Following Milestone FDA Approval, MSK Researchers Address Resistance to Larotrectinib through Next-Generation TRK-Targeted Therapeutic


LOXO-195, a next-generation TRK inhibitor also known as BAY 2731954, has shown signs of clinical activity in individuals with NTRK gene fusion-positive solid tumors that have become resistant to first-generation TRK inhibitors. Results from a phase I clinical trial and a US Food and Drug Administration expanded access program were presented by David Hyman, MD, the Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK), at the American Association for Cancer Research (AACR) Annual Meeting 2019. This research is featured in the meeting’s press program, and findings are being presented in the “Next Generation of Clinical Trials in Molecularly Driven Therapy” minisymposium.

Larotrectinib (Vitrakvi®), a selective TRK inhibitor, was approved by the FDA in November 2018 for the treatment of pediatric and adult cancers caused by a genetic mutation called a TRK fusion. This decision marked the first time that an entirely new treatment received a tumor-agnostic indication at its initial approval.

“While responses to TRK inhibition can be dramatic, we have known that acquired resistance may eventually limit the duration of the response. As we began to see resistance occur in early larotrectinib clinical trials, we simultaneously began working to provide a next-generation treatment option to this population,” explained Dr. Hyman. “By studying individuals with acquired resistance, we identified two primary mechanisms of resistance.” Researchers found that the tumors either acquired new TRK mutations that led them to maintain dependence on TRK for growth or developed the ability to grow with signaling from the TRK fusion.

The investigational anticancer therapeutic LOXO-195 is a next-generation TRK inhibitor designed to block TRK even if a tumor has acquired new NTRK resistance mutations. “This data confirms that LOXO-195 could eventually be a meaningful treatment for some individuals whose cancers are resistant to first-generation TRK inhibitors, such as larotrectinib,” said Dr. Hyman.

“This work sets a new precedent in next-generation drug development, following seamlessly on the heels of the first-in-class agent, and is an important second chapter of the milestone work that led to the larotrectinib approval,” explained Dr. Hyman. “Through a unique clinical trial design, we were able to test and develop LOXO-195 in predominantly the same population that proved the efficacy of the first-generation inhibitors.”

Patients received LOXO-195 via a phase I adult and pediatric study or through the FDA expanded access program, also referred to as a single patient protocol. Eligible patients for the phase I study were 4 weeks old or older with a locally identified TRK fusion and had progressed or were intolerant to at least one prior TRK inhibitor. The median duration on the prior TRK inhibitor was 9.5 months. As of December 2018, 31 patients (seven children and 24 adults) with 11 cancer types had been treated. The overall response rate on LOXO-195 in individuals with TRK resistant mutations was 45 percent (nine of 20). At this time, 29 individuals were evaluable for response, and ten people (34 percent) had achieved a complete or partial response, as assessed by RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. In the phase I clinical trial, LOXO-195 was well tolerated at all dose levels tested. The observed toxicities were consistent with the anticipated side effects of TRK inhibition. The most common reported adverse events were dizziness, nausea, anemia, muscle pain, abdominal pain, fatigue, and lymphopenia. Five people had dose-limiting toxicities. The complete or partial responses were seen in individuals whose tumors were determined to have become resistant by acquiring an NTRK gene mutation. In the ten patients who’d had prior TRK therapy but had no identified TRK-resistant mutations, no responses were observed. This was anticipated as these tumors are presumed to have developed the ability to grow without TRK signaling.

“We are continuing to push the assumptions of what is possible through precision oncology. Historically, it has taken years to bring next-generation inhibitors into the clinic,” explained Dr. Hyman. “By accelerating preclinical development timelines and by utilizing a novel first-in-human study design in order to rapidly reach therapeutic doses, we are able to extend the benefits of targeting TRK fusions in these individuals.”

Initial data from the first two patients to receive LOXO-195 were previously published in Cancer Discovery (June 2017).


This study was funded by Loxo Oncology and Bayer. Dr. Hyman has received compensation from Bayer for consultancy work and research funding from Loxo Oncology and Bayer.