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Loxo highlights benefits, challenges of promising 'tumor-agnostic' cancer drug

Loxo Oncology Inc. impressed the cancer community with research showing a 76% response rate to its experimental medicine larotrectinib, sending its stock price up more than 40%. The company's next challenge is to improve testing to make it easier to find patients whose tumors have the rare genetic mutation targeted by the treatment.

Data from 50 patients showed that the medicine was effective against 17 different cancers, according to a presentation at the meeting of the American Society of Clinical Oncology, or ASCO, in Chicago. That sets up the drug for a "tumor-agnostic," accelerated U.S. Food and Drug Administration approval following a filing in late 2017 or early 2018. A filing for European approval is expected in 2018.

FDA backing would mark the agency's second blessing of a biomarker-based indication rather than one for a specific cancer or initial tumor location, such as breast cancer. Merck & Co. Inc.'s Keytruda became the first, in May, when it gained an indication to treat solid tumors dubbed microsatellite instability-high.

All patients in Loxo's ongoing trials had tumors containing an abnormality in which a gene that encodes for proteins called tropomyosin receptor kinases, or TRKs, becomes fused to an unrelated gene. That leads to overproduction of the proteins, which is associated with various cancers, the company said on its website.

US market up to 5,000 patients

Larotrectinib inhibits the TRK receptors, and in doing so, appears to treat a variety of cancers among patients whose tumors exhibit the genetic abnormality.

Highlights of the trial include the 12% complete response rate — meaning that the cancer has disappeared — and the speed and long duration of those responses, as well as effectiveness among pediatric patients, study investigator David Hyman of Memorial Sloan-Kettering Cancer Center in New York said during a press conference at ASCO. None of the patients discontinued therapy due to side effects.

"More than 3 out of every 4 patients responded to therapy. You'd be hard-pressed to find a targeted therapy, even within a single-disease context, that has results like this," Hyman said.

If the candidate receives approval, physicians will determine whether to use larotrectinib as an initial therapy or reserve it for cases in which other treatments fail, according to the physician.

Loxo estimates the addressable patient population to be 1,500 to 5,000 U.S. patients per year, although Hyman said the 5,000 patient upper bound "may truly underestimate the rate" due to the limitations of existing technologies.

"It is going to take probably an order of magnitude in terms of years for us to really understand exactly what the frequency is," Loxo Chief Business Officer Jacob Van Naarden said during a June 4 investor presentation explaining the results.

Patient identification a central challenge

Appropriate diagnosis of TRK fusion-positive cancers will be central to Loxo's commercialization strategy. The company did not screen patients during the trial but rather relied on "real world" referrals that originated from 15 different diagnostic tests and technologies.

Diagnosis of the genetic abnormalities via tumor samples is imperfect and could use improvement, study investigators and company officials said during the investor presentation.

"We'll have to change the paradigm by which we test these patients," Hyman said.

Diagnosing tumors as TRK fusion-positive calls for increased use of comprehensive tests that simultaneously check for multiple genetic mutations, Hyman said, adding: "There are a growing number of cancer types where some genetic information is already needed to guide standard-of-care prescribing. In those tumor types, my personal opinion is that we should abandon testing that looks at one or two genes at a time and use broader testing. Even the cost differences between sequential single-gene and comprehensive testing are minimal."

Company officials told investors that technology to identify the tumor mutations is already fairly widespread, and Loxo recently created a website that lists providers, such as Foundation Medicine Inc.

But Hyman said "there are some labs that are better at testing for this than others."

"There may be some technically complex aspects of diagnosing these fusions," he said. "I think that the response rates you see here represent what we would expect if larotrectinib were approved and used in the real world, based on tests that are not specifically assessed for their technical validity for TRK-fusion detection."

Loxo is collaborating with Roche Holding Ltd.'s diagnostics unit Ventana Medical Systems Inc. to develop an immunohistochemistry test for the fusions, and said it will likely soon announce collaborations to develop improved sequencing-based tests for the biomarker as well.

Improving test reimbursement and increasing physician and pathologist awareness of the rare genetic abnormality are other challenges, Hyman said. Merck's related approval "makes people more aware of this tumor-agnostic opportunity for patients," he said, noting that microsatelite instability and TRK fusions are responsible for upward of 5% of all cancers.

2nd-generation 'rescue' candidate under development

Loxo said it has successfully treated two patients who relapsed on larotrectinib using a modified candidate that targets a mutation found among five of the six patients who developed resistance to the initial therapy.

The company will provide additional clinical information on the supplemental candidate by year-end if a sufficient number of appropriate patients are identified.

Additional details about the candidate, which is being developed solely for patients who relapse, as well as the two patients treated, were published June 3 in the journal Cancer Discovery.