TRK inhibitor shows ‘striking’ activity, durability across diverse adult and pediatric cancers

June 5, 2017|Oncology Practice

AT ASCO 2017

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

“One of the defining features of TRK fusions is the fact that they are not just found in one cancer type, but they are found in dozens of different cancer types, and not just in adults, but in both children and adults, spanning the entire lifetime of the person,” he noted. They are rare in common cancers and nearly universal in certain uncommon cancers; collectively, they are present in possibly 5,000 cancers diagnosed each year in the United States.

Dr. Hyman and his colleagues analyzed data from 55 patients having 17 discrete types of advanced cancer harboring TRK fusions who were treated with larotrectinib in phase I and II trials. Results showed an overall response rate of 76%, and the large majority of responses were still ongoing at 12 months.

“I believe these data support larotrectinib as a potential new standard of care for these patients,” he said. “However, I want to emphasize that really recognizing this benefit in the community will require that we test patients more universally for the presence of TRK fusions or other tumor-agnostic biomarkers, such as microsatellite instability.”

On the basis of these promising data, the drug’s manufacturer, Loxo Oncology, plans to submit a New Drug Application to the Food and Drug Administration later this year or early next year. Larotrectinib has already been granted both orphan drug designation (for drugs used to treat rare conditions) and breakthrough therapy designation (for drugs used to treat serious conditions showing greater efficacy than available therapies).

A randomized trial pitting larotrectinib against other therapies is unlikely given the low prevalence of TRK fusions, the lack of treatment options for the fairly heavily pretreated trial patients, and the drug’s impressive performance, according to Dr. Hyman.

“The efficacy is so striking that it really exceeds almost any existing standard of care for solid tumors,” he elaborated. “There is hardly any chemotherapy or targeted therapy that has a response rate or durability that looks like larotrectinib in these patients.”

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

“The real challenge moving ahead is for oncologists to determine whether larotrectinib would sit within existing treatment algorithms,” he maintained. “For rare cancers for which there is no established standard of care, such as salivary gland tumors, for instance, there may be a call to screen for relevant mutations right away. In the case of other diseases, such as colon cancer and prostate cancer, we’ll really have to sit down and determine how larotrectinib sits against existing standards such as chemotherapy or hormone therapy, respectively. These elements will all play into determining at what juncture molecular testing is offered to determine candidacy for larotrectinib.”

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”