Larotrectinib (LOXO-101)

Our lead therapy in clinical development, larotrectinib (LOXO-101), is an oral, potent and selective inhibitor of tropomyosin receptor kinases (TRK), a family of signaling proteins that play an important role in cellular communication and tumor growth.

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. Larotrectinib (LOXO-101) was purpose-built to directly target TRK, and nothing else, turning off the signaling pathway that allows TRK fusion cancers to grow. We believe that selectively inhibiting TRK is crucial to maximizing the potential for efficacy, while minimizing the risk of off-target toxicities. Larotrectinib (LOXO-101) is the only selective TRK inhibitor in clinical development.

The FDA has granted orphan drug designation to larotrectinib for the treatment of solid tumors harboring NTRK-fusion proteins. Additionally, the FDA granted breakthrough therapy designation to larotrectinib (LOXO-101) “for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments.” Loxo Oncology plans to submit a New Drug Application (NDA) for larotrectinib to the U.S. FDA in late 2017 or early 2018. Larotrectinib was developed through our discovery and development partnership with Array BioPharma.

Larotrectinib (LOXO-101) Phase 1 Trial

Larotrectinib is currently being evaluated in an ongoing multicenter, open-label, Phase 1 study in adult subjects with advanced solid tumors that have progressed or are non responsive to available therapies and for which no standard or available curative therapy exists.

Larotrectinib (LOXO-101) Phase 2 Basket Trial

In October 2015, we began a global, multi-center, single-arm, open-label Phase 2 basket trial in adult patients with solid tumors harboring TRK fusions. As a basket trial, the Phase 2 trial enrolls patients regardless of where their cancer arises in the human body, so long as the cancer harbors a TRK gene fusion.

Larotrectinib (LOXO-101) Phase 1/2 Pediatric Trial

In December 2015, we began a multicenter, open-label Phase 1 trial in pediatric patients with advanced solid or primary CNS tumors. The trial uses a liquid formulation of larotrectinib designed specifically for pediatric patients unable to swallow capsules.

For additional information about any of the larotrectinib clinical trials, please refer to www.clinicaltrials.gov or www.loxooncologytrials.com. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

Policy for Access to Investigational Agents

Loxo Oncology is committed to helping patients who have not responded to available therapies and may benefit from its investigational therapies. Loxo Oncology’s Policy for Access to Investigational Agents describes the principles that the company will follow when considering a request, view here.

Interim clinical data from all three ongoing larotrectinib trials were last presented at the 2017 American Society of Clinical Oncology Annual Meeting. These data, demonstrating a 76 percent confirmed objective response rate (ORR) across tumor types, were published on June 3, 2017 and are summarized below. These data can be viewed in more detail here; details regarding the larotrectinib pediatric data can be viewed here. An April 14, 2017 data cut-off date was used for the presentations.

TRK fusion patients enrolled in Loxo Oncology’s Phase 1 adult trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial (SCOUT) contributed to the primary efficacy analysis. The data are based on the intent to treat (ITT) principle, using the first 55 TRK fusion patients enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method.

Forty-three adult and 12 pediatric patients were enrolled, identified by 15 different lab tests. TRK fusion patients carried primary diagnoses of appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. One patient had central nervous system (CNS) metastases at study entry. 

  Enrolled Patients with Confirmatory Response Data Available (n=50) All Enrolled Patients (n=55)*
Objective Response Rate
(95% CI: 62% – 87%)
(95% CI: 65% – 88%)
Partial Response (PR) 64% 65%*
Complete Response (CR) 12% 13%*
Stable Disease 12% 11%
Progressive Disease 12% 11%


* Includes unconfirmed responses with confirmatory scans pending (4 PR, 1 CR). All patients with unconfirmed responses remain in response and ongoing on study.

As shown in the above table, the confirmed ORR is 76 percent in 50 patients for whom follow-up was sufficiently long to include a confirmatory scan. The ORR is 78 percent when an additional 5 patients, recently enrolled, with unconfirmed PR (n=4) and CR (n=1), are included. ORR was generally consistent across tumor types, TRK gene fusions, and various diagnostic tests. In the pediatric setting, larotrectinib showed promising activity in the pre-surgical management of patients with infantile fibrosarcoma, with 3 patients treated to best response, which allowed for subsequent referral to surgery with curative intent.

Median DOR and PFS have not been reached. Ninety-three percent of all responding patients either remain on drug or received surgery with curative intent. Seventy-five percent of all patients enrolled either remain on drug or received surgery with curative intent. 

The safety data encompass the entire larotrectinib safety database in cancer patients (n=125) intended to support an NDA. The most common adverse events, largely Grade 1 and 2, included fatigue, dizziness, nausea, and anemia. Seven (13%) of patients required a dose reduction due to an adverse event. Of note, all patients requiring dose reduction experienced tumor regression, which has continued on the reduced dose. Nearly all of the dose reductions were due to infrequent neurocognitive adverse events, likely a result of on-target TRK inhibition in the CNS. No patients discontinued larotrectinib due to an adverse event.

Six patients responded to larotrectinib but subsequently progressed, a pattern referred to as “acquired resistance.” Progression biopsies from five of six patients indicate a consistent mechanism of acquired resistance, namely a solvent front mutation. LOXO-195, Loxo Oncology’s next-generation selective TRK inhibitor, was designed to address solvent front and other acquired resistance mutations to potentially induce new responses in TRK fusion dependent cancers with acquired resistance mutations.

A research brief published in Cancer Discovery in June 2017 outlines the preclinical rationale for LOXO-195 and clinical proof-of-concept data from the first two patients treated.  Read the publication here.