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Precision Cancer Drug Shown Effective in Adults, Children

Chemotherapy vials

(National Cancer Institute)

22 February 2018. Results from 3 clinical trials show most cancer patients given an experimental drug that directly addresses a specific genetic mutation respond to the treatments, despite their cancers occurring in a variety of organs. Results of the studies appear in today’s issue of New England Journal of Medicine (paid subscription required).

The early- and intermediate-stage clinical trials are testing larotrectinib, a treatment candidate for solid tumor cancers made by Loxo Oncology Inc., a biopharmaceutical company in Stamford, Connecticut, also the studies’ sponsor. Larotrectinib is designed to block the effects of mutations in the tropomyosin-receptor kinase fused, or TRK, gene associated with solid tumors found in a number of organs. Proteins from these acquired mutations are believed to encourage tumor onset, growth, and development. The drug is taken twice a day as capsules or liquid.

The clinical trials are testing larotrectinib in groups of adults, children, and adolescents and adults with a variety of conventional solid tumor cancer types, but also with evidence of TRK fusion gene mutations, as determined by genetic profiling. While all 3 studies are watching for indicators of safety, dosage levels, or chemical effects of the drugs, researchers are also tracking tumor responses by patients. In the trial of adolescents and adults, tumor response is the study’s main success indicator, enrolling 155 participants.

The paper offers early findings from the trials, reporting on 55 participants, ranging in age from 4 months to 76 years, diagnosed with 17 different cancer types, but all expressing TRK fusion gene mutations. Investigations by independent researchers found three-quarters of the participants (75%) responding to larotrectinib treatments. After 1 year, 7 in 10 participants (71%) were still responding to treatments, with more than half (55%) remaining progression free. Because these rates exceed 50 percent, the authors could not compute a median duration of response and progression-free survival.

After more than 9 months, the vast majority of responding participants (38 of 44, or 86%) were continuing treatments or underwent surgery for their cancer. No participants discontinued their larotrectinib because of the treatments. Adverse effects were rated mild or moderate with serious or severe effects found in no more than 5 percent of participants, according to the authors.

Children’s Hospital Los Angeles is one of the clinical trial sites, where a patient with infantile fibrosarcoma, a cancer of connective tissue to bones took part. Infantile fibrosarcoma harbors a TRK fusion mutation, but is difficult to treat, says Leo Mascarenhas, the lead researcher for the hospital in the project, because it responds poorly to chemotherapy, and radiation can be harmful to patients long-term. “After treating our patient with infantile fibrosarcoma with larotrectinib,” says Mascarenhas in a hospital statement, “the cancer shrunk sufficiently and we were able to surgically remove the tumor while preserving the patient’s leg.” He adds, “This is truly a magic bullet for our patients with TRK-positive cancer.”

FDA granted orphan drug status to larotrectinib, and also designated it a breakthrough therapy for solid tumor cancers in adults and children expressing TRK fusion proteins that cannot be surgically removed or have become metastatic. Loxo Oncology expects FDA to complete its review early this year, and plans to submit larotrectinib for review in Europe in 2018 as well.

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