Combination therapy for melanoma: What are the current challenges in pricing & access from EU and US payers’ perspective?

By Tom Brockbank, Henrike Granzow and Alexandrosz Czira, GPI


Current treatment options and target indications

Malignant melanoma is the most lethal form of skin cancer1. In the UK approximately 15,400 new cases occur per year, and since the early 1990’s the incidence rate has more than doubled (128% increase)2. The incidence varies within Europe, from 3-5/100,000 in Mediterranean countries to 12-25/100,000 in Nordic countries3. The incidence rate in the US is also near the top end of this spectrum, at 20.6/100,000 for 2010-20144. With 10% of cases being diagnosed at late stage, and the 5-year prognosis at stage 4 being 20-30%1,5, many new treatments are being developed to improve this end-stage survival data and as a result, making this is a very competitive therapeutic space.

The development of targeted therapies originated from the observation that approximately 50% of cutaneous melanomas contain mutations in serine/threonine kinase BRAF6. Despite impressive responses to BRAF inhibitor monotherapy the results were usually brief, with median PFS of about 6.9 months. As a result, combination therapies were trialled to target multiple parts of the tumour development pathway and delay the time to relapse.


The leap forward with the launch of three combination therapies

Three combination therapies have been authorised by the EMA for marketing within the EU: nivolumab + ipilimumab, dabrafenib + trametinib and vemurafenib + cobimetinib. The combination of dabrafenib + trametinib demonstrated statistically significant improvements in endpoints Overall Survival (OS) and Progression-Free Survival (PFS). In the COMBI-d trial, OS was improved by 6.4 months versus dabrafenib alone and 7.6 months versus trametinib alone. Improvement in PFS was also seen with the vemurafenib + cobimetinib combination, with 9.89 months versus 6.21 months with vemurafenib alone. One more regimen has recently been approved by the FDA, encorafenib + binimetinib; Graph 1 below shows the median OS and median PFS data. Results from the phase 3 COLUMBUS trial have exhibited nearly 15 months median PFS and is the first targeted treatment to demonstrate over 30 months median OS7. Vemurafenib had already demonstrated improvement in survival data, and so the combination regimen improving on this was significant.


Whilst these therapies have shown superior efficacy in trials, the individual drugs alone are amongst the most expensive oncology products we use today and by combining them the price of treatment can almost double. Chart 2 below shows the annual treatment cost of three monotherapy oncology products in the EU5 and US, and how the prices of nivolumab and dabrafenib compares to another oncology product; everolimus. This product was selected as it has multiple indications (i.e. breast cancer, pancreatic cancer) and is currently still patent protected, meaning the price won’t be affected from the presence of generics on the market.



Payers acknowledge that these regimens produce significant improvement in clinical benefit, but they face an affordability challenge. Even more, they have become more price sensitive – amongst others – due to the budget impact of these combination regimens. As a result, manufacturers are having to ensure they meet the stringent criteria for clinical trial design such as payers’ preferred endpoints, specific comparators or minimum trial duration. Access considerations for these therapies also include a new focus on safety and tolerability and their effect on patient QoL, to account for the combined effect and increased safety risk using two powerful agents.


Pricing and access challenges for combination therapies in the EU

Despite payer’s price sensitivity and affordability issues, the three combination therapies of nivolumab + ipilimumab, dabrafenib + trametinib and vemurafenib + cobimetinib, have all received positive reimbursement outcomes from the individual EU5 HTA bodies; except for vemurafenib + cobimetinib in the UK. With the detailed assessments published from the UK, France and Germany we can understand the reasoning behind their decisions. The outcome from NICE (UK) was a result of the cost-effectiveness analyses producing an ICER of over £100,000 per quality-adjusted life year (QALY) gained. This is substantially out of the range usually considered as being cost-effective8. In France, all three regimens received positive reimbursement decisions, with vemurafenib + cobimetinib and dabrafenib + trametinib getting an ASMR III rating, implying a moderate improvement compared with current treatments available. The combination of ipilimumab and nivolumab, despite receiving a positive reimbursement with ASMR V, had its use restricted and it received an ASMR of insufficient in patients with brain metastases.

The monotherapy of ipilimumab also underwent two assessments, as more data became available. However, it was unable to improve upon the initial assessment in which it received an ASMR IV due to the low number of patient responders. The assessment from the G-BA found the combination of dabrafenib + trametinib indicated significant additional benefit compared to vemurafenib alone.

In the year after these combination regimens were approved, the individual drug prices for monotherapy were reduced in France and Germany. The Hospital Price in France reduced between 6.46% – 19.45%9because of the assessments of these combinations and the observed characteristics (e.g. safety, tolerability, etc.) of the individual drugs involved. For combinations nivolumab + ipilimumab and dabrafenib + trametinib, they both received restricted positive reimbursement from NICE in the UK, with the use of a Patient Access Scheme (PAS) resulting in a confidential discount.

For all three combination regimens, both assets are owned by the same manufacturer and this allows for flexibility around price negotiations. This price flexibility is shown visually in chart 3 above (adapted from Rupasinghe et al.10) and how the ownership of both drugs reduces pressure from payers when it comes to negotiations. This is due to the lack of restrictions to re-evaluate drug prices and reduce them if necessary to receive a positive reimbursement.

Manufacturers also have the freedom to strategically reduce prices themselves to overcome potential hurdles from payers or to outcompete competitors in terms of pricing. With the sales data from both drugs as well, they have the option to reduce the price of the drug not performing as well, whilst maintain the higher price of the drug performing well in other indications. The lack of flexibility to alter prices when using a competitor asset in the combination regimen can lead to issues during pricing negotiations with payers. This can be seen from NICE, who put a strong emphasis on the pharmacoeconomic analysis provided by the manufacturer to assess the cost-effectiveness of the asset and calculate the Incremental Cost-Effectiveness Ratio (ICER). Without the flexibility to adjust the price of one of the drugs within the combination regimen, it may be difficult for manufacturers to reduce the total cost into what is deemed as a cost-effective ICER. Typically, <£30,000/Quality Adjusted Life Years (QALY) or <£50,000/QALY if certain end-of-life criteria are met.


A different type of challenge facing providers in the US

The challenges and issues that combination therapies face in the US, where pricing is less restricted regulatory approval, are unlike those in the EU. One of the issues encountered by smaller medical practices is the lag time between purchasing the drug and getting reimbursed by payers. Ensuring that these high-cost drugs are appropriately reimbursed is resource intense and will likely lead to some of these practices switching from the buy-and-bill model to obtaining a receipt of patient-specific medication. Some may even opt to not stock them at all and refer patients to larger medical centres. Similarly, for these more expensive combination regimens that are prescribed by a specialist, a hospital may limit use & prescription to one site only (where these specialists work) to mitigate financial risks11.

Another mechanism which is starting to be introduced in the US is to link the price of some cancer drugs to their real-world performance. This has been seen by Express Scripts, one of the largest pharmacy benefits managers (PBM) in the US, and this new movement is seen as significant for the US; who have been slower than the EU at adopting these new reimbursement schemes12.


Not all combination therapies are success stories

The investigational combination of epacadostat and pembrolizumab recently failed to meet its survival endpoints. The data from ECHO-301/KEYNOTE-252 shows the combination regimen failed to meet its primary endpoint of PFS, compared to pembrolizumab alone, and is expected to also miss its second primary endpoint of OS13. This demonstrates that combining two already marketed immune-oncology (I-O) drugs doesn’t necessarily guarantee success in clinical trials. Despite this failure, with the combination therapies for oncology being such a hot space, it is unlikely manufacturers will be easily discouraged. F. Hoffman-La Roche currently have a combination of emactuzumab + atezolizumab and emactuzumab + selicrelumab in phase I development for melanoma14,15, and several other combinations are being investigated in new indications and cancer types. Again, demonstrating manufacturers’ desire to enter this profitable therapeutic space. With this desire, comes the need for manufacturers to understand ways to overcome the barriers payers have for these expensive combination therapies in the EU.


Challenges facing manufacturers moving forward into the combination therapy space

A challenge which has been consistent for many years is the need for manufacturers to adapt to new strategies required to demonstrate value to payers and receive a positive reimbursement. With these increasingly more expensive treatments being developed and competitive landscape becoming more crowded, manufacturers will need to do more than simply develop a drug to meet an unmet need and price them without sufficient evidence generation. The new strategies required will begin with early-phase developers who will need to alter and plan more effectively the required evidence and how payers will be defining the value for the population when it comes to negotiations. Challenges facing them will be how to optimize protocol designs, streamlining data that is collected, keeping clinical trial costs down and using endpoints which will demonstrate significant value16.

Going forward it will also be key to work with patients to understand what value to them is and introduce a more open approach to future drug developments. In situations where payers are unsure of the value of a product, whether it is due to immature data or uncertainty surrounding the target population, the use of managed entry agreements will become more prominent. An example of this being a ‘risk-sharing agreements’ between manufacturers and emerging markets. With many European markets relying on External Price Referencing (EPR) for their pricing policies, manufacturers have been reluctant in the past to launch in these low-price countries. However, with emerging markets now surpassing EU5 economies in pharmaceutical spending, with a total market size of $281 billion compared with $196 billion in the EU5 (in 2014)17, these markets will become important contributors to pharmaceutical spending in the coming years. Risk-sharing agreements will be key for pharmaceutical companies to access these markets, without them having to give a direct discount. These agreements will ensure payers receive a rebate for all sales in which patients’ response meets a certain threshold. Schemes like these provide more opportunity for patients to receive these treatments, with reduced risk to payers in losing large amounts of money if an adequate response is not met.

Another pathway considered, but not yet implemented as a standard practice, is indication-based pricing (IBP) which would allow for the maximising of a drug’s value across its many indications. It is estimated that 50% of cancer drugs have more than one indication, and with the value varying across these indications, the pricing can become inefficient18. An example of this can be seen in table 1 below, which demonstrates how the cost per Year of Life Gained varies greatly when one indication has a significantly lower value than another for the same drug. With the current pricing pathway, manufacturers can set a high price to target their high-value indication, however, are missing out on revenue from their other indications in which this value hasn’t been met. In case of using IBP, a costly cancer treatment can be priced per indication according to the value, safety and tolerability that the product has demonstrated.


Summary and outlook

  • Despite the high price of these combination regimens, by demonstrating significant improvements in survival gain these combination treatments have received positive reimbursed in almost all EU5 markets and the US.
  • For manufacturers moving forward into the space of combination therapies, being able to have some control over the prices of both assets is essential. Without this, the ability to overcome hurdles from EU & US payers is extremely challenging and will greatly inhibit launch potential of these treatments. Having control of price over both assets allows the flexibility to overcome these hurdles and both could be managed easily during pre- and post-launch of the combination treatment.
  • Simply combining two successfully marketed oncology monotherapies doesn’t guarantee a success in combination therapy. With the increase in price, payers will demand more stringent criteria for clinical trial endpoints, choice of comparator, patient population and duration of a trial.
  • The greater implementation of Managed Entry Agreements and Risk-Sharing Agreements will allow manufacturers to gain further access to EU or emerging markets. However, launching in these markets will require more strategic and specific evidence generation, potentially even at the local level, to demonstrate value to payers. This will require greater communication between cross-functional teams within pharma companies at a much earlier stage to prepare for the launch into specific markets.
  • With the use of these agreements also starting to be instigated in the US, the need for manufacturers to ensure they are launching these combination therapies with strong evidence demonstrating value, safety and tolerability, is essential more than ever.
  • Not only will indication-based pricing provide greater access to medications for patients but will also allow manufacturers to market their drugs for indications not previously reimbursed. The price level will no longer just be set for whichever indication has demonstrated the best value.
  • Moreover, there is an increasing need for new models of collaboration and partnership, even early dialogues, between companies and payers to avoid any consideration of the combination therapy as “1+1=2” which ultimately results to large discounts as opposed to perceiving them as a single entity. Thus, innovative pricing schemes with adequate payers’ management are crucial for successful launching strategy in case of combination therapy for cancer patients.


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