Larotrectinib Shows 93% Response Rate In Pediatric Cancer

Larotrectinib, a first-of-its-kind drug targeting a fused gene found in many types of cancer was effective in 93 percent of pediatric patients tested, researchers at UT Southwestern’s Simmons Cancer Center has announced.

Most cancer drugs are targeted to specific organs or locations in the body. Larotrectinib is the first cancer drug to receive FDA breakthrough therapy designation for patients with a specific fusion of two genes in the cancer cell, no matter what cancer type.

“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. What’s unique about the drug is it is very selective; it only blocks TRK receptors,”

said lead author Dr. Ted Laetsch, Assistant Professor of Pediatrics and with the Harold C. Simmons Comprehensive Cancer Center.

Larotrectinib vs. TRK Fusions

Larotrectinib targets TRK fusions, which can occur in many types of cancer.

While the TRK fusions occur in only a small percentage of common adult cancers, they occur frequently in some rare pediatric cancers, such as infantile fibrosarcoma, cellular congenital mesoblastic nephroma, and papillary thyroid cancer, said Dr. Laetsch, who leads the Experimental Therapeutics Program (ETP) in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Health in Dallas.

“Every patient with a TRK fusion-positive solid tumor treated on this study had their tumor shrink. The nearly universal response rate seen with larotrectinib is unprecedented,”

Dr. Laetsch said.

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. Larotrectinib was awarded orphan drug status in 2015 for soft tissue sarcoma and breakthrough therapy designation in 2016 for the treatment of metastatic solid tumors with NTRK fusion.

Tropomyosin Receptor Kinase

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. 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.

Larotrectinib belongs to a class of molecules known as kinase inhibitors, which work by cutting back on the enzymatic 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, and none of the patients with TRK fusions had to quit the study because of a drug-induced 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.

Laetsch, Theodore W et al.
Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study
The Lancet Oncology DOI: https://doi.org/10.1016/S1470-2045(18)30119-0

Image: Anne Weston, LRI, CRUK, Wellcome Images