Prepping for FDA filing, Loxo rolls up data on its site-agnostic cancer med larotrectinib

At the ASCO meeting in Chicago on Saturday, Loxo Oncology rolled out response-rate data on the site-agnostic cancer med it hopes to get to the FDA by early 2018.

CHICAGO—When Merck & Co.’s Keytruda won approval last week to treat tumors based on a common biomarker rather than the location in the body where the tumor originated, talk was that the true start of precision medicine had arrived.

The $1.3 billion market cap biotech Loxo Oncology is hoping to be a part of that journey. At the American Society of Clinical Oncology meeting Saturday, Loxo posted the latest data for its experimental larotrectinib (LOXO-101), a medication it hopes will treat an array of cancers in nearly a dozen sites across the body.

The data showed that 50 larotrectinib patients with tumors harboring tropomyosin receptor kinase (TRK) fusions had a 76% objective response rate (ORR) across tumor types. The drug met its primary endpoint; key secondary endpoints, including progression-free survival and duration of response, had not yet been reached.

The data drew from three trials, a phase 1 study in adults, a phase 2 study called Navigate, and a phase 1/2 pediatric trial called Scout. The results were based on the intention-to-treat principle, using the first 55 TRK fusion patients enrolled to the three trials, regardless of their prior therapy or tumor-tissue diagnostic method.

In all, 44 adults and 12 younger patients were enrolled, with tumors identified by 14 different lab tests. The TRK fusion patients carried a host of primary diagnoses, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor, infantile fibrosarcoma, lung cancer and more.

The confirmed overall response rate was 76% in 50 patients, with these rates “generally consistent across tumor types, TRK gene fusions, and various diagnostic tests,” Loxo said in a statement.

In the pediatric setting, larotrectinib also showed “promising activity” in the presurgical management of patients with infantile fibrosarcoma, with three patients treated to best response.

The drug, developed in partnership with Array Biopharma, has a breakthrough designation from the FDA to treat children and adults with metastatic or inoperable solid tumors that test positive for the TRK biomarker, and who've either failed on previous treatments or have no acceptable alternatives.

In the safety department, Loxo says that seven (13%) of the study patients had their doses reduced because of side effects, but no patients stopped taking larotrectinib after suffering side effects.

All patients whose doses were lowered experienced tumor regression, which then continued on the reduced dose. “Nearly all of the dose reductions were due to infrequent neurocognitive adverse events, likely a result of on-target TRK inhibition in the [central nervous system],” Loxo explained.

Loxo added that six patients responded to larotrectinib but later progressed, a pattern referred to as “acquired resistance.”

The company is gathering other evidence for larotrectinib's application for FDA approval, slated for late this year or early next. A central, independent radiology review will be performed in the second half of 2017, and Loxo plans to announce that data before the end of the year. A separate assessment by independent radiologists, not yet conducted, will also be required to support its regulatory filing, the company notes.

TRK is a neuron-stimulating factor that is active in fetal development but has its expression switched off later in life. In some cases, the TRK gene can fuse with other genes and reactivate, causing various forms of cancer.

Loxo's development program for the drug is agnostic to any particular tumor type, focusing instead on recruiting patients whose cancer cells express the TRK gene. If approved, the drug could be prescribed across multiple solid tumor types on the strength of genetic testing for neurotrophic TRK (NTRK) fusion proteins, which it will do with the help of Roche.

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NTRK mutations crop up in a small percentage of patients with any particular cancer, but they add up. The company estimated last year that between 1,500 and 5,000 late-stage cancer patients could be eligible for treatment in the U.S. each year, with a similar number in Europe.

“[T]he larotrectinib TRK fusion story fulfills the promise of precision medicine, where tumor genetics rather than tumor site of origin define the treatment approach," said David Hyman, lead investigator in the Navigate trial and chief of the early drug development service at Memorial Sloan Kettering Cancer Center.  "It is now incumbent upon the clinical oncology and pathology communities to examine our testing paradigms, so that TRK fusions and other actionable biomarkers become part of the standard patient workup."

The company also has two follow-up candidates—LOXO-292 and LOXO-195—which target other cancer-causing genes resulting from fusions with kinase genes. 

The company's shares jumped Monday on the weekend update, up 50% midday.