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.

Both the FDA and EMA have granted orphan drug designation for larotrectinib for treatment of patients with soft tissue sarcoma. 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.

Initial larotrectinib clinical data were last presented at the 2016 ESMO Asia Meeting. These data, published on December 18, 2016, are summarized below and can be viewed in more detail here.

Larotrectinib (LOXO-101) Phase 1 Results

Larotrectinib is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of November 10, 2016, 59 patients with advanced cancer had been treated at six dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID, 200 mg QD and 200 mg BID. The median age of these patients is 59 (ranging from 19-82) and the median number of prior treatments is three (ranging from 0-24). 

Safety Analysis

Larotrectinib has been well tolerated in the 59 patients treated, including 34 patients at a dose of 100mg BID. Adverse events reported regardless of attribution to study drug are generally consistent with those previously presented. The most common adverse events, largely Grade 1 and 2, include fatigue (37 percent), dizziness (29 percent), anemia (25 percent) and dyspnea (25 percent). No individual Grade 3 or 4 adverse events occurred in more than three patients treated at 100mg BID or more than five patients in the entire study population. The frequency of toxicities did not correlate with dose level. The MTD has not yet been defined.

Efficacy Analysis

As of November 10, 2016, eight patients with cancers harboring TRK fusions had been enrolled, representing a broad range of tumor types, namely mammary analogue secretory cancer of the salivary glands (MASC, n=3), gastrointestinal stromal tumor (n=2), soft tissue sarcoma, thyroid carcinoma and non-small cell lung cancer. Seven patients with TRK fusion cancers were on study sufficiently long for an efficacy assessment, while an eighth TRK fusion patient had been recently enrolled and was not yet evaluated for response. Six of the seven efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. A seventh patient, as previously reported, demonstrated clear radiographic tumor regressions, including in the central nervous system, and remains on study, but had not met the threshold required for a RECIST response. All responders remained in response, with one patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one month.