publication date: Feb. 23, 2018

Clinical Roundup

NEJM publishes Loxo’s larotrectinib clinical data

The New England Journal of Medicine Feb. 22 published data for larotrectinib in the treatment of pediatric and adult patients whose tumors harbor tropomyosin receptor kinase gene fusions. Loxo Oncology Inc. and Bayer AG are developing the agent

The paper provides additional clinical details and patient follow-up from the 2017 American Society of Clinical Oncology Annual Meeting presentation. It includes the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers treated across Loxo Oncology’s phase I adult trial, phase II trial (NAVIGATE), and phase I/II pediatric trial (SCOUT), using a July 17, 2017 data cutoff.

“Ongoing treatment with larotrectinib continues to demonstrate striking and durable efficacy coupled with minimal side effects, across a diverse patient population,” said David Hyman, the NAVIGATE global principal investigator, chief of the Early Drug Development service at Memorial Sloan Kettering Cancer Center and senior author of the NEJM paper. “The efficacy of larotrectinib warrants screening for TRK fusions alongside other actionable targets in patients of all ages with advanced solid tumors

In December, Loxo Oncology initiated submission of a rolling New Drug Application to FDA for larotrectinib, utilizing the same patient population and data cutoff as outlined in the NEJM paper. The rolling NDA submission is expected to be complete in early 2018 and a Marketing Authorisation Application submission by Bayer in the European Union is expected in 2018. The larotrectinib program has continued to enroll and treat newly identified patients with TRK fusion cancers, beyond the 55 patients described in the publication.

The anti-tumor activity and safety of larotrectinib in these additional patients are consistent with the data reported in the publication, and will be included for supportive analyses in the NDA and MAA submissions. Loxo Oncology expects to present these additional data in the second half of 2018.

The published data were based on the intent to treat 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, and other cancers.

The primary endpoint for the analysis was overall response rate. 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.

Median duration of response and median progression-free survival 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 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 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.

Copyright (c) 2018 The Cancer Letter Inc.