NICE fast-tracks Keytruda for advanced melanoma

Merck Sharp & Dohme's (MSD) first-in-class treatment for cancer, Keytruda (pembrolizumab), has been given a rapid thumbs-up from NICE for use in advanced melanoma.

The final draft guidance has come a month earlier than expected, reflecting the high profile nature of the drug. Keytruda is the first of a new generation of PD-1 'checkpoint inhibitor' immunotherapy treatments which could help extend lives significantly and produce fewer severe side effects compared to chemotherapy.

The drug was the first to be fast-tracked through the UK's Early Access to Medicines Scheme (EAMS), which allows limited use of potentially groundbreaking drugs ahead of regulatory approval.

This means the government is keen for Keytruda to stand as an example of how the most promising drugs can reach patients faster.

While doctors and patients are excited about the potential, the drug has yet to prove its potential 'groundbreaking' status.

It and other immunotherapies promise a 'step change' in survival, but this hasn't yet been proven in trial data for these patients. NICE says patients taking the drug can expect to live on average 3.5 month longer than patients on chemotherapy – a significant period, but not beyond the gains seen in other new cancer treatments.

But this promise has persuaded NICE to skip a step in its usual process in order to speed up its decision, issuing a positive Final Appraisal Decision (FAD) following the first appraisal committee meeting.

MSD is delighted with the decision, which, it says, shows that the UK's many regulatory bodies can work in a joined-up way. The rapid decision is especially good news for MSD, as it gives it a lead over Bristol-Myers Squibb's rival PD-1 inhibitor Opdivo (nivolumab). NICE currently estimates its appraisal of Opdivo in advanced melanoma won't be ready until May 2016, giving Keytruda time to establish itself.

Restricted use

However MSD hasn't had it all its own way: Keytruda has a broad European licence as an alternative to existing immunotherapy, BMS's Yervoy, and as a treatment in patients who relapsed on the drug. But NICE has only approved it in this latter group (who must also have the BRAF V600 mutation), which will restrict its use to an end-of-life treatment for a small group of patients.

This means an estimated 600 people could receive the drug in the first year, with the figure falling to around 300 thereafter.

NICE recommends that Keytruda is made available on the NHS as a treatment for some patients with advanced melanoma, which is either unresectable or metastatic.

The acquisition cost of Keytruda is £1,315 per 50 mg vial (excluding VAT). The company has agreed a 'patient access scheme' price discount with the Department of Health, but the level of price reduction remains confidential.

Keytruda has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'.
But NICE's appraisal only looked at its use in people already treated with Yervoy (ipilimumab). Keytruda is recommended for the indication covered by the company evidence submission, that is:

• after the disease has progressed with ipilimumab and, for BRAF V600 mutation-positive disease, a BRAF or MEK inhibitor (such as dabrafenib or vemurafenib [BRAF inhibitors] or tramentinib or cobimetinib [MEK inhibitors]), and

• when MSD provides Keytruda with the discount agreed in the patient access scheme.

Professor Carole Longson, Health Technology Evaluation Centre director said: "We are pleased to be able to recommend pembrolizumab, the first EAMS drug, in final draft guidance. In 2011, over 13,000 people were diagnosed with skin cancer in the UK, and it accounts for more cancer deaths than all other skin cancers combined. I am sure this will be welcome news to patients and healthcare professionals alike."

Life science minister George Freeman is trying to encourage greater uptake of innovation in the NHS, and has championed the EAMS route in particular.

"I am delighted that Merck, Sharp & Dohme has decided to use the Early Access to Medicines Scheme to accelerate access for our NHS patients," said Freeman.

He is also behind the Accelerated Access Review (AAR), which aims to re-shape UK market access to provide a 'lit runway' for effective new innovation.

Freeman says the AAR will make practical recommendations to further increase the pace of getting innovative products to patients.

The draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues final guidance, NHS bodies should make decisions locally on the funding of specific treatments.

Mike Nally, UK managing director, MSD said "MSD is proud to have helped bring this breakthrough immunotherapy to patients and that the value it can bring has been recognised and enabled patients who could not afford to wait to gain early access."

He added: "This offers a world-leading example of how different stakeholders in a healthcare system can work together to ensure 'joined up', accelerated access for patients across agencies involving industry, government, MHRA, NICE and NHS England."

Lots of leeway on the data

NICE appears to have allowed Keytruda considerable leeway on its cost effectiveness and clinical effectiveness data.

MSD's raw data shows no statistical difference in overall survival between Keytruda and chemotherapy.

Furthermore, NICE's analysis produced a 'most plausible' cost-effectiveness ratio (ICER) of less than £50,000 per QALY gained – well above NICE's usual 'threshold range' of £20-30,000.

Despite all of these doubts, NICE agreed with the firm that the progression-free survival data underestimated the benefits of the drug compared to chemotherapy. It also concluded that by re-modelling the data, the best available evidence suggested a medial overall survival gain of 3.5 months.

Following a consultation, Keytruda looks likely to reach NHS patients by the beginning of 2016. This will allow it to bypass the Cancer Drugs Fund, currently at the centre of great controversy because of its de-listing process.

NICE is also reviewing the drug in Yervoy-naive unresectable metastatic melanoma, with guidance expected in January 2016, which will prove to be more important in terms of potentially reaching more patients.