FDA Approves Another Tumor-Agnostic Cancer Drug

Nick Mulcahy


August 15, 2019

The US Food and Drug Administration (FDA) has granted accelerated approval to entrectinib (Rozlytrek, Genentech/Roche) today for the treatment of adult and pediatric patients with a variety of tumors that are positive for fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene. Additionally, the drug was similarly approved for the treatment of metastatic, ROS1-positive non-small cell lung cancer (NSCLC).

For the first approval, the drug is to be used in patients with locally advanced or metastatic solid tumors expressing NTRK that have progressed following prior therapies, and it can also be used as a first-line treatment when there are no effective therapies.

NTRK gene fusions are tumor agnostic, which means the biomarker defines the cancer rather than an organ where the disease originated, as is typically the case.

"We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We're seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine," said FDA Acting Commissioner Ned Sharpless, MD, in a press statement.

Entrectinib becomes the second tumor-agnostic approved drug to target NTRK+ tumors, following larotrectinib (Vitrakvi, Loxo Oncology/Bayer), which was approved by the FDA in 2018, as reported by Medscape Medical News. The new drug is the third agent overall to have a tissue-agnostic indication approved by the FDA. The first was pembrolizumab, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017.

Entrectinib is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins.

"Entrectinib represents a unique approach to cancer treatment that can potentially target a range of hard-to-treat and rare NTRK fusion-positive tumors regardless of their site of origin, as well as treat ROS1-positive non-small cell lung cancer," said Sandra Horning, MD, chief medical officer, Genentech, in a press statement.

The new approvals are based on results from an integrated analysis of data from a set of four early phase clinical trials, according to company and FDA data.

The integrated analysis included data from 54 patients with locally advanced or metastatic NTRK fusion-positive solid tumors (10 tumor types, > 19 histopathologies) and 53 patients with ROS1-activating gene fusions.

In patients with NTRK+ solid tumors treated with entrectinib, overall response rate (ORR) was 57%. Responses were seen across 10 different tumor types. Among responders, 61% had their tumors shrink for 9 months or longer.

Tumor types evaluated in the studies with NTRK+ patients included breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, and thyroid cancers.

In patients with locally advanced or metastatic, ROS1-positive NSCLC treated with entrectinib, the ORR was 78%. Among responders, 55% had tumor shrinkage for 12 months or longer.

The most commonly reported adverse reactions seen among entrectinib-treated patients included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, weight gain, cough, vomiting, fever, arthralgia, and vision disorders.

The most serious side effects of entrectinib are congestive heart failure, central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders.

One difference between entrectinib and larotrectinib is activity in the central nervous system (CNS), said Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative in Denver, earlier this year.

This means that entrectinib provides intracranial responses and larotrectinib does not, said Doebele, who has financial ties to Genentech as well as to other pharmaceutical companies.

This is particularly important in NSCLC, he explained. One third of patients with NSCLC have brain metastases at diagnosis and two thirds are likely to develop brain metastases during treatment.

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