Patient Engagement, Pharma

Loxo, Bayer’s Vitrakvi wins FDA approval. Now comes the hard part: finding patients

An oncologist compared NTRK fusion patients to a needle in a haystack, but had some clues of how to find them. Still, drugs like Vitrakvi call for genomic sequencing of all cancer patients, he said.

dna, genomics

The Food and Drug Administration on Monday approved a cancer drug designed to treat the patient’s disease not based on what tissue it effects, but on whether it expresses a particular genetic biomarker — regardless of where it occurs in the body.

The agency granted accelerated approval to the drug, Vitrakvi (larotrectinib), with a label that includes solid tumors in general that exhibit genetic abnormalities known as NTRK fusions, are metastatic or where surgery is likely to result in severe morbidity and that lack alternative treatments or have progressed following treatment. The drug was developed and commercialized by Stamford, Connecticut-based Loxo Oncology and German drugmaker Bayer. The drug comes in a capsule and an oral solution. After-hours trading of Loxo shares was suspended ahead of the announcement.

NTRK fusions occur in a wide variety of solid tumors and help to drive their growth, but their occurrence varies considerably from one cancer histology to the next. Yet, among patients with the fusion, about 80 percent responded to treatment, according to data presented last month at the European Society for Medical Oncology meeting.

But the accelerated approval – based on three clinical trials of 55 pediatric and adult patients – was the easy part. Now comes the hard part: finding patients to use the drug.

Vitrakvi is the second cancer drug to win a tissue-agnostic, biomarker-based label. The first was Merck & Co.’s PD-1 checkpoint inhibitor, Keytruda (pembrolizumab), which received approval last year for patients with microsatellite instability-high and mismatch repair-deficient – or, respectively, MSI-H and dMMR – cancers. But an important distinction is that Keytruda was already approved for other, much more widespread cancer indications and has received additional approvals since. By contrast, Vitrakvi’s first indication is for a group of patients that Dr. Vivek Subbiah, an assistant professor of medicine at The University of Texas MD Anderson Cancer Center, described as a proverbial needle in a haystack. “We need to come to a paradigm in which we test all patients, not just for [NTRK], but across multiple diseases,” he said in a phone interview.

According to an educational site run by Loxo and Bayer, NTRK fusions occur in at least 91 percent of patients with infantile fibrosarcoma. Fibrosarcomas account for 10 percent of the already rare childhood soft tissue sarcomas, according to the National Cancer Institute. Thyroid cancer has the second largest incidence of NTRK fusions, with 2-12 percent of patients exhibiting them, followed by 10 percent of high-grade gliomas – a type of brain cancer – among children, according to the educational site. Otherwise, they occur in 1 percent or less of sarcomas, colon cancer, glioblastoma and head and neck cancers, and anywhere from 0.2 percent to 3 percent of lung cancers.

The exact number of patients with NTRK fusions is difficult to quantify, which should improve with more testing and diagnostic availability, a Bayer spokesperson wrote in an email. Loxo announced in April a partnership with Illumina to develop a multi-gene next-generation sequencing diagnostic to detect NTRK and also RET fusions, the target of another drug it has in development, LOXO-292.

On Nov. 7, BioPharm Insight reported that Vitrakvi and its successor, LOXO-195, would face hurdles defining their market given the difficulty in finding NTRK fusion patients, citing oncologists. LOXO-195 is also an NTRK inhibitor, but designed to address escape mechanisms that may cause patients to eventually develop resistance to Vitrakvi.

The Bayer spokesperson said the company has sponsored multiple continuing medical education programs around NTRK fusions and testing and is working with payers to ensure they understand the clinical data about Vitrakvi and the need for confirmation of the presence of the fusions. “We appreciate that this will be a long-term effort, but we are committed for the long haul because we believe that larotrectinib can be a transformative therapy for many patients,” she wrote.

But there are also geographic limitations. “Academic centers are used to testing, but in the rural and community setting it’ll be a challenge,” Jillian Scaife, principal of the consultancy Trinity Partners, said in a phone interview.

The challenge of finding NTRK fusion patients is comparable to that of finding patients with MSI-H and dMMR for Keytruda, Subbiah wrote in an email. While ideally all cancer patients should undergo genomic testing at diagnosis, for now, any patient with colorectal and endometrial cancers is tested for MSI-H and dMMR, along with younger cancer patients, while others are tested on a case-by-case basis, he wrote.

Currently, the National Comprehensive Cancer Network guidelines recommend MSI-H and dMMR testing in patients with 14 cancers, a Merck spokesperson noted. In the studies supporting Keytruda’s approval for those patients, MSI and mismatch-repair status was determined using local, lab-developed tests like immunohistochemistry and polymerase chain reaction, and Merck is now working with Foundation Medicine to develop a next-generation sequencing-based companion diagnostic.

In a phone interview, Subbiah listed some categories of patients who would be candidates for NTRK testing. For example, patients with MSI-H cancers tend to have NTRK fusions as well, and they occur in at least 92 percent of mammary analogue secretory carcinomas, a form of breast cancer. Other cancers in which to look include salivary gland tumors, pediatric sarcomas and soft-tissue sarcomas, he said.

Another way to find patients who qualify is through other genetic mutations and fusions that may predict NTRK’s presence or absence, Subbiah said. For example, anaplastic thyroid cancer patients with BRAF mutations likely won’t have NTRK, nor will those with CKIT-mutated gastrointestinal stromal tumors. RET fusions also rule out the likelihood of NTRK fusions, and those patients would be candidates for LOXO-292 anyway. Subbiah is MD Anderson’s principal investigator for Loxo’s LOXO-292 study. There is also some evidence that immunohistochemistry or fluorescence in situ hybridization testing can help predict the presence of NTRK, but that currently either has insufficient scientific support or is impractical, he added.

How to price the drug is going to be another challenge, Scaife said. “When you think about pricing a new therapy that can be used across many different tumor types, there’s often an established standard of care in each tumor type,” she said. From the perspective of payers, testing will also be a challenge, as genomic tests cost thousands of dollars.

But as MedCity ENGAGE speaker, prostate cancer survivor and early genomic sequencing subject Bryce Olson said ahead of the Nov. 6-7 conference, that’s a price that may be worth paying. While the genomic tests he’s taken have cost $3,000-4,000 each, that has actually saved his health insurer money by enabling him to take drugs with a high probability of working rather than wasting money going through drugs that will not.

Photo: iLexx, Getty Images

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