Our lead therapy in clinical development, larotrectinib, is an oral 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 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 is the only selective TRK inhibitor in clinical development.
The FDA has granted larotrectinib the following designations:
In December 2017, Loxo Oncology initiated submission of a rolling New Drug Application (NDA) for larotrectinib to the U.S. FDA, which was completed in March 2018. In May 2018, the FDA accepted the company’s NDA and granted Priority Review for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion. The FDA has set a target action date of November 26, 2018, under the Prescription Drug User Fee Act (PDUFA).
Larotrectinib was developed through our discovery and development partnership with Array BioPharma.
Larotrectinib 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 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 Phase 1/2 Pediatric Trial
In December 2015, we began a global, 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 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.
An article published in the New England Journal of Medicine in February 2018 provides interim clinical data for larotrectinib in the treatment of pediatric and adult patients whose tumors harbor tropomyosin receptor kinase (TRK) fusions. These data can be viewed in more detail here. A July 17, 2017 data cut-off date was used for the publication.
The NEJM publication provides additional clinical details and patient follow-up from the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting presentation. It includes the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers treated across Loxo Oncology’s Phase 1 adult trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial (SCOUT). The published data were based on the intent to treat (ITT) principle, using the first 55 TRK fusion patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method.
The analysis included both adult and pediatric patients, ranging in age from four months to 76 years, who carried 17 unique TRK fusion-positive tumor diagnoses. Tumor types included salivary gland, infantile fibrosarcoma, thyroid, colon, lung, melanoma, gastrointestinal stromal tumor (GIST), and other cancers.
|Central Assessment (%)
|Investigator Assessment (%)
|Overall response rate (95% CI)
(ORR = PR+CR)
|75% (61–85%)||80% (67–90%)|
|Partial Response (PR)||62%||64%*|
|Complete Response (CR)||13%||16%|
|Could not be evaluated||4%||0%|
* Data include one patient who had a partial response that was pending confirmation at the time of the July 17, 2017 data cut-off. The response was subsequently confirmed, and the patient’s treatment and response were ongoing as of the data cut-off date.
As shown in the table above, as previously reported, the ORR was 75% by central assessment and 80% by investigator assessment. Median duration of response (DOR) and median progression-free survival (PFS) had not been reached after median follow-up durations of 8.3 months and 9.9 months, respectively. At 1 year, 71% of responses were ongoing. As of the July 17, 2017 data cutoff, 86% of responding patients remained on treatment or had undergone surgery with curative intent. The first patient treated with a TRK fusion tumor remained in response and on therapy at 27 months.
Larotrectinib was well tolerated with the majority of all adverse events being grade 1 or 2. Few grade 3 or 4 adverse events, regardless of attribution, were observed with the most common being anemia (11%), alanine or aspartate aminotransferase increase (7%), weight increase (7%), and neutrophil count decrease (7%) (all grade 3 events). There were no treatment-related grade 4 or 5 events, and no treatment-related grade 3 adverse events occurred in more than 5% of patients. Eight patients required larotrectinib dose reductions. Adverse events leading to dose reductions included AST/ALT elevation, dizziness, and neutrophil count decrease, all grade 2 or 3 events. In all cases, patients whose doses were reduced maintained their best response at the lower dose and none discontinued larotrectinib due to an adverse event.
Primary resistance was observed in six patients in the study. Of the six, one patient had been previously treated with another TRK inhibitor and tumor sequencing prior to larotrectinib dosing revealed a solvent front mutation, a known resistance mechanism. Tumor tissue was analyzed for three of the five remaining patients. In all three patients, TRK immunohistochemistry failed to demonstrate TRK expression, potentially implicating a false positive initial TRK fusion test result and therefore possibly explaining the lack of response in these patients.
The publication also details mechanisms of acquired resistance to larotrectinib. Ten patients experienced disease progression while on treatment after a documented objective response or stable disease for at least six months, a phenomenon known as acquired resistance. Nine of the ten patients had assessments of post-progression tumor or plasma samples, and NTRK kinase domain mutations were identified in all of those samples tested. In seven of those assessed, investigators identified solvent front mutations as a convergent mechanism of acquired resistance; other NTRK kinase domain mutations were identified in the remaining two patients tested. Of the 10 patients who developed acquired resistance, 80% continued treatment with larotrectinib beyond progression.
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.
In March 2018, The Lancet Oncology published results for larotrectinib in the treatment of pediatric patients with TRK fusion cancers. The publication included Phase 1 safety results which revealed that larotrectinib induced an objective response rate (ORR) of 93% (14 of 15) in pediatric patients with TRK fusion-positive solid tumors.