The Food and Drug Administration’s accelerated approval of Loxo Oncology and Bayer’s Vitrakvi (larotrectinib) last week was widely heralded, marking the second time that the agency gave a tissue-agnostic, biomarker-driven label to a drug. But it’s also a significant milestone in the development of value-based healthcare.
As I reported the day of the approval, a major challenge the companies face is finding patients who harbor the genetic abnormality that Vitrakvi targets, known as NTRK fusions. The drug is approved for any solid tumor cancer that includes an NTRK fusion, but while they occur in a wide variety of cancers, their incidence varies considerably, from nearly 100 percent of some tumors to less than 1 percent of others.
On the one hand, the fusions’ rarity makes it more challenging to find patients who qualify for the drug. But on the other hand, it makes Vitrakvi something of a poster child for the concept of value-based care.
In a nutshell, value-based care means reimbursement based on outcomes, as opposed to the traditional fee-for-service model. In the context of oncology, that entails identifying treatments with a high probability of success, particularly by testing for biomarkers to guide therapy. For example, the National Comprehensive Cancer Network Guidelines recommend non-small cell lung cancer patients undergo broad molecular profiling, especially for markers like ALK rearrangements, ROS1, EGFR and BRAF. For example, if there’s an ALK rearrangement, patients qualify for treatment with Pfizer’s Xalkori (crizotinib). While ALK is estimated to occur in only 3-5 percent of NSCLC patients, 74 percent of ALK-positive patients in the clinical trial that led to Xalkori’s approval responded to the drug.
This stands in contrast to the old one-size-fits-all approach. “What you’re doing is moving from phenotypic medicine to genotypic medicine,” said Dr. Timothy Triche, professor of pathology at the University of Southern California Children’s Hospital Los Angeles, in a phone interview.
Vitrakvi is hardly the first drug to fit into this mold – Merck & Co.’s Keytruda (pembrolizumab) won the first tissue-agnostic FDA accelerated approval last year, for microsatellite instability-high and mismatch repair-deficiency cancers. And Novartis’s Gleevec (imatinib), now available as a generic, is a de facto tissue-agnostic drug as well, Triche argued.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
However, Vitrakvi won’t be the last, either. Ignyta, which Roche acquired for $1.7 billion last year, has entrectinib, an NTRK and ROS1 inhibitor in Phase II development for NTRK fusion cancers and ROS1-positive NSCLC. Loxo is also developing LOXO-292, which targets RET fusions, which is also the target of Blueprint Medicines’ BLU-667. Another Loxo drug is LOXO-195, an NTRK inhibitor for patients who develop resistance mutations against Vitrakvi.
At the same time, a key distinction between Vitrakvi and Keytruda is that while Keytruda received its MSI-H and dMMR label in addition to several tissue-specific indications, Vitrakvi only has the tissue-agnostic label.
While that makes finding patients a challenge, it is also part of how Vitrakvi’s approval plays into value-based care. Like ALK, NTRK isn’t just any genetic mutation, but what is known as an oncogenic driver, meaning it plays a key role in cancers’ growth. This means that, similar to Xalkori, the drug has a good chance of working in patients who have an NTRK fusion. The accelerated approval last week was based on a small sample size – 55 adult and pediatric patients across three trials with a variety of advanced solid tumors – but with a 75 percent overall response rate, including 22 percent who had complete remissions. And the responses were durable, with 73 percent of the 41 responses lasting six months or longer.
A caveat of those data – and one key to the question of value – is that they don’t indicate whether the drug will produce a benefit in survival, considered the gold standard of cancer treatment. Viktravi’s accelerated approval means it will likely have to demonstrate a benefit on one or more survival endpoints in a larger, randomized trial. But Triche said the durability of those responses is impressive and indicative of its value nonetheless.
Another caveat is the drug’s steep list price of nearly $400,000 per year. But Triche said the high price does not detract from the drug’s value because it will only be given to those patients who harbor NTRK. To give an illustrative hypothetical example, he said that if 10 percent of lung cancer patients harbor an actionable mutation, then giving a drug targeting it to all lung cancer patients yields a 10 percent response rate. “But if you treat patients with that mutation, you have a blockbuster,” he said.
The whole point of value-based care, after all, is for payers to cover the treatments that will likely work, rather than paying haphazardly for ones that won’t. A Bayer spokesperson told me that the company is working to ensure payers are aware of the data and the need to confirm the presence of NTRK fusions.
I hope that patients will not have to pay huge sums out of pocket. Cancer patients frequently do, especially those with high-deductible plans, as numerous heartbreaking stories of patients and their families driven to financial ruin have shown. But when highly targeted drugs like Vitrakvi and Xalkori are used appropriately, covering them is money well-spent for payers. Even if they paid the full list price – which they won’t, thanks to cost sharing with patients and discounts and rebates negotiated by pharmacy benefit managers – that would still be more efficient than spending even more money throwing one ineffective treatment after another at patients to see which one sticks. As MedCity ENGAGE closing keynote speaker Bryce Olson pointed out, the cost of care for his prostate cancer has been cheap for his insurer, Cigna, thanks to his taking diagnostic tests that cost a few thousand dollars upfront, but enable him to take drugs with a high probability of working.
One expert I interviewed for the Vitrakvi story, Dr. Vivek Subbiah at The University of Texas MD Anderson Cancer Center in Houston, advocated testing of all cancer patients. While this would be pricey in itself, doing it intelligently would save money in the long run by helping many patients do what Olson has. As more biomarker-driven drugs like Vitrakvi reach the market, this may become a necessity, but it will also play an essential role in driving value-based care in oncology.
Photo: Hong Li, Getty Images
