[Updated 11/26/18. See below.] Going deeper into the new world of genetic medicine, the FDA has for the second time approved a drug that targets a tumor’s DNA fingerprint, no matter where in the body that cancer is found. And more could be on the way.
The drug is larotrectinib (Vitrakvi), from Loxo Oncology (NASDAQ: LOXO), and it has been designed to knock out tumors in which a gene called NTRK has abnormally fused to another gene. The abnormality occurs in up to 1 percent of all solid tumor types, including cancers of the kidney, bladder, stomach, and lung.
The FDA has approved larotrectinib for children and adults with solid tumors that have an NTRK fusion, regardless of where those cancers are found. “We now have the ability to make sure that the right patients get the right treatment at the right time,” FDA commissioner Scott Gottlieb said in a statement. “This type of drug development program, which enrolled patients with different tumors but a common gene mutation, wouldn’t have been possible a decade ago because we knew a lot less about such cancer mutations.”
To get the Loxo drug, patients must be ineligible for surgery, and either have no alternative treatments available or have failed other treatments, according to the FDA’s guidance for prescription, or “label.”
[The following paragraphs have been updated with pricing information, refund details, and diagnostic availability.] Bayer, which shares larotrectinib rights with Loxo, is taking the lead selling larotrectinib. The wholesale cost will come in between $11,000 and $32,800 a month, Bayer said Monday evening. “For the majority of patients, we expect that monthly out-of-pocket costs will be $20 or less,” said Bayer spokeswoman Sasha Damouni. Bayer said it would provide the drug at no cost for patients without insurance or who can’t afford it.
The firm also said it would offer a refund if patients don’t see a clinical benefit after three months of treatment. When asked to define “clinical benefit,” Damouni told Xconomy that the patient’s doctor would determine the goal that needs to be met, be it total or partial tumor clearance or even a halt of its progression. Doctors will not have to provide documentation of a patient’s condition, she said.
To receive larotrectinib, a patient’s tumor must first test positive for an NTRK fusion. Loxo in 2017 cut a deal with a subsidiary of Roche to develop a companion diagnostic, but there are several commercial and academic labs whose tests will suffice, according to Loxo and Bayer.
The companies’ ability to sell larotrectinib will be a touchstone for the commercial viability of precision cancer medicines, which hold out the promise of less trial-and-error in finding the right drug to match each patient. But the payoff has been elusive. Even the breakthrough of cancer immunotherapy, with some of its pioneers winning this year’s Nobel Prize for medicine, only helps a minority of patients, often with no ability to predict which patients will benefit.
The agency’s decision today is just the second of its kind. The only other tissue-agnostic approval belongs to the immunotherapy pembrolizumab (Keytruda), which the FDA cleared in 2017 for previously treated tumors with one of two genetic problems, microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). (MSI-H and dMMR tumors have lost the ability to repair their own DNA errors.)
But pembrolizumab, from Merck (NYSE: MRK), wasn’t specifically developed as a tissue-agnostic drug. It was first approved for various cancer types—skin, lung, kidney, and more—and had an established safety profile. And while it was approved to treat any cancer with a specific genetic signature, the data that led to approval was heavily weighted toward patients with colon cancer.
By comparison, larotrectinib has no commercial track record, making it a truer test of not just the regulatory roadmap for tissue-agnostic drugs, but their commercial potential.
Loxo took a streamlined path to approval. The FDA nod came just roughly four years after clinical testing began. Loxo has tested the drug in 179 total patients in three studies and compassionate use cases. The largest of its tests was a “basket” trial that enrolled patients with 17 different cancers that have NTRK fusions. Most groups showed encouraging results.
Basket trials are a fairly new phenomenon in oncology and have their share of skeptics. This essay in the New England Journal of Medicine in 2015, for instance, warned that the small number of patients in each arm of a basket study could lead to “over-interpretation” of the results from any one arm.
Loxo’s results are an example of relying on those types of data. The most recently published results show that of the first 55 patients to receive larotrectinib, 44 (80 percent) have seen their tumors shrink for a median follow-up of 17.6 months. Many responses were still ongoing as of the latest update, and 18 percent of them were “complete,” meaning the cancer couldn’t be seen on a scan. Those are heartening numbers, but each sample size was small: The most common tumor type amongst those patients was salivary gland (12). There were just four patients each with cancers of the lung, colon, or skin.
Still, Loxo repeated those results in a subsequent group of 54 patients. Among that group, Loxo said in October, 44 of 54 (81 percent) of patients saw their tumors shrink, with 17 percent showing no trace of cancer after a median of 7.4 months of follow-up.
Most side effects to larotrectinib, like fatigue, nausea, and dizziness, have been mild; just one patient with an NTRK fusion stopped treatment because of them, according to the label.
Prior to approval, CEO Josh Bilenker told Xconomy the FDA had been very “forward looking” about the dataset and wouldn’t “require statistical rigor on every small subset in question.” That’s been borne out with today’s approval. Other drug makers running similar experiments for tissue-agnostic drugs can now feel more confident in their trial designs. Behind Loxo, for example, is entrectinib, from Roche, also for NTRK fusions. The drug is in late-stage testing. Others such as Blueprint Medicines (NASDAQ: BPMC) are in the mix. The FDA decision is “a significant validating event for Loxo’s clinical development and regulatory strategy,” wrote Leerink analyst Andrew Berens in a note to investors.
Which patients with NTRK fusions actually receive larotrectinib will depend, at least in part, on how payers and doctors feel about the evidence, and how they weigh the drug against others already approved for tumors of, say, the lung or skin. (The FDA is no longer conservative about drug approvals, but doctors or insurers, or both, can be just as cautious as ever when it comes to new drugs.)
There are other factors at play as well. As Xconomy has reported previously, pharmacy benefit manager Express Scripts (NYSE: ESRX) wants to move away from issuing a single price for a drug, regardless of the cancer it’s being used for, and toward a flexible price that corresponds to its effectiveness in each tissue type. Whether a sliding scale of prices comes into effect for larotrectinib remains to be seen.
Meanwhile, DNA sequencing tests that check patients’ tumors for a wide range of genetic alterations have struggled commercially, though regulators have increasingly supported their use. The larotrectinib approval is a good sign for test makers like Foundation Medicine (NASDAQ: FMI), which is owned by Roche, because knowing a tumor’s profile will be increasingly critical to pairing it with the right drug. Larotrectinib “is really the poster child for why comprehensive genetic testing is critical,” says Foundation chief business officer Melanie Nallicheri.
Alex Lash and Corie Lok contributed to this report.