When the FDA last week approved Merck’s cancer drug pembrolizuamb (Keytruda) for tumors with a specific genetic signature, regardless of what body part they originated in, it was a watershed moment for oncology and a victory for the concept of precision medicine.
But Merck isn’t alone; others are following suit with similar plans, and their progress is worth watching. One of the closest to the finish line is a four-year-old company named Loxo Oncology. Cancer experts believe that the data the company is presenting this morning at the American Society of Clinical Oncology not only demonstrate the potential of one promising new drug, but also represent another step forward for targeted cancer drugs as a class, which could in turn spur broader adoption of cancer genetic tests.
“We’re at a time where we’re realizing the potential of personalized medicine,” says Sumanta Pal, a medical oncologist at City of Hope in Duarte, CA, who isn’t associated with Merck or Loxo. “I truly feel that the data that’s emerged [from Merck and Loxo] are really going to drive increased utilization of genomic testing, and in many cases, I think that’s entirely appropriate.”
Loxo (NASDAQ: LOXO), of Stamford, CT, and South San Francisco, CA, reports this morning that 78 percent of the 55 total patients in three separate clinical trials of its drug, larotrectinib, have responded to treatment, meaning their tumors at least partially shrunk.
What makes those numbers particularly significant is Loxo enrolled patients with 17 different types of cancer—among them kidney, bladder, stomach, and lung—and found consistent results, according to CEO Josh Bilenker. These studies, called “basket” trials, took on patients with different cancers that share one important commonality: a genetic alteration known as a TRK fusion that Loxo’s drug is designed to target. The abnormality is present in 0.5 percent to 1 percent of solid tumors, he says.
“Simply put, larotrectinib is highly effective in patients with TRK fusions regardless of cancer type, and that’s a statement that really until recently we haven’t been able to make about any cancer therapy,” says David Hyman, a medical oncologist at Memorial Sloan Kettering Cancer Center and the principal investigator in the trials.
The most common side effects seen were dizziness, nausea, and fatigue. Though seven patients had their dose lowered because of side effects, none stopped treatment, which Hyman called “incredibly unusual” for a cancer drug trial.
The idea of targeted cancer therapies isn’t new. Drugs like imatinib (Gleevec), trastuzumab (Herceptin), vemurafenib (Zelboraf), and crizotinib (Xalkori) were approved many years ago for patients who have a particular type of cancer—lung cancer for crizotinib, for instance—and test positive for a specific molecular marker, like a genetic mutation or overexpression of a particular protein.
These drugs have made it common practice for, say, melanoma patients to get tested for a BRAF mutation (the target of vemurafenib), or breast cancer patients to be tested for expression of the HER2 protein (trastuzumab), and were thus important steps forward for targeted cancer medicines. Now better, cheaper sequencing technologies, more insight into tumor genetics, and creative clinical trial designs are leading to more efforts to try to see if these and other molecular signatures can impact many cancers, not just a few.
In 2015, for example, researchers conducted a basket study of the melanoma drug vemurafenib in a variety of cancers. Earlier this year, Hyman was an investigator in a basket trial testing the experimental Puma Biotechnology (NASDAQ: PUMA) drug neratinib, which is currently under an FDA review for HER2-positive breast cancer patients. Both studies produced mixed results, but there are others ongoing, like the 30-arm NCI-Match trial that began in 2015 that includes patients with lymphomas, solid tumors, and myelomas. And like Loxo, San Diego, CA-based Ignyta (NASDAQ: RXDX) is aiming for a tissue-agnostic approval of a drug, entrectinib, though its drug targets both TRK fusions and other mutations.
“If the biology supports a tumor-agnostic approach,” says Hyman, “then I think you’re going to be seeing more and more companies and investigators that are willing to take that risk and actually engage in this newer paradigm of drug development.”
Based on the data it already has in hand, Loxo aims to file for FDA approval of larotrectinib either later this year or in early 2018. It’s gearing up for a commercial launch next year. If that were to happen, larotrectinib would join only Merck’s (NYSE: MRK) pembrolizumab as a drug specifically approved for a cancerous mutation, regardless of where a tumor has originated.
There are still key questions for Loxo’s drug to answer. For one, Loxo has yet to report how durable responses to the drug are, though Bilenker says that’s a positive sign—too few people have failed treatment to generate that data, he says, and some responders have been on larotrectinib for over two years. Six patients’ cancers have developed resistance to the drug and progressed, though. Once more granular information is available about relapse rates and durability for specific cancers, it will help doctors see how they should use Loxo’s drug. Pal, for instance, says while there will be a “temptation across disease types” to test for TRK fusions, it’s unclear how Loxo’s drug compares to the myriad other treatments for, say, lung or kidney cancer. “What we really need to know,” he says, is “can patients potentially fare the same or better with standard therapy?”
But the broader question is will patients get the chance to see if they are eligible for Loxo’s drug? That will at least partly depend on adoption of broad cancer genetic tests, like the FoundationOne test sold by Foundation Medicine (NASDAQ: FMI), which can test for hundreds of genetic abnormalities in tumors, among them TRK fusions. These tests have struggled to gain traction for a variety of reasons, from payer pushback to resistance from community oncologists and questions about their utility, and are most commonly used in clinical studies and major cancer centers. “They are considered investigational or exploratory tests, and those are very difficult to get reimbursement for,” says Yuri Nikiforov, the director of the University of Pittsburgh Medical Center’s molecular and genomic pathology division.
Foundation has spent years fighting for insurance coverage, and has applied for FDA approval of the FoundationOne, a decision that is expected this year. A second test from Thermo Fisher Scientific (NYSE: TMO), Oncomine, is also under FDA review, with a decision pending. Approvals for both tests may help, but Bilenker says Loxo is hedging the market anyway. It cut a deal with Roche in March to develop a companion diagnostic specifically for TRK fusions. That test uses old school immunohistochemistry stains, a cheaper and more widely used diagnostic method. “In the intermediate and long-run, we think [broad tumor sequencing] is the modality of the future,” Bilenker says, but “we’re taking a bifurcated approach.”
Loxo’s decision shows the hurdles that these testmakers still face. Pal, for instance, says City of Hope has been using molecular profiling tests in kidney and bladder cancer patients, where they typically aren’t used. Pal used to reserve these tests for patients who had failed a number of treatments, but is being “gradually more motivated” to try them earlier. He’s convinced they can help lead patients to drugs they might not otherwise get, and ultimately better health outcomes—something testmakers like Foundation are fighting to prove. But payers push back. “I have gone to great lengths to justify the utilization of these tests on a case by case basis,” he says.
Nikiforov says UPMC has been finding TRK fusions in the tumors of thyroid cancer patients “every 2 to 3 weeks.” For these patients—often young people who develop brain metastases—insurers may cover the expensive cancer drugs to treat them, but not the sequencing tests. Could Loxo’s data, and Merck’s approval, start to change things?
More validated molecular markers, and approved drugs based on genetic alterations—like a TRK fusion—might mean that oncologists have more reason to test for a wide swath of tumor abnormalities with a single exam. Without these options, broad tumor profiling tests can spit out a lot of data that, in the end, amount to an expensive exam that doesn’t accumulate useful signals, just noise.
“I certainly hope that these are the data that we’ve been waiting for to justify essentially universal adoption of this as a standard-of-care for all patients with advanced cancer,” Hyman says.