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FDA approves Rozlytrek for cancers with NTRK gene fusion, ROS1-positive non-small cell lung cancer
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The FDA today granted accelerated approval to entrectinib for the treatment of adults and children with cancers that harbor neurotrophic tyrosine receptor kinase, or NTRK, gene fusion and for whom there are no effective treatments.
This marks the third approval of a tissue-agnostic cancer therapy indicated for treatment across cancer types based on the presence of a specific biomarker. Previous tissue-agnostic indications approved by the FDA included pembrolizumab (Keytruda, Merck), in 2017, for tumors with microsatellite instability-high or mismatch repair deficient tumors and larotrectinib (Vitrakvi, Bayer), in 2018, for NTRK gene fusion tumors.
“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,” FDA Acting Commissioner Ned Sharpless, MD, said in a press release. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for [patients with cancer]. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”
Data from four clinical trials of 54 patients with NTRK fusion-positive tumors — which included cancers of the lung, salivary gland, breast, thyroid and colon/rectum — supported the approval of entrectinib (Rozlytrek, Genentech). Study results showed an overall response rate of 57% across the four studies, with 7.4% of patients achieving complete response.
Sixty-one percent of the 31 patients with tumor shrinkage had responses lasting for at least 9 months.
“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the release. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”
The FDA also approved entrectinib for the treatment of adults with ROS1-positive metastatic non-small cell lung cancer.
In studies that included 51 patients with ROS1-positive NSCLC, entrectinib induced an ORR of 78%, with a 5.9% complete response rate. Fifty-five percent of responders had tumor shrinkage that persisted for at least 12 months.
Adverse events associated with entrectinib include fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, weight gain, cough, vomiting, fever, arthralgia and vision disorders.
Serious adverse events related to treatment include congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation and vision disorders.
Entrectinib also received priority review, breakthrough therapy and orphan drug designations.
Perspective
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Darrell J. Yamashiro, MD, PhD
From a pediatric oncology perspective, this approval probably applies to a relatively small number of children. Still, it gives us a unique targeted therapy for patients aged 12 years and older with NTRK gene fusion tumors who may not have very effective therapies. For instance, this could be a treatment option for patients with inflammatory myofibroblastic tumors who have these novel fusions.
Patients with NTRK gene fusions have shown remarkable responses with entrectinib as a single agent, and it likely will have a substantial impact as we start to look for this fusion in a wide variety of cancers.
Larotrectinib also was approved last year for NTRK fusion-positive cancers. However, entrectinib has a bit broader mechanism of action, and also was approved for lung cancer with ROS1 mutations. Hopefully this will lead to the use of entrectinib among that group of patients as well.
Further, data show entrectinib has efficacy for patients with brain tumors, supporting that the drug can penetrate the brain. Among adults, data show entrectinib induces responses for central nervous system metastasis. If a patient has a brain tumor positive for a TRK fusion, one might be apt to use entrectinib rather than larotrectinib.
Cost also may be a factor in drug choice, especially if a patient is experiencing partial response that may be sustainable if they remain on the drug.
As we continue to identify drugs that are targets for unique fusions, hopefully these tissue-agnostic approvals will continue. Regardless of whether for children or adults, and no matter the tumor location, these might be some of the first drugs that we consider for these patients.
This approval, and the data supporting it presented at this year’s ASCO Annual Meeting, is recognition of the valuable work of our colleagues that is leading to new treatment options for our pediatric patients.
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