Bayer's Tumor-Agnostic Therapy Larotrectinib Nominated for Priority Review in China

Source: PharmaCube Info

On May 26, the official website of the Center for Drug Evaluation (CDE) indicated that Bayer's marketing authorization application for larotrectinib capsules and oral solution is proposed for priority review and has entered the public notification period. Indication: For the treatment of adult and pediatric patients with solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions, who have locally advanced or metastatic disease, or for whom surgical resection is likely to result in severe morbidity, or who have no satisfactory alternative treatments.

NTRK gene fusions (fusions between members of the NTRK gene family—NTRK1, NTRK2, or NTRK3—and another unrelated gene) are a class of genetic alterations that lead to the constitutive activation of chimeric TRK fusion proteins. These fusion proteins act as oncogenic drivers that promote tumor cell proliferation and survival. TRK fusion cancers are not restricted to specific cell or tissue types and can occur in any part of the body. Tumor types harboring NTRK gene fusions include breast cancer, colorectal cancer, lung cancer, and thyroid cancer, among others. Cancer patients need to undergo specific testing based on next-generation sequencing (NGS) or immunohistochemistry (IHC) to confirm whether they harbor TRK fusion cancers.

Larotrectinib is a next-generation, highly selective oral TRK inhibitor developed by Loxo Oncology and Bayer. It is a novel anticancer drug designed from the early stages of development to target specific genetic mutations rather than specific cancer types. During its development, clinical trials evaluating its efficacy employed a "basket trial" design. Specifically, patients were enrolled based on the molecular characteristics of their tumors rather than the primary tissue of origin.

Larotrectinib was first approved by the FDA in 2018 under the brand name VITRAKVI for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring NTRK gene fusions. It is the second drug approved by the FDA for a tumor-agnostic indication targeting a specific genetic alteration, following the approval of Keytruda for all solid tumors exhibiting high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

The FDA approval of larotrectinib was based on pooled data (N=55) from the Phase I adult LOXO-TRK-14001 trial, the Phase II NAVIGATE trial, and the Phase I/II pediatric SCOUT trial. In the pooled analysis, as assessed by an Independent Review Committee, larotrectinib demonstrated an objective response rate (ORR) of 75%, with 22% of patients achieving a complete response and 53% achieving a partial response. 73% of patients had a duration of response (DOR) of 6 months or longer, and the median DOR and progression-free survival (PFS) had not been reached at the time of analysis.

Currently, in addition to larotrectinib, Roche's ROS1/ALK/Trk inhibitor entrectinib also received FDA approval on August 15, 2019, becoming the third "tumor-agnostic" anticancer therapy and the second FDA-approved therapy for the treatment of cancers harboring NTRK gene fusions.

In China, Bayer's larotrectinib is the first TRK inhibitor to be filed for marketing approval, while Roche's entrectinib, Anbiopharm's ROS1/TRK inhibitor AB-106, and InnoCare Pharma's TRK inhibitor ICP-723 are in Phase II clinical trials.