– Marked and Durable Responses Across TRK Fusion Cancers –
– 75 Percent Overall Response Rate by Central Assessment; 80 Percent Overall Response Rate by Investigator Assessment –
– 86 Percent of Responding Patients Remain on Larotrectinib or Underwent Surgery with Curative Intent –
– Median Duration of Response and Progression-Free Survival Not Reached –
The NEJM publication provides additional clinical details and patient follow-up from the 2017 American Society of Clinical Oncology (
“Ongoing treatment with larotrectinib continues to demonstrate striking and durable efficacy coupled with minimal side effects, across a diverse patient population,” said
“It is exciting to see the NEJM share the larotrectinib experience in TRK fusion cancers with the broader clinical and research communities,” said
Overview of Data Published in NEJM
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.
The primary endpoint for the analysis was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival, and safety. As shown below, as previously reported, the ORR was 75% by central assessment and 80% by investigator assessment.
|Central Assessment (%)
|Investigator Assessment (%)
|Overall response rate (95% CI)
|75% (61–85%)||80% (67–90%)|
|Could not be evaluated||4||%||0|
* Data include one patient who had a partial response that was pending confirmation at the time of the
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, respectively. At 1 year, 71% of responses were ongoing. As of the
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 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 due to ongoing clinical benefit.
About Larotrectinib (LOXO-101)
Larotrectinib is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). 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. In an analysis of 55 RECIST-evaluable TRK fusion adult and pediatric patients, larotrectinib demonstrated a 75 percent independently-reviewed confirmed overall response rate (ORR) and an 80 percent investigator-assessed confirmed ORR, across many different types of solid tumors. Larotrectinib has been granted Breakthrough Therapy Designation Rare Pediatric Disease Designation and Orphan Drug Designation by the U.S. FDA. For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or visit www.loxooncologytrials.com.
In November 2017, Loxo Oncology and Bayer entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a next-generation TRK inhibitor. Loxo Oncology leads worldwide development and U.S. regulatory activities. Bayer leads ex-U.S. regulatory activities and worldwide commercial activities. In the U.S., Loxo Oncology and Bayer will co-promote the products.
About TRK Fusion Cancer
TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. TRK fusions occur rarely but broadly in various adult and pediatric solid tumors, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, GIST, infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. TRK fusions can be identified through various diagnostic tests, including targeted next-generation sequencing (NGS), immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH). For more information, please visit www.TRKtesting.com.
About Loxo Oncology
Forward Looking Statements
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