How to assure screening for patients in whom just-approved Vitrakvi (larotrectinib) most likely will help is something "we've been working very hard for the last nine months" to establish, Joseph Germino, vice president of medical affairs for oncology with Bayer AG, told BioWorld. "The drug is so effective – it doesn't work in everybody [but] it works in most people – that it would be a shame if somebody were not able to get it because nobody checked" for eligibility.

Loxo Oncology Inc. and partner Bayer chalked up an expected win with the accelerated clearance by the FDA for Vitrakvi to treat adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without an acquired resistance mutation (ARM).

The drug is a small-molecule inhibitor of the tropomyosin receptor kinase (TRK) family of signaling kinases and takes aim at tumors that are metastatic or in which surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments, or in patients who have progressed following treatment. The marketing nod is based on overall response rate (ORR) and duration of response in experiments with the compound.

Raymond James analyst Dane Leone wrote in a report that, "while we expect the commercial launch to be limited by the number of NTRK-positive cancer patient cases (U.S. incidence: about 4,500) and identification methodology (tumor biopsy), we do anticipate Vitrakvi and LOXO-195 to collectively surpass $1 billion in sales" by about 2026. "The reason the apparent market is smaller than the potential revenue opportunity is twofold: we expect premium pricing for Vitrakvi given the small patient population, unmet need, and efficacy, and duration of response with the drug has been impressive, indicating that patients could stay on the drug well over 12 months," he said.

Vitrakvi, the first such oral drug, also is the first treatment to receive a tumor-agnostic indication at the time of first FDA approval. In clinical trials of patients with this form of cancer, Vitrakvi turned up an ORR of 75 percent (n=55) (95 percent CI, 61 percent, 85 percent), including a 22 percent complete response rate. LOXO-195, which is undergoing phase II tests, works similarly and is meant for patients who develop one of four known ARMs to the approved therapy.

NTRK gene fusions are genomic alterations that result in constitutively activated chimeric TRK fusion proteins that can act as oncogenic drivers, boosting cell proliferation and survival in tumor cell lines. Vitrakvi, developed by Leverkusen, Germany-based Bayer and Loxo, of Stamford, Conn., is designed to inhibit the culprit proteins. Fusions are known to occur in many types of solid tumors that affect children and adults, and Vitrakvi has proved its mettle across various tumor types. They include lung, thyroid, melanoma, gastrointestinal stromal tumors (GIST), colon, soft tissue sarcoma, salivary gland and infantile fibrosarcoma.

The premium price forecast by Leone materialized. Vitrakvi's wholesale acquisition cost is $32,800 for a 30-day supply of 100-mg doses, or $393,600 per year. A liquid oral formulation will cost about $11,000 a month for pediatric patients, and is based on body surface area. Bayer, though, is offering what it dubbed the Vitrakvi Commitment Program and the TRAK Assist patient support program. The former will refund the cost of Vitrakvi to payers, patients and third-party organizations paying on behalf of patients if patients do not show clinical benefit within 90 days of treatment start, if they've received the drug from an in-network specialty pharmacy. TRAK Assist provides what Bayer called "comprehensive reimbursement support and patient assistance services." Bayer estimates that the ultra-rare cancer affects between 2,500 and 3,000 new patients in the U.S. per year, most of whom currently go undiagnosed, and the company maintained that the breakthrough therapy is priced right. For the majority of patients, Bayer predicts that monthly out-of-pocket costs will be $20 or less.

"We expect about 70 percent of the patients to [have] commercial insurance," Germino said. "Medicaid typically charges between $8 and $10 per prescription for 30 days of therapy." Medicare coverage's "donut hole" of missing benefits can often be offset by support programs. These expectations were factored together to arrive at the $20 estimate, he said.

Leone deemed the approval "in line with our positive outlook" on Vitrakvi. "Importantly, a review of the FDA label yields no surprises or unexpected annotations regarding toxicity of the drug."

Under the terms of the companies' deal, Bayer takes responsibility for 50 percent of the commercial costs and will receive 50 percent of profits in efforts to commercialize the compound, and could qualify for a priority review voucher. Vitrakvi will be available in the U.S. market immediately. Bayer submitted a marketing authorization application in the EU in August.

Oppenheimer analyst Leah Rush Cann was optimistic about revenues, too, saying in a report that her firm "continue[s] to estimate that larotrectinib will launch in the U.S. in the fourth quarter of 2018, and sales will increase to $1.12 billion in 2024."

Fewer mutations means better chance

LOXO-195 has a long history, Germino said. "What Array [Biopharma Inc.] did and Loxo did prior Bayer's involvement, was say, 'OK, we know these things happen. They happen for other kinases, so they likely happen for this kinase inhibitor. Let's do a screen to find a drug that will bind in the presence of these mutations.' And that's what they did. If a patient gets on [Vitrakvi], in most cases – honestly, we don't know how long the average patient stays on, because we haven't reached the median duration of response – but at some point most patients if they've not been cured, will progress. Some of them might [remain stable for] 10 years, some might be two years, and some might be 18 years. At the time of progression, what a doctor should do, and obviously we will be counseling them to do this, is sequence that kinase domain. It's very simple, it's very cheap, and they can do it by PCR. If one of these four mutations comes up, they would be eligible to go on the trial, if the trial is still open, or on the drug, if the drug is approved by then." Asked how soon LOXO-195 might be available, Germino said "it all depends on the number of patients they get [for the study]. Right now, the pipeline [of subjects] coming in, because [Vitrakvi] works so well, has not been really fast. I think it's at least a couple years off at the minimum, but it depends on accrual."

Meanwhile, Bayer is working with academia and groups such as Friends of Cancer Research and the American Society of Clinical Oncology, as well as screening companies that already test for mutations related to the efficacy of, for example, lung cancer drugs. The problem is that, although Vitrakvi is tumor-agnostic, each tumor type brings a different proportion of patients who might benefit. In GIST, where about 5,000 patients show up in a given year in the U.S., several drugs are approved for use in those with specific mutations. "You don't need to test all your GIST [patients], just test the 10 percent that don't have these other mutations," Germino said. In fibrosarcoma, which afflicts only 30 to 50 U.S. patients a year, "probably 90 percent have a fusion," he said.

The next step may be to devise a drug that works where both Vitrakvi and LOXO-195 fail. "Why did Vitrakvi not work in the first place?" Germino said. "Was it because of one of these gatekeeper mutations or was there something else in the tumor? We're going to need research to find out what it is that causes the cancers to evade Vitrakvi. There might be mutations in downstream proteins. Now that the drug is approved, there will be many more opportunities to study what happens."

On the upside, for most cancer types, Vitrakvi-eligible patients have fewer mutations in the DNA of the tumor than other cancer patients, which means more opportunities for therapies "once we identify what the pathways are that are getting activated," Germino said. Researchers might be able to "come up with an entirely different drug that would then work, because [the patients] don't have the hundreds of mutations that a typical cancer patient has, they only have a few. We can then direct this strategy to those few. That's the idea."

The scarcity of mutations could explain why Vitrakvi lasts for so long when it works, he said. "When you attack the base of the tree, the tree falls. But when you have a forest, you can knock down one tree and other trees take over."

Loxo landed its deal with Bayer, valued as high as $1.55 billion, in late 2017. (See BioWorld, Nov. 15, 2017.)

On the testing front, Basel, Switzerland-based Roche Holding AG on Tuesday launched the Ventana pan-TRK (EPR17341) assay, the first automated in vitro diagnostic immunohistochemistry assay to detect TRK proteins in cancer. "That doesn't mean it's a fusion but [having the assay available] will reduce the number of patients who would need to have sequencing," Germino said.

Shares of Loxo (NASDAQ:LOXO) closed Tuesday at $139.10, down $13.60.

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