Independent dosing trials need to be established: Less can be more

In a Letter to the Editor published in the September edition of Leukemia, Thilo Zander from the Department of Oncology, Luzerner Kantonsspital, Lucerne, Switzerland, raises the important issue of drug dosing and cost effectivity. Zander uses pomalidomide, an established immunomodulatory drug (IMiD) indicated to treat Multiple Myeloma (MM) as an example, and highlights the fact that many preliminary phase I trials, conducted by drug companies, do not adequately perform test dosing in order to establish watertight schedules based on the pharmacodynamics of individual drugs. This issue is closely linked to the spiraling cost of cancer treatment, as many triplet, and even quadruplet, drug regimens are established using backbone regimens with higher than necessary doses. With a growing worldwide population, solutions need to be found in order to keep costs down so that effective treatments are available to all. 

The following key points were raised:

• Early pomalidomide trials established 4 mg daily (on a day 21/28 schedule) as the Maximum Tolerated Dose (MTD)
• This high dose has been linked with severe adverse effects (AEs), leading to dose reductions
• Several studies have indicated that a dose of 2 mg daily may be equally effective
• Pricing of pomalidomide is such that 1 mg = 2 mg = 3 mg = 4 mg, so simply lowering the daily dose will not affect the overall cost
• Pomalidomide has a longer than average half-life for IMiDs (7.5 hrs) and is an ideal candidate for alternate-day dosing
• Several independent studies have used different dosing schedules of pomalidomide with good results: 5 mg on alternate days and 2 mg daily
• Treatment with 4 mg daily and 2 mg daily appear to be equally effective, with 2 mg daily more tolerable in terms of AEs
• Pomalidomide, often along with dexamethasone, currently serves as a backbone regimen for many novel agents, such as monoclonal antibodies, therefore the lowest possible MTD is necessary to limit AEs

Zander concludes his article by stating that the optimum pomalidomide dosing schedule remains unclear but that there is sufficient evidence to suggest alternate dosing would be equally effective clinically, whilst clearly more cost-effective. Zander explains that it is only through independent trials financed by academia and non-commercial institutions, that clinicians can start to build a picture regarding the true efficacy of lower and/or alternate dosing, to ensure that patients are best served. Finally, he invites physicians that may be persuaded to try lower/alternate dosing for pomalidomide to collaborate, so that real-life data can be collated.  

The points raised in this communication were picked up by Philippe Moreau, who published a Perspective in the same edition of Leukemia. Moreau states, “This paper is of utmost importance since it points out several ongoing issues of drug development in MM.” He seconds Zander’s criticism of phase I dosing trials, explaining how data for pomalidomide is based on very small numbers, with insufficient dosing ranges. The same is true for carfilzomib, for which optimal dosing is not clearly established and is used at doses ranging from 27 to 70 mg/m², on either a weekly or bi-weekly schedule. Both panobinostat and ixazomib are also examples for which the MTD was established using a small number of patients - 17 and 15 patients, respectively. Moreau highlights the importance of taking into account both pharmacokinetics and pharmacodynamics, as well as safety and efficacy, when establishing the optimal MTD, in particular for targeted drugs where dose may not have a linear relationship with efficacy and toxicity. Moreau explains how the International Myeloma Working Group (IMWG) is committed to establishing cost-effective treatment pathways that can be adapted for routine practice, and in agreement with Zander, suggests that cleverly designed, independently-led, phase 3 trials should be the platform on which this takes place. Other challenges in order to deliver cost effective treatments include the development of biomarkers to select patients that will benefit sufficiently from a given treatment, as well as defining optimal drug partners. For example, pomalidomide-dex plus carfilzomib, bortezomib, oral cyclophosphamide, or even daratumumab, are all combinations that have been trailed in patients with relapsed disease, but valid cross-comparisons of the triplet regimens are lacking.

Conclusion

This discussion is extremely valid, as it illustrates how the race for new treatments can often run away with itself, and places a responsibility on academic and independently led institutions to test more comprehensively for MTDs before moving forward with clinical development. In addition, it highlights the need for the regulatory agencies themselves to demand both a greater number of patients and wider dosing ranges, in early testing. Only this way will the latest advances in cancer treatments remain available to all.