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Novartis Launches Free BRAF Testing Program Hoping to Close Access Gaps, Maintain Market Lead

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NEW YORK – Earlier this month, Novartis announced it will fully subsidize BRAF testing via Quest Laboratories for all melanoma patients meeting certain criteria, which the drugmaker hopes will help close test access gaps.

While it's not clear the extent to which melanoma patients currently lack access to covered single-gene BRAF testing, the free testing program can certainly help Novartis maintain its leading position in the BRAF and MEK inhibitor market against at least two other competing companies — though the drugmaker wouldn't comment on this point.

The program for Stage III and Stage IV melanoma patients subsidizes access to bioMérieux's THxID-BRAF kit, a test that gauges BRAF V600E and V600K mutations, which the US Food and Drug Administration specifically approved as a companion diagnostic for two Novartis drugs, dabrafenib (Tafinlar) and trametinib (Mekinist). The FDA has also approved the same test as a companion diagnostic for a newer melanoma drug combination, encorafenib and binimetinib (Array Biopharma's Braftovi and Mektovi), which may also see a boost from the free testing program.

However, this program also comes at a time when leading cancer centers and academic institutions are increasingly using next-generation sequencing panels to identify markers that can inform precision oncology treatment options. In the community setting, however, where the use of NGS panels is less prevalent, the provision of a free testing program may sway oncologists away from first trying broader testing approaches that could simultaneously identify whether a late-stage melanoma patient was BRAF negative but had other markers that could be targeted by non-standard therapeutic options or whether they are candidates for certain clinical trials.

Novartis declined to comment when asked about these complex downstream impacts of its free testing program.

Novartis Executive VP and US Oncology Head Ameet Mallik said in a statement that the "Know Now" free testing program is intended to "empower the melanoma community" to overcome barriers that keep patients from being tested.

Individuals accessing the program's website are directed to a test requisition form that an oncologist can  order from Quest Diagnostics, with Novartis footing the bill.

Although Novartis stressed its intentions to help overcome barriers to BRAF testing, it is not clear that test cost is the most pressing factor precluding individuals with melanoma from being assessed.

Adil Daud, director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, said that in his experience, barriers to timely BRAF testing are more structural than they are financial, at least in current practice.

"What I understand is that it is mainly logistical. For us in academia, it's not as much of a deal because people have their surgery and you have their pathology accessible," Daud said. However, many patients have their biopsy performed in a dermatologist's office and then see a medical oncologist, who doesn't have access to the samples for genetic testing to inform therapy.

This can take several weeks to work out, but "in the meantime, the patient has no treatment," Daud said.

Instead of demonstrating undertesting, some studies of test rates have even seemed to suggest that more US melanoma patients are being tested than there should be eligible cases in a year. An analysis of real-world annual test volumes conducted a few years ago by Diaceutics consulting subsidiary Labceutics, for example, concluded that the number of BRAF V600E mutation tests performed in the US in the year 2015 actually overshot the number of eligible stage III or IV cases that would have been expected based on incidence numbers.

According to Daud, patients aren't routinely presenting to his institution with a lack of coverage for the type of single-gene BRAF assessment that Novartis has pledged to subsidize. However, he noted that the UCSF melanoma team does at times see patients for whom there is a question of insurance coverage for comprehensive sequencing, which can identify markers beyond BRAF V600E and V600K mutations and point to more investigational treatment strategies for those who test negative for alterations in that gene.

UCSF performs a 500-gene NGS panel, which can result in the patient having to pay around $1,800 if insurance refuses to pay. "A lot of times it's hard to know upfront whether the commercial insurance will accept it or not because this is still an area of flux," Daud added. "What can be stressful for patients is to have to sign yet another waiver or release saying that you could be on the hook for thousands of dollars."

In cases where there is a real worry about a patient possibly being responsible for a big bill, Daud said he and his colleagues will sometimes order a single-gene BRAF test instead, which only risks costing a few hundred dollars out of pocket if insurance refuses to pay.

Although he doesn't know how many individuals in the US with metastatic melanoma might be in a position where their insurance would pay for neither NGS nor a single-gene BRAF test, Daud said that incidence numbers suggest that there should be at least a few thousand who "would [at least] be happy to have another option."

"BRAF is the most common mutation in advanced melanoma and is seen in approximately 50 percent of cases. It's important for patients to know their BRAF status since it is an important factor in determining the best treatment option. That's why testing should be available to all patients, regardless of insurance coverage," Novartis' Mallik said in an email this week.

According to Daud, although the importance of testing for BRAF mutations has been canon for many years now, the standard of care for this group of patients has shifted recently from single agents to dual BRAF/MEK inhibitor treatment, a market that Novartis is not alone in, though it appears to hold a financial lead.

Sales of the company's BRAF/MEK inhibitor combination of dabrafenib and trametinib were $1.16B in 2018, according to a financial presentation earlier this year.  Genentech also competes in this market with its BRAF/MEK combo, vemurafenib and cobimetinib (Zelboraf and Cotellic), but holds far less market share than Novartis' combination.

Daud said that in his experience most physicians turn first to dabrafenib and trametinib because the combo is not associated with the severe skin side effects that are seen in the alternative. "Both [combinations] have looked like they were about equivalent in terms of efficacy," he said. Although there hasn't been a head-to-head comparison, Daud cited analysis from a few years ago that suggested that patients treated with the vemurafenib/cobimetinib combo tended to experience more skin rashes and liver function and kidney problems, while patients on the Novartis combo had more fevers and chills.  

Adding to these two original competitors, new entrant Array Biopharma's encorafenib and binimetinib were approved last July and has been steadily increasing in sales, bringing in $35.1 million in the third quarter of fiscal 2019. Pfizer also said this June that it would buy Array, which means more marketing power behind that combo in coming years.

Daud said the Array drug combination "looks pretty good," and doesn't appear to have either the photo sensitivity association, or the fever side effects. "In a way it avoids the worst side effects of both [of the other combinations] but seems to be just as effective or maybe even more effective," he said. There are still important unanswered questions, however: a lack of long-term data for the new offering, as well as questions about whether the compounds penetrate effectively into the brain, Daud added.

The free testing program stands to help facilitate access to Novartis' and Array's combinations, but Genentech's drugs were approved with a different companion diagnostic, Roche's cobas 4800 BRAF V600 Mutation Test.

Adding to this, there are now several immunotherapies approved for melanoma, which in turn means that treatment decisions for metastatic melanoma patients have become a little more complicated than just figuring out whether a patient is BRAF-positive or BRAF-negative, Daud noted.

This is why UCSF and many other academic cancer centers are using NGS to broadly test cancer patients for a panel of genes whenever possible. For the 50 percent of melanoma patients who are BRAF negative, single-gene testing closes the door on further precision oncology approaches, whereas an NGS panel leaves open the chance to identify other actionable alterations.

"If someone is BRAF negative, then you have to ask for NRAS and then C-KIT … and it ends up costing more if you keep doing this reflexively," Daud said. "Time is also valuable, the weeks and months that you are fooling around with your testing."

Reflecting this, the most recent cutaneous melanoma guidelines from the NCCN recommend that for patients presenting with initial stage IV disease or clinical recurrence, doctors test tissue for BRAF "and in the appropriate clinical setting" also for KIT. "Consider broader genomic profiling … if the test results might guide future treatment decisions or eligibility for participation in a clinical trial," the guidelines state.

In line with this, US insurers are now also beginning to shift to cover comprehensive genomic panels that include not just BRAF but other genes that might harbor alterations that make patients eligible for targeted drugs or an emerging molecularly driven clinical trial. With the FDA and the Centers for Medicare and Medicaid Services embrace of next-generation sequencing panels for Stage III and IV solid tumors (including melanoma) last year, access to comprehensive panels has expanded to a much larger population.

Moving forward, Daud predicted that comprehensive approaches are likely to become more and more standard, which raises questions about Novartis' approach. The firm declined to comment on why its free testing program is limited to bioMérieux's single-gene assay at a time when the field of precision oncology is moving to NGS panel testing.