Debate over pembrolizumab dosing gives rise to a national guidance on de-escalation strategies and off-label use

"You may wonder why most dose optimisation and de-escalation studies come from the Netherlands"

Last week, the Healthcare Institute, the governmental body overseeing the Netherlands' public insurance package, published its guidance on off-label use to ensure that dose optimisation and de-escalation strategies are rolled out safely and responsibly. Before we discuss the guidance, let me give you some context and tell you how it all started. Finally, I’ll share my idea about where we should be heading.

The art of doing more with less

You may wonder why most dose optimisation and de-escalation studies come from the Netherlands. Well, Dutch people tend to embrace practical, no-nonsense solutions and avoid wastefulness in many aspects of life. Part of this is perhaps due to the country’s history of trade, part of it stems from Calvinism, which considers wastefulness morally wrong, and part of it is likely influenced by geography, as a portion of the country has been reclaimed from the sea (via dikes and dams). As a result, there is a strong focus on sustainability, efficient resource management and doing more with less.

For instance, Dutch hospitals use immunotherapy based on weight-adjusted dosages instead of the standard registered fixed dose. The fixed dose of pembrolizumab, for example, is set for someone with an average weight of 100 kilos.

In practice, one could treat two patients weighing 50 kilos with that same dose. This is exactly what Dutch hospitals do, and it helps them save resources

Some companies do actually invest in de-escalation

Most companies do show understanding for our need to do more with less. But some, like Bristol Myers Squibb (BMS), may even occasionally invest in such studies. For example, the design of the NADINA trial may not have initially seemed commercially attractive to BMS, as it leads to shorter treatment duration for their product. However, the company still invested in the trial. The results demonstrated that adjuvant nivolumab for melanoma could be omitted in patients who achieve a major pathological response after neoadjuvant therapy (59.0% of the patients). Since last week, the NADINA regimen is reimbursed in the Netherlands (translation here). Implementing the NADINA strategy not only improves recurrence-free survival rates but also saves 1 euro per person per year in healthcare costs in the Netherlands, as was concluded by the Healthcare Institute. This money can then be used for other patients.

Merck, Sharp and Dohme: “not a relevant scientific question”

One company that openly expresses its disapproval of de-escalation studies is Merck, Sharp and Dohme (MSD). In a letter to Follow the Money they write: “We believe that scientific research should primarily be driven by relevant scientific questions that advance knowledge, and not primarily by (fictitious) cost savings.” Regarding the weight-adjusted dosage of pembrolizumab instead of the standard registered fixed dose they write: “Without high-quality randomised controlled studies, it is not scientifically responsible to extrapolate the weight-based dosing of these indications [referring to the first indications they studied themselves based on weight-based dosing] to other indications.” Some may argue, however, whether the weight-based dosing of pembrolizumab is considered off-label, as it is still mentioned in the SmPC.  Besides, comparability is not a one-way equation. When the company showed that the 200 mg Q3W fixed-dose regimen is comparable to the 2 mg/kg Q3W regimen (based on PK and exposure data), it means that the 2 mg/kg Q3W regimen is also comparable to the 200 mg Q3W fixed-dose regimen. We do not suddenly need to conduct a randomised controlled trial for each indication to prove that this equivalence works both ways.

The letter from MSD was written in response to the investigations by Follow the Money, which examined the company's “aggressive approach” in sending letters to the Society of Medical Oncology and insurance companies to stop the weight-based dosing strategy. A separate journalistic investigation conducted by the national television also highlighted the company's conduct (translation here). In the end, this resulted in medical societies asking for guidance from the Healthcare Institute.

Guidance on responsible de-escalation and off-label use

The Healthcare Institute acknowledges that de-escalation, cost-efficiency strategies and off-label use may enhance the quality of care, affordability and accessibility. Last week the institute published it’s guidance to help the field in rolling out such strategies:

• De-escalation/off-label use should be based on the recommendations of medical societies

• The recommendations should be based on scientific evidence.

• The recommendations should preferably be developed in collaboration with (hospital) pharmacists and approved by relevant medical societies. Involvement of patient organisations in their development is advised.

• It is important that the recommendations are publicly accessible. Ideally, they should be published on the website of the relevant medical society.

• It must be explored how informed consent can be obtained. Written informational materials, such as a brochure, may be used for this purpose.

Where should we be heading?

A new European initiative, the Cancer Medicine Forum (CMF), has been established under the auspices of the EMA and EORTC to identify treatment optimisation questions and priorities and to facilitate addressing these priorities. Ideally, treatment optimisation and de-escalation strategies should be studied on a multinational, regional or even international level. Think of research questions such as: is it really necessary to give a year of adjuvant therapy or three years of maintenance therapy?

While it is often suggested that companies may raise the price of medicines to compensate for declining revenues resulting from de-escalation strategies, we must recognise that optimising treatment by itself alone can save time, toxicity and resources.

The initial approved dosage of a medicine is like the launch of a new smartphone model—effective but not yet optimized for every situation. Just as smartphones receive software updates to improve performance and fix issues, the dosing strategy may require adjustments to reduce side effects and streamline treatment for both patients and healthcare providers. Therefore, I hope that governments and healthcare funders support the CMF initiative to help our healthcare system become more resilient.