EU OK for First 'Histology-Independent' Cancer Drug

Hailed as a 'Game Changer'

Zosia Chustecka


July 26, 2019

The first so-called histology-independent cancer treatment has been recommended for approval in the European Union.

The product is larotrectinib (Vitrakvi, Bayer), which targets a specific gene mutation, the neurotrophic tyrosine receptor kinase (NTRK) gene fusion.

Larotrectinib is indicated for the treatment of pediatric and adult solid tumors that harbor an NTRK gene fusion, regardless of where they are found in the body.

Treatment with larotrectinib is recommended for patients whose disease has spread or cannot be surgically removed and for whom there are no other satisfactory treatment options.

Before treatment is started, the presence of the mutation in the tumor should be confirmed by a validated test, noted the European Medicines Agency's Committee for Medicinal Products for Human Use.

Larotrectinib was approved in November 2018 in the United States and has been hailed as a "game changer" by clinicians who have used the drugs for the treatment of cancer.

Screen Patients for This Mutation

As previously reported by Medscape Medical News, these NTRK gene fusions — also refered to as tropomyosin receptor kinase (TRK) fusions — are thought to occur in 0.5% to 1% of many common cancers, including lung, colon, breast, and thyroid cancers, as well as melanoma.

They are also seen in more than 90% of certain rare cancers, including salivary gland cancer, a form of juvenile breast cancer, and infantile fibrosarcoma.

All cancer types with an NTRK gene fusion have shown a similar high rate of response to larotrectinib, commented David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York City, who reported early clinical data on the drug in 2017. The overall response rate was 76%, which is "quite unusual for a targeted therapy"; complete responses were seen in 12% of patients, all of whom had advanced cancers, which is "nearly unheard of," commented discussant Trever Bivona, MD, PhD, from the University of California, San Francisco.

These clinical data on larotrectinib have since been published in the New England Journal of Medicine. At the time, Hyman said that the latest data on this drug "suggest larotrectinib is likely to be the most effective treatment option for any patient with an advanced solid tumor harboring a TRK fusion."

For some of the patients who are candidates for receiving this drug, all other treatment options have been exhausted. Other patients face surgery that would result in major morbidity.

For example, for two pediatric patients with locally advanced infantile fibrosarcoma who were treated with larotrectinib, the tumor shrunk enough to allow curative, limb-sparing surgery. Negative margins were confirmed, and at 4.8 months' and 6.0 months' follow-up after treatment, the patients remained progression free.

This is truly a magic bullet for our patients with TRK-positive cancer. Dr Leo Mascarenhas

"This is truly a magic bullet for our patients with TRK-positive cancer," said coauthor Leo Mascarenhas, MD, deputy director of the Children's Center for Cancer and Blood Diseases in Los Angeles, California, in a statement. Currently, surgical management of advanced infantile fibrosarcoma can be highly disfiguring or require amputation, he pointed out.

"After treating our patient with infantile fibrosarcoma with larotrectinib, the cancer shrunk sufficiently, and we were able to surgically remove the tumor while preserving the patient's leg," said Mascarenhas, who helped design the trial's pediatric protocol.

"This is a big deal in the pediatric and adult oncology world," said Noah C. Federman, MD, director of the Pediatric Bone and Soft Tissue Sarcoma Program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA). "In over a decade of experience treating advanced solid tumors in children, adolescents, and young adults at UCLA, I have never witnessed the responses seen with larotrectinib.

"As trite as the word 'game-changer' is in oncology, this is one of the few times this descriptor is warranted," he told Medscape Medical News.

As trite as the word 'game-changer' is in oncology, this is one of the few times this descriptor is warranted Dr Noah Federman

When asked for his take-home message to pediatric and medical oncologists, Federman said: "Screen your patients for TRK fusions, particularly in advanced or metastatic solid tumors."

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