FDA Grants LOXO-101 Breakthrough Designation for Solid Tumors

The FDA granted the selective tropomyosin receptor kinase inhibitor LOXO-101 a breakthrough therapy designation for the treatment of adult or pediatric patients with unresectable or metastatic solid tumors with NTRK-infusion proteins who progressed on prior therapy or have no other available treatment options.

Josh Bilenker, MD

The FDA granted the selective tropomyosin receptor kinase (TRK) inhibitor LOXO-101 a breakthrough therapy designation for the treatment of adult or pediatric patients with unresectable or metastatic solid tumors with NTRK-infusion proteins who progressed on prior therapy or have no other available treatment options.

The designation, which will expedite the development and review of LOXO-101, is based on 3 early stage trials, according to Loxo Oncology, the company developing the drug. Available data from across the studies showed that 6 of 7 evaluable patients receiving LOXO-101 had a confirmed partial response.

“We’re pleased to have been a granted breakthrough therapy designation for LOXO-101 and look forward to working more closely with the FDA to bring this therapy to patients with TRK fusion cancers,” Josh Bilenker, MD, CEO of Loxo Oncology, said in a statement. “Data presented to date from the ongoing adult and pediatric studies of LOXO-101 have demonstrated durable antitumor activity across TRK fusion cancers, further validating LOXO-101’s potential to address the unmet medical need among patients with these genetically defined cancers.”

LOXO-101 is a highly selective oral inhibitor of the TRK family of neurotrophin receptors: TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively). In discussing the rationale for investigating LOXO-101, Loxo Oncology’s press release explained, “Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body.”

Results from an ongoing phase I trial of LOXO-101 in adult patients with advanced solid tumors were presented in April at the 2016 AACR Annual Meeting.1 The multicenter, open-label, 3+3 dose escalation trial had enrolled 41 patients at the time of the data analysis.

Patients received oral LOXO-101 at a once or twice daily dose for continuous 28-day cycles. LOXO-101 was administered at either 50 mg/daily, 100 mg/daily, 200 mg/daily, 100 mg twice daily, or 150 mg twice daily.

There were 7 patients with NTRK fusions across 5 tumor types, which included sarcoma (n = 1), papillary thyroid cancer (n = 1), mammary analog secretory carcinoma of the salivary glands (n = 3), non—small cell lung cancer (n = 1), and GI stromal tumor (n = 1). All 7 patients were still receiving treatment at the data cutoff, and the duration of therapy ranged from 1 to 13 cycles.

Six of these 7 patients were evaluable for response. Among the 6 patients, 5 had confirmed partial responses (RECIST), and the sixth patient demonstrated a tumor regression of 21%. The study authors noted that objective antitumor activity had not been observed in patients without an NTRK fusion.

The maximum-tolerated dose for LOXO-101 had not yet been reach at the time of the analysis. The most common adverse events were grade 1/2 fatigue (29%), dizziness (24%), and nausea (20%).

A separate phase I trial is examining LOXO-101 in pediatric and young adult patients (aged 1-21) with locally advanced or metastatic solid tumors or primary CNS tumors that have progressed or are nonresponsive to available therapies or no standard therapy exists.2 Patients can also be enrolled if they are ≥ 1 month old and have infantile/congenital fibrosarcoma with a documented NTRK fusion. In the study, the dose of LOXO-101 for a patient is determined using a weight and age adjusted dose algorithm that approximates adult exposures achieved with a dose of 100 mg twice delay.

Results were published in April 2016 for 1 patient from the trial with infantile fibrosarcoma (IFS) with NTRK3—ETV6 fusion. The patient was diagnosed with IFS at 6 months, and following surgery and the failure of standard chemotherapy regimens, she was enrolled in the phase I trial in December 2015, at the age of 16 months. She had a partial response to LOXO-101 that, according to the researchers, was “rapid.”

In a recent meeting, the Pediatric Subcommittee of the FDA’s Oncologic Drugs Advisory Committee pedsODAC voiced its support for this pediatric trial of LOXO-101. “The committee feels that the safety profile of the drug appears to be very favorable. This protocol offers a unique opportunity to study not only the activity but the pharmacokinetics and short- and long-term toxicities of this drug in young patients,” Alberto S. Pappo, MD, chairperson of pedsODAC, said at the meeting.

The third study the FDA considered in granting LOXO-101 a breakthrough therapy designation was a global phase II basket trial (NCT02576431) enrolling patients aged ≥18 years with advanced solid tumors and primary CNS malignancies harboring TRK gene fusions.3

Patient must have NTRK1, 2, or 3 fusions and have progressed on standard treatment. In the basket trial design, patients are assigned to 1 of 8 cohorts. The 8 cohorts are defined by cancer type and include non—small cell lung cancer, thyroid cancer, sarcoma, colorectal cancer, salivary cancers, biliary cancers, CNS malignancies, and all others. All patients receive LOXO-101 at 100 mg orally twice daily for continuous 28-day cycles.

Commenting on the status of the phase II study, Bilenker said, “We remain on track to provide an enrollment update regarding the LOXO-101 phase II trial in the second half of 2016.”


  1. Hong DS, Farago AF, Brose MS, et al. Clinical safety and activity from a phase I study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions Presented at the 2016 AACR Annual Meeting; April 16-20; New Orleans, Louisiana. Abstract CT008.
  2. Nagasubramanian R, Wei J, Gordon P, et al. Infantile fibrosarcoma with NTRK3—ETV6 fusion successfully treated with the tropomyosin-related kinase inhibitor LOXO-101 [published online April 19, 2016]. Pediatr Blood Cancer. doi:10.1002/pbc.26026.
  3. Drilon AE, Hong DS, Cruickshank S, et al. A phase II basket study of the oral trk inhibitor loxo-101 in adult subjects with ntrk fusion-positive tumors. J Clin Oncol 34, 2016 (suppl; abstr TPS2599).

In their conclusion, the authors wrote, “This case report supports the clinical development of selective TRK inhibitors, such as LOXO-101, in pediatric patients with an NTRK fusion.”