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Loxo Unveils More Data, Paves a Path Forward In Precision Oncology

Xconomy National — 

An experimental cancer drug from Loxo Oncology has shown early signs that it might impact multiple tumor types, regardless of where in the body they originated. The clinical results come with caveats, but they add to a slowly growing body of evidence supporting so-called tumor “agnostic” drugs, which are markers for the progress of precision cancer medicines. Loxo could later this year become only the second company to have such a drug on the market.

At the American Society of Clinical Oncology meeting this morning, Loxo (NASDAQ: LOXO) reports that in a Phase 1 study, 30 of 39 evaluable patients (77 percent) with a specific genetic fingerprint for their cancers have responded—meaning, at minimum, their tumors shrank—to treatment with its experimental therapy LOXO-292.

To be clear, these results are early, from a study designed to find the best dose to use in further tests. And they come from a very small number of patients. It’s also unclear how long these responses will last; the longest response, which came from the first patient dosed, has lasted 10 months so far.

But the data are nonetheless noteworthy because the patients in the study had different tumor types—lung, pancreas, or thyroid—that all had alterations to a gene called RET. The data show that 23 of 30 patients with non-small cell lung cancer responded, as did 7 of 7 with thyroid cancer. The tumors in the two patients with pancreatic cancer didn’t shrink enough to be counted, but Loxo chief business officer Jacob Van Naarden says both are “clinically responding,” meaning the tumors are somewhat smaller.

Among a separate group of patients with a particularly rare form of thyroid cancer known to be driven by a RET mutation, medullary thyroid cancer, 10 of 22 patients, or 45 percent, responded. (Loxo reported these data separately because there are approved treatments for RET mutation-driven medullary thyroid cancer, whereas there are no drugs specifically approved for RET fusion cancers overall.)

Most side effects from LOXO-292 were mild, including fatigue, diarrhea, constipation, and nausea. There was one case of tumor lysis syndrome, a dangerous condition in which tumor cells break down and die so fast the kidneys can’t remove the cells’ contents from the blood. It’s a sign a drug might be working, but it can be fatal. “If we start to see it more we’ll have to think about more proactive ways of managing it,” Van Naarden says.

Altogether, however, what Loxo has seen was “more or less what we expected,” and the company plans to enroll more patients in the Phase 1 study and start talking to regulators about a path to approval, Van Naarden says. That may seem outlandish given the sample sizes, but Loxo has been down this road before. It filed for approval of another tissue-agnostic drug, larotrectinib, for tumors with TRK fusions, based on data from 55 patients. An FDA decision is expected on larotrectinib by Nov. 26—some four years after clinical testing began.

The company is trying the same plan with LOXO-292. RET fusions—in which the RET gene abnormally fuses to another gene, causing a tumor to grow—occur in about 10 to 20 percent of papillary thyroid cancers, and most importantly from Loxo’s perspective, 2 percent of non-small cell lung cancer cases (lung cancer is the most common form of cancer-related death in the U.S.) A mutation in the RET gene occurs in 60 percent of patients with medullary thyroid cancers. Loxo is one of two companies with RET-targeting drugs in clinical testing, along with Blueprint Medicines (NASDAQ: BPMC). Both are aiming for speedy approvals. And larotrectinib could help set the bar for both.

Last year the FDA approved Merck’s (NYSE: MRK) immunotherapy pembrolizumab (Keytruda) for tumors with two specific types of genetic defects—the first decision of its kind. But pembrolizumab had already been approved for several cancers. As Keith Flaherty, director of clinical research at Massachusetts General Hospital Cancer Center, told Xconomy earlier this week, pembrolizumab already had an established safety profile, and half the patients in the data that triggered the approval had colon cancer, so it’s “not exactly tissue-agnostic.” Loxo is up next, and by comparison, it tested larotrectinib in 17 different types of cancers. (Flaherty is a founding director of Loxo and chairs its scientific advisory board.)

In that sense, then, Loxo will have important ground to break with the FDA, and payers. Will the FDA, for instance, approve larotrectinib for all patients with TRK fusions? Or just subsets of patients with the strongest data? Loxo CEO Josh Bilenker says this was a “bigger concern in our minds two years ago,” but that concern has eased after all the conversations the company has had with the agency on these types of issues and draft guidance the FDA published recently. “The FDA has been very forward looking,” he says, and won’t “require statistical rigor on every small subset in question.”

Payers will have similar issues to work through. As Xconomy reported Thursday, pharmacy benefit manager Express Scripts (NYSE: ESRX) is working to change its cancer-drug pricing, from using just a single price regardless of the  cancer type to a price set according to a drug’s tissue-specific effectiveness. How will Express Scripts and others handle larotrectinib? “We’re starting to engage in those conversations,” Van Naarden says, but declined to comment further.

Another point critical not just to Loxo’s success, but others that come after it: Will the broad tumor-profiling tests that can detect rare genetic abnormalities like TRK and RET fusions be widely covered by insurers? Payer pushback and other issues have blunted the adoption of such tests, but they’re gained traction over the past year. In March, for instance, the Centers for Medicare & Medicaid Services, which administers the federal Medicare insurance program, began covering such tests that are approved by the FDA. “A key next step is to see how the private payers react and revise their policies over time,” Van Naarden says.

He’s also watching to see if the agency starts approving tumor-profiling “kits,” which pathology labs can buy from companies like Illumina (NASDAQ: ILMN) or Thermo Fisher Scientific (NYSE: TMO). If so, these tests could be run in-house by more institutions, rather than be sent out to specialized test-makers like Foundation Medicine (NASDAQ: FMI). These kits could be more convenient and test results could come back faster, says Van Naarden. “I think that’s where we see things headed,” he adds. “It’s not yet a 2018 phenomenon, but I think those timelines are inching in, not out.”