Effectiveness and cost-effectiveness of combination therapy versus monotherapy in malignant melanoma

Özdemir and Büssgen Journal of Pharmaceutical Policy and Practice https://doi.org/10.1186/s40545-023-00611-7 (2023) 16:106 Journal of Pharmaceutical Policy and Practice Open Access REVIEW Effectiveness and cost‑effectiveness of combination therapy versus monotherapy in malignant melanoma Dilay Özdemir1 and Melanie Büssgen2*    Abstract Background Until 2010, stage III or IV malignant melanoma (MM) had a poor prognosis. The discovery of immune checkpoint inhibitors (ICIs) in 2011 changed the treatment landscape. Promising results in patient survival with a checkpoint inhibitor prompted research into combination therapies. In 2016, the first combination therapy has been approved as first-line therapy for advanced MM. Objective The aim of this work is to investigate to what extent combination therapy is (cost-)effective compared to monotherapy in stage III or IV MM. Methods A systematic literature search was performed (Web of Science, PubMed, PubPharm, EconLit, and Cochrane Library); searching for publications published over the past decade that examine the cost-effectiveness in terms of cost/QALY and the effectiveness in terms of survival and response of combination therapy in comparison to monotherapy in stage III or IV MM patients. Results A total of 11 randomized controlled trials (RCTs) and five cost–utility analyses met our inclusion criteria. Nine clinical trials demonstrated superiority of combination therapy over monotherapy. The combination of B-rapidly accelerated fibrosarcoma (BRAF) protein and mitogen-activated kinase (MEK) protein inhibitors is not cost-effective in any country. Three analyses demonstrate the cost-effectiveness of combination therapy with ICI compared to monotherapy. Conclusion Combination therapy is more effective compared to monotherapy. While combined ICIs are cost-effective compared to monotherapy, this is not the case for the combination of BRAF and MEK inhibitors. Keywords Cost-effectiveness, Effectiveness, Melanoma, Malignant melanoma, Oncology, Immune checkpoint inhibitors, BRAF inhibitor, MEK inhibitor, Targeted therapy, Combination therapy *Correspondence: Melanie Büssgen 1 University of Hamburg, Hamburg, Germany 2 Hamburg Center for Health Economics, University of Hamburg, Hamburg, Germany Introduction Skin cancer is the 17th most common cancer worldwide [1] with an incidence of approximately 325,000 [2]. Malignant melanoma—which is a type of skin cancer that develops from the pigment-producing cells known as melanocytes—is among the most aggressive skin cancers and causes more than 90% of all skin cancer deaths in Germany [3]. The incidence is increasing yearly across the world [4]. Whereas early-stage MM is curable, metastatic melanomas are difficult to treat. The 5-year survival © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Özdemir and Büssgen Journal of Pharmaceutical Policy and Practice rate for a MM that has spread to nearby lymph nodes is 62% [5, 6] and for MM that has spread to distant lymph nodes or other areas of the body ranges from 10 to 25% [7]. Adjuvant treatment of stage III or IV MM was limited to chemotherapy until 2010. The discovery of ICIs revolutionized the therapeutic landscape. The introduction of ipilimumab (IPI) (CTLA-4-inhibitor), the first checkpoint inhibitor approved by the FDA in 2011, demonstrated an increase in overall survival (OS) compared to chemotherapy. While the OS rate at 24 months with IPI was 23.5%, it was 13.7% with chemotherapy [8]. This breakthrough innovation was also approved in Europe in 2011 [9]. The discovery of the immune checkpoint PD-1 as another therapy-relevant target has led to the development of several PD-1 antibodies. In June 2015, the first anti-PD-1 antibody nivolumab (NIVO) was approved in Europe [10]. In the same year, the European Medicines Agency (EMA) granted approval for the second PD-1 antibody pembrolizumab (PEM) [9]. In recent years, the number of combination therapies available on the drug market has risen rapidly. Combination therapies are drugs that contain more than one active ingredient. The fixed combination of two substances in one drug is intended to simplify administration for patients and lead to an increase in adherence to therapy. Compared with monotherapy, this is expected to result in better efficacy and thus lower costs. A combination therapy of NIVO plus IPI, resulted for the first time in improved effectiveness compared to monotherapy with IPI [11]. The study results led to its approval as first-line therapy in patients with advanced melanoma in Europe in 2016 [12]. Furthermore, the discovery of the BRAF mutation in melanoma led to the approval of the BRAF inhibitors vemurafenib (VEM) in 2011 and dabrafenib (DAB) in 2013, after which the MEK inhibitors cobimetinib (COB) and trametinib (TRAM) were approved for combination therapy with BRAF inhibitors [7]. DAB plus TRAM showed an improvement in OS compared to DAB and VEM [13, 14]. Thus, DAB plus TRAM, the first targeted combination therapy for adults with advanced melanoma with BRAF mutation, was approved in Europe in 2015 [15]. To date, the costeffectiveness of these combination therapies compared to monotherapy remains open. However, the long-term potential of combination therapy remains controversial: For example, the fixed combinations limit individual adjustment of the dose regimen, which can lead to a reduction in efficacy. In addition, current knowledge about the safety of combination drugs is not comprehensive. Accordingly, the long-term effect of combination drugs compared to monotherapy on the health care systems remains controversial. Despite (2023) 16:106 Page 2 of 15 the approval of combination therapies, clinical data are not yet fully mature to assess long-term effectiveness. In addition, combination therapy is associated with additional costs. Given the attention devoted to pharmaceutical costs being at an all-time high, the issue of cost-effectiv (...truncated)