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UK's NICE Cites Lack of Response Markers for BMS' Yervoy as Factor in Negative Recommendation


Originally published Oct. 18.

By Turna Ray

The UK's National Institute for Health and Clinical Excellence last week cited the absence of validated molecular tests for identifying which patients are likely to have a sustained and robust response to Bristol-Myers Squibb's Yervoy as one of its reasons for recommending against the melanoma therapy's use.

Among various reasons cited for the negative recommendation, Andrew Dillon, chief executive of NICE, noted that "unfortunately, no patient characteristics or biomarkers have yet been identified to help identify [the] small group of people most likely to gain long-term benefit from receiving [Yervoy]."

Clinical studies have shown that around 30 percent of people treated with the drug have improved survival and only around 10 percent are likely to have long-term benefits. There are between 400 and 500 melanoma patients in the UK each year whose disease progresses beyond second-line treatment.

NICE, an advisory body to the UK's National Health Service, evaluates the efficacy and cost-effectiveness of medical interventions and recommends whether NHS should pay for a particular treatment or test. The recommendation on Yervoy was issued as a draft guidance and has not yet been issued to the NHS. Until it issues its final guidance on the drug, NICR recommends that NHS "make decisions locally on the funding of specific treatments."

Yervoy (ipilimumab) was approved by the European Medicines Agency in July. NICE's draft guidance on the drug was based mainly from data on MDX01020, a trial involving 676 advanced melanoma patients who were randomized to receive Yervoy plus gp100, an investigational peptide vaccine; Yervoy plus placebo; or gp100 plus placebo. Results showed that patients in the Yervoy plus gp100 arm gained 3.5 months in median overall survival compared to those in the gp100 alone arm. Between those receiving just Yervoy or gp100, Yervoy increased median overall survival by approximately 3.7 months. There was no significant difference in median overall survival between patients treated with Yervoy plus gp100 compared with those treated with just Yervoy.

NICE found several flaws with the data submitted by BMS on Yervoy. Although "the results did show the drug could potentially be very effective for a small percentage of patients," the agency took issue with the fact that the sponsor didn't compare Yervoy to standard treatments used to treat advanced or metastatic melanoma. Additionally, the follow-up from the trial was "too short to determine" how long the drug's efficacy would last in those who were seeing a survival advantage.

"The drug is also associated with a number of adverse reactions including diarrhea, rash, fatigue, nausea, vomiting, decreased appetite, and abdominal pain, which can significantly affect a patient's quality of life," Dillon said. “The Committee considered all these factors and concluded that, on the basis of the evidence provided so far, [Yervoy] could not be considered a cost-effective use of NHS resources."

The recommended dose for Yervoy, an antibody that binds to the molecule CTLA-4 expressed on immune response-regulating T-cells, is 3 mg/kg administered intravenously every three weeks, resulting in a total of four doses. Given an average cost per dose of around £20,000 ($31,400), NICE estimated that the cost per year to the NHS for every year of improved health following Yervoy treatment would be between £54,000 and £70,000 ($84,800 and $109,900).

"Probabilistic sensitivity analysis reported a 14 percent chance of [Yervoy] being cost effective compared with best supportive care at £50,000 per [quality-adjusted life year] gained," NICE found.

NICE's preliminary recommendation is available for public comment until Nov. 4. "The manufacturer can also consider whether it wishes to reduce the acquisition cost to the NHS of the drug by proposing a patient access scheme," Dillon said in a statement.

In recent years, NHS has made several controversial decisions against covering certain cancer drugs that have failed to meet NICE's cost-effectiveness thresholds. As a result, drug developers have increasingly been engaging in creative cost-sharing schemes in which the sponsor agrees to pay for treatment for patients who don't see a benefit and NHS pays for the drug only when it is effective. In the personalized medicine space, AstraZeneca's patient-access scheme with the NHS represents the first example of a risk-sharing arrangement involving genetic testing.

Last year, NICE recommended that the NHS pay for AstraZeneca's first line, non-small cell lung cancer drug Iressa only for patients with EGFR mutations, if the drug developer provides the drug at a fixed price per patient, regardless of how long the patient has been treated. The £12,200-per-patient fixed price agreed upon by AstraZeneca and the UK's Department of Health included the cost of the drug and pre-treatment EGFR testing (PGx Reporter 6/2/2010).

Although a similar patient-access scheme for best responders may be a possibility in the case of Yervoy, the fact that there are no tests that can be used to reliably identify best responders can pose a barrier.

NICE noted in its draft guidance that the European Medicines Agency "considered a number of ancillary analyses carried out by the manufacturer in an attempt to identify possible subgroups of people who might (or might not) benefit from treatment with ipilimumab. However, the subgroups were small and [NICE's Evidence Review Group] determined that no conclusions could be drawn from this analysis."

Meanwhile, the drug developer is in the process of conducting pharmacogenomic studies that would provide insights in this regard.

At the American Society of Clinical Oncology's annual meeting this year, BMS said it was investigating whether combining Yervoy with Roche/Plexxikon's Zelboraf, a melanoma drug for BRAF-mutated patients, could further improve outcomes in molecularly defined subpopulations of melanoma patients (PGx Reporter 6/8/2011). The FDA in August approved Zelboraf simultaneously alongside a companion test for gauging BRAF mutations.

Aparna Krishnan, senior research analyst from IHS Global Insight, suggested that BMS might have had a better shot at gaining a positive recommendation from NICE for Yervoy if the treatment was developed with a companion test to help physicians pick out best responders with greater confidence.

Citing the example of Zelboraf, Krishnan observed that even though that drug only benefits around 50 percent of the BRAF-mutated melanoma population, "NICE could be more inclined to reimburse Zelboraf because the existence of the companion diagnostic means that there's a greater chance of success for the patients who receive the drug." The EMA hasn't yet issued a decision with regard to Zelboraf.

Although BMS is investigating Yervoy's efficacy in the BRAF-mutated melanoma population and possibly in other molecularly defined patient subsets, it is unknown whether the sponsor has any mature biomarker data that can help change NICE's opinion in the short term.

Recently reported independent research may be able to shed some light on the response markers of interest. Researchers led by Paola Queirolo of the National Institute for Cancer Research in Genoa, Italy, have conducted a study to investigate CTLA-4 gene polymorphisms in advanced melanoma patients treated with the anti-CTLA-4 treatments Yervoy and MedImmune's tremelimumab. The study, presented at the ASCO annual meeting this year, characterized 14 metastatic melanoma patients' response to either drug according to whether they had five CTLA-4 SNPs: -1660A>G, -657C>T, -318C>T, +49A>G, and CT60A>G.

Genotyping was performed by T-ARMS PCR and results were confirmed by direct sequencing on DNA extracted from patients' peripheral blood. The researchers, who didn't claim any conflict of interest with industry, reported that five patients were alive and nine were dead after the follow-up period. All the patients who were alive at the end of the observation period carried the CT60 G/A genotype.

This genotype was "at variance with CT60 A/A or G/G genotypes," and strongly correlated with better response and significantly with overall survival," the researchers reported. The other CTLA-4 SNPs or haplotypes did not significantly correlate with treatment response.

"Our data suggest the possible impact of CTLA-4 polymorphisms on the clinical outcome of metastatic melanoma patients receiving antibody-mediated CTLA-4 blockade," Queirolo et al. concluded.

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