Zosia Chustecka

April 25, 2016

NEW ORLEANS ― A new drug directed at a new target has shown significant tumor regression in a small number of patients in a phase 1 clinical trial. The investigational oral agent, LOXO-101 (under development by Loxo Oncology), selectively targets a family of proteins known as neurotrophic tyrosine kinase receptors (NTRKs).

The product has shown "incredibly dramatic activity" in some patients with tumors that harbor NTRK gene fusions, lead investigator David S. Hong, MD, deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, in Houston, told Medscape Medical News.

The results come from a phase 1 clinical trial that enrolled "all comers," he commented, explaining that the trial included patients with any advanced or metastatic cancer who had experienced disease progression on standard therapy. Only later were the tumors tested for gene mutations, and six patients were found to have tumors with NTRK gene fusions.

"We've now seen efficacy with significant tumor regression in all six patients whose tumors had NTRK fusion," Dr Hong said. Five of the six patients had confirmed significant partial responses in accordance with RECIST 1.1 criteria. Some of these were "really dramatic responses," Dr Hong said: one patient experienced an 80% reduction in tumor volume, and another with a sarcoma had close to a complete response.

Dr David Hong

The sixth patient had an 18% tumor regression (of bone-only metastases from non–small cell lung cancer [NSCLC]).

A seventh patient with an NTRK fusion in the tumor recently joined the study and is not yet eligible for a response assessment, Dr Hong said.

All seven patients remain in the study with no evidence of progressive disease.

In contrast, the drug showed no activity in the patients whose tumors did not have this abnormality.

Responses Regardless of Histology

The responses were seen regardless of histology, Dr Hong noted. The seven patients had a range of cancer types, including sarcoma, papillary thyroid cancer, mammary analogue secretory carcinoma of the salivary glands (MASC), NSCLC, and gastrointestinal stromal tumor (GIST).

There is no link between any of these tumor types, and it appears that the NTRK gene fusion really is a driver mutation. Targeting this has a clinical benefit regardless of where the tumor is situated. "The responses look to be durable. One patient has been in the trial for 14 months now," Dr Hong commented.

However, he said that it is likely that resistance will eventually develop, and he noted that another second-generation product (LOXO-195) is already under development for use in such cases.

Overall, the NTRK gene fusion does not occur often in cancer patients. Dr Hong said he would guess that it occurs in fewer than 10% of patients, but it looks as if it occurs at much higher rates in some of the rarer tumor subtypes. For example, with the rare MASC tumors, the NTRK gene fusion may occur in up to 75% of patients, and it occurs in about 25% of young patients with BRAF-negative papillary thyroid cancer. It could also occur at high frequency among patients with C-kit and PDGFR double-negative GIST (who would not respond to imatanib or regorafenib or other available drugs).

Dr Hong said that LOXO-101 has been well tolerated. The phase 1 trial was a dose-escalation trial, with patients receiving 50 mg, 100 mg, or 200 mg once per day, or 100 mg or 150 mg twice per day. The maximum tolerated dose has not been reached, and the most common adverse events are grade 1 and 2 fatigue, constipation, and dizziness.

A phase 2 basket study of LOXO-101 is now underway. It will test the drug (at 100 mg twice daily) in more patients with a wider variety of tumors, but only in patients who have tested positive for NTRK fusions.

"To find these patients, you have to test, and you have to test with a comprehensive panel," said Josh Bilenker, MD, chief executive officer of Loxo Oncology. "There are some reimbursement issue, insurance issues, and patient communication issues that make that harder today than it should be," he commented in an interview with Medscape Medical News. He said his message to physicians is to test tumors with a comprehensive panel, and if they find an NTRK gene fusion, he would encourage them to enroll that patient into the company's clinical trial. The company provides help with travel and logistics to enable patients to have access to the drug. This is a highly actionable mutation, LOXO-101 is a highly selective drug targeting it, and there is a good chance that patients will respond to it, Dr Bilenker said.

Interested physicians and patients can make inquries via a hotline: 1-855-NTRK-123.

The study was funded by Loxo Oncology. Dr Hong has conducted research for Loxo Oncology and Ignyta Research.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract CT-008, presented April 17, 2016.

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