Positive Larotrectinib Study Results Highlight Importance of Molecular Profiling of Tumors

Recent study results published in The New England Journal of Medicine (NEJM) showed that larotrectinib provided marked and durable antitumor activity in patients with tropomyosin receptor kinase (TRK) fusion—positive cancer, regardless of the age of the patient or the tumor type.

With the use of molecular profiling, the researchers identified patients with TRK fusion—positive cancers and enrolled them into 1 of 3 studies: a phase 1 adult study, a phase 1 and 2 pediatric study, or a phase 2 adolescent/adult study. Reported in NEJM were results from the first 55 consecutively enrolled patients, ranging from 4 months to 76 years and with 17 unique cancer diagnoses, including mammary analogue secretory carcinoma of the salivary gland, infantile fibrosarcoma, melanoma, and thyroid tumor.

The overall response rate was 75% according to independent review, and 80% according to investigator assessment. At year 1, 71% of responses were ongoing, and 55% of the patients remained progression-free. At median follow-up of 9.4 months, 85% of patients with a response were still receiving treatment or had undergone surgery intended to be curative.

There are a couple of factors that make these findings unique and important, said David Hyman, MD, chief of Early Drug Development, Memorial Sloan Kettering Cancer Center, co-corresponding author of the study, in an interview with The American Journal of Managed Care^®. Aside from this being the first time that this alteration has shown to be a validated target for patients, it’s the first time that a targeted therapy has been shown to be effective regardless of cancer type.

“To date, all targeted therapies have been developed against a specific mutation within a specific or set of specific cancers, and that’s generally because the context in which the mutation is found does matter, but it seems that, for this target, that’s not the case,” said Hyman. “Just simply the presence of the mutation, regardless of the cancer type in which it’s seen, results in a very high likelihood of benefit.”

Notably, there is benefit seen in both pediatric and adult patients, which could potentially lead to the first treatment developed and approved simultaneously for adult and pediatric patients.

In addition to implications for the treatment of genetic alterations across tumor types, these study results underscore the importance of molecular profiling of tumors, through which patients were identified for the studies, on ensuring that precision medicine is used in practice while simultaneously providing a cost-effective tool.

In oncology right now, there is an increasing number of genetic alterations, which are detectable through a single comprehensive test that in certain cases are disease-specific genetic alterations, and in other cases are so-called tissue or tumor agnostic genetic alterations, explained Hyman.

“You’re talking about individualizing therapy based on the genetic alterations that are present in that patient,” said Hyman. “I think it’s important to distinguish between a kind of theoretical promise of individualizing care for every patient and delivering this standard of care. To me, the results of this study take out the experimental. If you have a TRK fusion, you should receive larotrectinib.”

At the same time, there’s a cost argument to be made, said Hyman. The costs of comprehensive tests are being driven down dramatically, and there are many cases in which they are more cost-effective than all the different tests needed within certain tumor types, even to fulfill widely accepted standards of care.

Hyman gave the example of colorectal cancer, where there is a consensus guidance around expanded RAS testing. Now, doctors must look for microsatellite instability, which might require up to 4 immunohistochemical markers. Layering in all the costs of those individual tests, a universal testing strategy provides a more cost-effective approach.

“The real cost of cancer care is being driven by other factors,” said Hyman. “It’s not diagnostic molecular testing, but primarily the cost of pharmaceuticals or hospitalizations, and what we’re talking about here is: we’re identifying the right therapy for patients. A lot of times those therapies avoid other, more costly therapies, or it will identify therapies that won’t work for patients.”

According to Hyman, there needs to be a shift in the conversation from whether we should be obtaining these tests to how we manage the results of the test. While there is no question about what to do when the test finds an alteration associated with an FDA-approved therapy, there is a complexity in what to do if there is an alteration that has no approved therapy. “I think there are principled conversations to be had about how do you manage those situations,” said Hyman.

Reference

Drilon A, Laetsch T, Kummar S, et al. Efficacy of larotrectinib in TRK-fusion positive cancers in adults and children. [Published online February 20, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1714448. Accessed February 23, 2018.