TRK Inhibitor Shows Early Promise

Preliminary findings from a phase I study indicate that LOXO-101 (Loxo Oncology), an inhibitor of the TRK receptor tyrosine kinase family, is effective in patients with chromosome translocations that produce fused NTRK genes. The results were presented by David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston, during the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in Boston, MA, November 5–9.

NTRK fusions, which result in TRK proteins having constitutive, oncogenic activity, were first identified in colorectal cancer and have also been found in glioblastoma, as well as lung and breast cancers. They appear more in rare tumor types, such as infantile fibrosarcoma and mammary analog secretory carcinoma (MASC), a cancer of the salivary glands. LOXO-101 was “designed to selectively suppress TRK, with almost no off-target effects,” Hong said.

To date, the ongoing study has enrolled six patients with NTRK fusions, three of whom could be evaluated as of October. Each had a different, heavily pretreated advanced disease: soft-tissue sarcoma; gastrointestinal stromal tumor (GIST); and MASC. All three had confirmed partial responses to LOXO-101 within 3 to 4 months; at 8 months, the patient with soft-tissue sarcoma had a near-complete response. In each case, key tumor-related symptoms—shortness of breath, severe pain, and a persistent cough—were resolved within the first 2 weeks.

The responses have been durable, Hong noted, with all three patients still receiving therapy. He's also encouraged that LOXO-101 is well tolerated and has a manageable toxicity profile, with the main side effects being fatigue, dizziness, and anemia.

Buoyed by these early data, Loxo Oncology has initiated a multicenter phase II basket trial of LOXO-101, enrolling patients with any kind of NTRK fusion–positive solid cancer. “This should shed further light on the tumor types in which these fusions are prevalent,” Hong said, “and we may learn more about how LOXO-101 actually works.” So far, the drug's sole target appears to be genetically rearranged NTRK; it has been ineffective not only in patients lacking any NTRK alterations, but also in a few with NTRK mutations. Nevertheless, “its mechanism of action has yet to be nailed down,” Hong cautioned.

LOXO-101 is “a dramatic example of a therapy where the target is what matters, not the tumor histology,” said Lee Helman, MD, acting director of the NCI's Center for Cancer Research in Bethesda, MD. “I'm encouraged that there may be a new drug and target for sarcomas, because treatment options for these rare cancers haven't changed much for the last 20 years.”

Although NTRK fusions have mainly been observed in uncommon cancers, Hong pointed out that “as genomic profiling becomes standard, it will likely reveal more such patients than we anticipate.”

Helman agreed. “GIST used to be misdiagnosed as leiomyosarcoma, and we didn't know to look for KIT mutations,” he said. “As soon as we had imatinib [Gleevec; Novartis], we were able to find and treat the right patients. If the data for LOXO-101 hold up, we'll be looking harder for patients with NTRK fusions, and we'll find them.”