Getting Advanced Stage Cancer Patients on TRK with Targeted Therapy

Up to 80 percent of patients with stage 4 metastatic cancers carrying tropomyosin receptor kinase (TRK) fusions who have exhausted most standard treatment options respond to larotrectinib, a new receptor inhibitor in development, according to multicenter, nationwide studies.

“It’s almost miraculous,” says study author Davendra Sohal, MD, MPH, staff in the Department of Hematology and Medical Oncology at Cleveland Clinic, one of the sites for the phase 1/2 clinical trials published in The New England Journal of Medicine.

“Generally fewer than 10 percent of these patients respond to additional attempts at chemotherapy or other standard treatments,” he says. However, results reveal that larotrectinib demonstrated efficacy regardless of patient age or type of solid tumor.

What the 55 patients in the studies had in common were TRK fusion genetic alterations. Unlike a traditional genetic mutation where an oncogene switches into overdrive, in this case one gene in a tumor combines with another, causing uncontrolled activity of TRK gene. “That leads to uncontrolled growth of the tumor, one that is very resistant to standard therapies,” Dr. Sohal says.

Larotrectinib is able to target this genetic alteration in a majority of patients. Although TRK fusions only arise in about 1 in 100 tumors, they are “surprisingly responsive to therapy if one can find the fusion and find the drug [to target it],” he adds. In this case, Loxo Oncology is developing the oral inhibitor larotrectinib (LOXO-101), which “essentially stops that fusion. It shuts it down.”

Patients in the clinical trials ranged from 4 months to 76 years old. They presented with 17 different types of TRK fusion-positive cancers. Independent reviewers and investigators agreed on overall clinical response, 75 and 80 percent, respectively.

The research also revealed a durable response, with 71 percent of initial responses continuing at one year. Fifty-five percent of the participants remained progression-free from cancer.

After a median follow-up of more than nine months, 86 percent of the responders (38 of 44 participants) continued treatment or underwent surgery intended to be curative.

Most adverse events were grade 1 in severity. Grade 3 or 4 treatment-related adverse events were reported in less than 5 percent of participants, and no patients discontinued treatment because of these adverse events.

Genomics-driven expertise

The current study is one of many made possible by a strong clinical genomics program at Cleveland Clinic. Many tumors undergo testing for genomic alterations, which get reviewed by the Genomics Tumor Board, a regular meeting with various oncologists, translational scientists, pathologists and genetic counselors.

Experts then alert each patient’s physician to recommended, individualized treatment options, as well as to clinical trials for which the patient might be an appropriate candidate. “It seems to work very well,” Dr. Sohal says. “We offer tumor genomic profiling to every patient who is eligible.”

Many cancer patients need to consider the financial implications of cutting-edge therapies as well, Dr. Sohal says. “We have clinical studies and can treat patients while deferring their out-of-pocket costs. Even when patients have to pay for genomic testing, we have a very strong financial assistance program to minimize their out-of-pocket cost.”

The clinical trials allow patients unique access to promising agents in development. “And sometimes we hit the jackpot, like in this case.”

Photo Credit: Russell Lee