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One of the most remarkable papers from this year’s big cancer meeting drew attention to an experimental drug called larotrectinib. This novel medicine, a pill manufactured by Loxo Oncology, helped children and adults with 17 types of otherwise incurable cancers, including some notoriously hard-to-treat forms. The drug shrank tumors in 76% of patients who tried it in early-phase clinical trials sponsored by the company. Larotrectinib (Loxo 101) received breakthrough designation from FDA last summer; it may be approved next year.
The key to these positive results is molecular matching: Patients received larotrectinib, a TRK inhibitor, only if their cancers were marked by a switch, or fusion, involving a TRK gene. The paper supports the clinical benefit of all advanced cancer patients having access to genomic testing. If confirmed, this preliminary report represents an excellent example of precision medicine in oncology.
Dr. David Hyman of Memorial Sloan Kettering Cancer Center in New York presented the findings at the ASCO meeting in Chicago. Larotrectinib is well-tolerated; as reported so far, none of 55 patients in three clinical trials have discontinued the medication due to toxicity. Responses appear to be durable: 79% of those who responded continued to do well for at least one year. Of the first 50 patients enrolled in larotrectinib trials, 12 had salivary gland cancers, and 17 had sarcoma, including cases of infantile fibrosarcoma. A few have pancreatic or bile duct cancers.
“This is an extraordinary result,” said Dr. George Demetri. “The response rate is so high and relatively durable,” he observed. Demetri is a medical oncologist and professor at the Dana Farber Cancer Institute and Harvard Medical School in Boston who specializes in sarcomas and development of new cancer drugs. We spoke in Chicago.
“This trial shows how important it is to screen cancer patients for tumor-causing genetic mutations.” TRK abnormalities are rare. “Lots of doctors don’t realize there’s a possibility that their patients might have this genetic change,” he considered. “They don’t screen for TRK mutations, so 9 in 10 cancer patients who might benefit from this drug likely don’t have the opportunity to try it.”
Demetri described a woman, age 47, whose dramatic response to larotrectinib impressed him about the drug’s potential to help selected patients. Doctors initially thought she had a kind of intestinal cancer called GIST. But upon consultation and additional pathology testing, it turned out she had a poorly differentiated sarcoma. Genetic evaluation revealed a TRK fusion change. He offered treatment with larotrectinib in a basket-type clinical trial.
“She had a tumor the size of a cantaloupe in her pelvis, and smaller metastatic tumors elsewhere, including the liver,” he said. “She had an immediate response to the drug. Her tumor shrank within a month, and she felt better”
“This targeted drug is powerful because it blocks the molecule that triggers the cancer,” Demetri said. “ It’s a perfect example of how precision medicine can benefit patients with rare conditions. It’s hard to find cancers with TRK fusions, but when we do, the drug is very likely to help.”
“The nice thing about these drugs is they’re well-tolerated,” Demetri said. Larotrectinib isn’t the only N-TRK inhibitor, he mentioned. Ignyta, a San Diego company, has a new drug targeting NTRK in advanced-stage clinical testing. That drug also recently received breakthrough designation from the FDA. To date, it seems that blocking TRK doesn’t cause severe side effects, he said.
The most frequent observed side effects were fatigue and “mild” dizziness, Hyman said at the press meeting. Some neurological toxicity was expected, as the normal TRK plays a role in controlling balance. No patients needed to stop treatment due to side effects, he emphasized. A few, 11%, required dose reductions. According to the abstract, 28% of the trial participants experienced nausea.
In response to a question about if larotrectinib seems to work better in cancer forms, Hyman responded: “There is no trend of one tumor type responding better than another.”
TRK (pronounced “trak”) stands for the tropomyosin receptor kinase, and refers to any of several human receptors (TRK-A, -B or -C) for nerve growth factor, normally involved in fetal neurologic development. (The receptor and oncogene is sometimes called “NTRK.”) Scientists have known about rearrangements of TRK genes in human cancers since the 1980s. Before next-generation sequencing of many tumors became technically feasible, these were hard to find. TRK fusions are implicated in as many as 0.5 to 1% of human cancers.
I spoke with Josh Bilenker, CEO of Loxo Oncology. He’s a physician who worked in the FDA’s Office of Oncology Products for several years before entering industry. He received his medical degree from Johns Hopkins in Baltimore and trained in internal medicine and oncology at the University of Pennsylvania.
In July 2016, Loxo received breakthrough designation from the FDA for development of larotrectinib (Loxo-101). The company discussed the path toward approval for this targeted drug with agency officials last summer, Bilenker told me. “Based on those discussions, we collected data prospectively for 55 patients with TRK fusion changes in the tumors,” he said. “We think the data sufficient to support our filing for drug approval. We expect to submit the data to FDA by year end of 2017 or early 2018.” Larotrectinib might be approved by mid-2018, he said.
I asked Bilenker why the information presented at ASCO includes 55 patients in three separate trials, and if any other patients are receiving the drug but unreported. “This was the plan, discussed with the FDA last summer. We’ve included all patients, on an intent-to-treat basis, who enrolled on any of the three clinical trials before the cutoff date,” he said. “It was prospective. The 55 patients were the first 55 patients enrolled in any of our 3 clinical trials,” he continued. (Those would be this Phase 1 trial in adults; the SCOUT trial in pediatrics; and the NAVIGATE trial, ES). “Patient number 1 was the first ever treated with the TRK inhibitor,” he said. The only other patients who’ve received larotrectinib got it on a compassionate-use basis or after we reached our pre-set accrual target, he said.
“We didn’t cherry-pick patients for reporting,” Bilenker said. The reasons for compiling data were several. First, pediatric patients were enrolled in a separate study, he said. “Because we’re seeking approval for use in both adult and pediatric patients, at the very least we need two studies.” Second, this path to approval acknowledges that these are very rare cancers with TRK mutations. It’s a matter of “geographic practicality,” he said. “We’re a small company with trial sites throughout the world. We want to gather information on all patients taking this drug, wherever they are.”
I asked about the non-randomized nature of the compiled clinical information. “We have a nearly 80% response rate,” Bilenker said. He referred to updated data, for all 55 patients, in this Loxo press release. “Keytruda had a 30% response rate and got approved. When you’re in the 80% response range, it’s clear enough that the drug is effective to merit approval,” Bilenker said. “Even if the results get diluted, with such a high response rate, it’s clear.”
In what Bilenker described as an exceptional strategy, Loxo has already developed another drug, a second-generation TRK inhibitor, that might be used in patients who become resistant to larotrectinib. A few patients have developed resistance due to solvent-front-type mutations. At least two cancer patients with TRK fusions who developed resistance to larotrectinib have had excellent responses to the next drug, LOXO-195. The chemical aspects of LOXO-195, designed to overcome acquired solvent front-type mutations and the two patients’ early clinical responses to that drug, are detailed in a report published this week.
In the future, patients taking larotrectinib could be screened or serially monitored for resistance by liquid biopsy, Bilenker suggested. “It’s unusual for a company to have two drugs for the same kind of tumor in same pipeline, both in development,” he added. “We expect to be able to offer durable disease control, so that when patients progress through drug A, they can move on to drug B.”
Bilenker said larotrectinib is superior to other investigational TRK inhibitors because it specifically inhibits the NTRK molecules. “Our drug is more selective in its activity. That gives us a nice therapeutic window. We can go high on dose without so much toxicity,” he told me.
I asked Bilenker what additional data the company would provide before the FDA reviews this drug. “First, we will confirm the response rate by central radiology review. Second, we will continue to follow these patients,” he said. “We have enough data to know the data are not preliminary. N of 55 will be the basis of the submission."
I asked Bilenker about costs. “It would be premature to comment on pricing,” and added: “This study speaks to the need for high-quality genetic testing. Not every patient gets referred for comprehensive genetic workup. At Memorial it’s standard of care,” he said (referring to MSKCC). “But that’s not how it is in community hospitals. For more people to benefit from this drug, more cancer patients should be evaluated with better-quality tests.”
For many patients, costs and lack of reimbursement for molecular cancer testing are limiting, creating disparity in treatment options for cancer patients. If genomic evaluation is only available at major cancer centers, people with advanced malignancies treated in regular hospitals and off-protocol many not have the opportunity to consider targeted medicines, even if they’re FDA-approved, because their tumors won’t be checked.
“The key challenge is increasing the availability of screening.” It’s hard getting doctors and patients to consider this kind of evaluation early in the diagnostic process, Demetri added by email. NTRK fusions might be hiding in many different forms of cancers as diverse as sarcomas, salivary gland tumors and even rare forms of breast cancers, he noted.
Demetri holds consulting and advisory positions with over a dozen biotech and pharma companies. He currently serves on the scientific advisory board and board of directors of Blueprint Medicines (which had previously disclosed preclinical findings on TRK kinases as a target in cancer), but has no relationships with Loxo Oncology or any firm with a competing clinical product.
