Cancer drug targeting ‘gene fusions’ has 93% response rate in children

In In The News by Barbara Jacoby

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A drug targeting a gene fusion that occurs across many types of cancer was effective in 93 percent of pediatric patients, researchers at UT Southwestern’s Simmons Cancer Center announced. The drug is the first cancer drug to receive FDA-breakthrough therapy designation for patients with a specific gene fusion, no matter the site of origin of the cancer. The research appears in Lancet Oncology.

The drug, larotrectinib, targets TRK fusions, which can occur in many types of cancer, said Dr. Ted Laetsch of UT Southwestern’s Department of Pediatrics and theHarold C. Simmons Comprehensive Cancer Center. While the TRK fusions occur in only a small percentage of many adult cancer, they occur frequently in certain rare pediatric cancers, such as infantile fibrosarcoma, cellular congenital mesoblastic nephroma, and papillary thyroid cancer, said Dr. Laetsch, lead author of the study.

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“In some cancers, a part of the TRK gene has become attached to another gene, which is called a fusion. When this occurs, it leads to the TRK gene being turned on when it’s not supposed to be and that causes the cells to grow uncontrollably,” said Dr. Laetsch, an Assistant Professor of Pediatrics at UT Southwestern Medical Center, which is recognizing its 75th year. “What’s unique about the drug is it is very selective; it only blocks TRK receptors.”

Larotrectinib was highly effective in “Every patient with a TRK fusion-positive solid tumor treated on this study had their tumor shrink, with all but one patient meeting the criteria for an objective response. The nearly universal response rate seen with larotrectinib is unprecendented,” Dr. Laetsch said.

Briana Ayala of El Paso, a tall, square-shouldered 13-year-old who aspires to a career in fashion design, was one such patient. In 2016, Briana was found to have a rare tumor called a retroperitoneal sarcoma. The large tumor in Briana’s abdomen was wrapped around her aorta, and surgeons in her hometown told her family it would be too dangerous to operate. The family brought Briana to Children’s Health in Dallas, where UT Southwestern Professor of Surgery Dr. Stephen Megison, in a dramatic surgery, removed part of the aorta in the process of removing most of the tumor.

After the surgery, however, Briana continued to have pain and swelling in her abdomen and her tumor started to grow again. There was no further treatment available, and Briana went home on palliative care. But while she had been in Dallas, Dr. Laetsch had sent her tumor for genetic testing. The news was good: Briana’s tumor had a TRK fusion, meaning the new drug might help.

Briana enrolled in the phase 1 clinical trial of larotrectinib and began taking the drug twice a day. Within weeks her pain and the swelling in her abdomen were diminished. A month after she started the drug, scans showed no signs of the tumor.

Two years later, Briana is back in school; back to playing with her dog, Goofy, and the family’s seven parakeets; back to her sketch pad and her dreams of a New York City fashion career.

“These are the kind of amazing responses we’ve seen with larotrectinib,” said Dr. Laetsch, “and this is why I’m so excited about it.”

In addition to the strikingly high response rate, Dr. Laetsch said the study is also noteworthy for the simultaneous testing of the drug in both children and adults. The results of the larotrectinib trial in adult patients – a 75 percent response rate – were published last month in the New England Journal of Medicine.

The multicenter pediatric study enrolled patients up to 21 years who had advanced central nervous system tumors. Larotrectinib is available as a liquid, which made it easy for the young children in the study to take, and it was well-tolerated by the pediatric patients, said Dr. Laetsch, who also leads the Experimental Therapeutics Program in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Health.

TRK, short for tropomyosin receptor kinase, is a gene that plays a key role in brain and nervous system development and has a limited role in nervous system functions such as regulating pain in later life.

The TRK-fusion mutation can be present in many types of cancers, including lung, colon, thyroid, and breast cancer, as well as certain pediatric tumors.

Larotrectinib belongs to a class of molecules known as kinase inhibitors, which work by cutting back on the activity of a key cellular reaction. The selectivity of the drug means it does not cause the severe side effects associated with many traditional cancer treatments. None of the patients with TRK fusions had to quit the study because of a side effect.

Equally important, the response was long-lasting for most patients. “For some of the targeted drugs in the past, many patients responded initially, but then resistance developed quickly. To date, the response to this drug seems to be durable in most patients,” said Dr. Laetsch, who investigates the use of tumor molecular profiling to guide therapy in UT Southwestern’s Pediatric Hematology and Oncology Division.

A next step in the research is a clinical trial involving a similar drug for those patients who developed resistance. Dr. Laetsch will be the national leader for that clinical trial in children.

Briana returns to Dallas for a follow-up exam once a month, but so far there are no signs of resistance developing. “I have reasonable hope that she is cured,” Dr. Laetsch said.

“I want everyone involved to know how much I appreciate the new treatment,” said Briana. “I feel better each day.”

The larotrectinib research was supported by Loxo Oncology Inc., the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the National Center for Advancing Translational Sciences, and Alex’s Lemonade Stand Foundation. Dr. Laetsch is a paid consultant for Loxo Oncology Inc.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 49 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center is among just 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. 

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.