had complete responses. “These data are early, and there needs to be some equipoise when interpreting them,” said Trever Bivona, MD, PhD, of the University of California, San Francisco. However, he added that the complete response rate “is nearly unheard of” in advanced cancers.
In total, 93% of responding patients remain on therapy—including one ongoing at 25 months—or have had surgery. The five patients who hadn't been on the study long enough to have a confirmatory scan had an objective response to larotrectinib and remain on the study, Hyman said.
There was no trade-off between improvement and side effects, as larotrectinib was extremely well tolerated, Hyman said, with just 13% of patients requiring a change in dose. No patients discontinued therapy due to adverse events, the most common of which were dizziness, fatigue, and nausea.
In the United States, researchers estimate that 1,500 to 5,000 patients a year are diagnosed with a cancer that harbors a TRK fusion. However, the true number may well be higher because most assays don't capture TRK fusions.
“You only find what you look for,” said John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. “I think you see very clearly that patients who have this alteration, which is rare, and get this drug, have a dramatic benefit. This speaks to the importance of expanding what we're looking for.”
Hyman agreed. “Really recognizing this benefit in the community will require that we test patients more universally for TRK fusions or other tumor-agnostic biomarkers such as microsatellite instability,” he commented.
Bivona stressed that cancer researchers also need to look for mechanisms of resistance early in the drug development process. “No matter how effective a targeted therapy is initially, virtually all patients relapse due to resistance and, oftentimes, mutations in the target of the drug,” said Bivona. In the case of larotrectinib, six patients developed resistance to the drug, five of whom had the same mutation.
A patient with sarcoma whose disease metastasized to the lungs (left) had a marked response to larotrectinib, as seen at 16 weeks (right). (Originally published in Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, et al. Cancer Discov 2015;5:1049–57.)
To address that, researchers tested another agent, LOXO-195, which demonstrated promising activity in two patients who had been treated with larotrectinib (Cancer Discov 2017 June 3 [Epub ahead of print]). These data “highlight the potential value in anticipating those mechanisms of resistance and developing second-generation drugs that target them,” said Bivona.
Loxo Oncology plans to submit an application to the FDA late this year or early in 2018 for the approval of larotrectinib. –Suzanne Rose
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