Elucidating value: the role of cost-effectiveness analysis in the decision-making process for the management of BRAF V600E/K mutation-positive melanoma

Introduction

In 1970, the prolific Greek poet Alkis Alkaios indited his famous poem “Malignant Melanoma” as a requiem for one of his late friends. Alluding to the deadly course of the disease, its unknown aetiology and rapid progression, the term of malignant melanoma in the poem embodied a swift and terminal event, which abruptly disrupted life and culminated to the utter loss. The term of malignant melanoma also portrayed, in a philosophical albeit bleak manner, the lack of any potent treatment modalities for the management of this fatal disease.

From 1970 to 2000, the dry spell in the therapeutic management of malignant melanoma was interrupted only a handful of times: in 1975, dacarbazine was launched, followed by high-dose interferon alpha-2b, as an adjuvant treatment in 1995, and ultimately the high-dose interleukin-2, as palliative care, in 1998. The armamentarium of malignant melanoma was only recently bolstered by the entry of immunotherapy, along with the introduction of targeted therapies. This has revamped the landscape of malignant melanoma management, which is depicted in the survival rates of the disease¹. In early 2000s, a new era in the management of malignant melanoma began to unfold, as the role of BRAF V600 mutation in the disease was brought to light. Approximately, 50% of melanoma patients have tumours that harbour BRAF V600 mutations, an attribute which underpins its profound importance in disease management.

Dabrafenib (Tafinlar^®, Novartis) and Trametinib (Mekinist^®, Novartis) are small-molecule targeted inhibitors of BRAF and MEK kinase, respectively^2–3. The COMBI-AD trial reported an overall survival (OS) of 86% in the dabrafenib and trametinib arm compared to 77% in the placebo group (HR0.57:95%CI:0.42–0.79)⁴. These results granted a regulatory approval for the combination of dabrafenib and trametinib as an adjuvant treatment of patients with stage IIIA-IIIC melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. ESMO recommends the combination of BRAF and MEK inhibitors in patients presenting with symptomatic, bulky metastases from a BRAF-V600-mutated melanoma, as first and second treatment⁵. Patients are anticipated to experience a rapid response and improvement in quality of life. Nevertheless, no robust recommendations, pertaining to the sequence of checkpoint inhibitors and kinase-inhibitors combinations in patients with BRAF mutant metastatic melanoma, apply.

While the concerns regarding the effectiveness and safety of these new agents were appeased by the two trials, the optimism that embraces the array of new products, is compounded by their soaring costs. The relentless price increase of new agents comprises a stress test for health systems worldwide. This phenomenon is further exacerbated in the oncology sector, since the confluence of lack of potential treatments, the fictional monopoly stemming out of the guidelines' fragmentation, coupled with the fear of death and the grave psychological effect on patients, nullify market interventions⁶. To this direction, the assessment of the cost-effectiveness profile of the two agents is imperative for payers, to proceed with informed, value-based, decision-making, provide timely-access especially for rapid-progressing diseases, while safeguarding the long-term funding structure of the health systems.

A cost-effectiveness analysis assesses whether the incremental cost for a new intervention aligns with the additional incremental benefit and is perceived to be the holy-grail in the decision-making context. In this perspective, an economic analysis is a means rather than a target and as such, it should abide by some fundamental rules, in order to forestall bias that are nested in its intricate and multidimensional structure. Since a significant part of the cost-effectiveness analysis is founded on hypothesis and data extrapolation, the quality should be on the spotlight, in order not to deprive patients from potentially effective treatments, due to flaws and bias.

In a study published in the Journal of Medical Economics, Gerbasi et al fathom the cost-effectiveness profile of dabrafenib with trametinib as an adjuvant treatment of melanoma⁷. They constructed a non-homogenous semi-Markov cohort model which consists of five discrete health states: (1) Relapse-free survival (RFS) state; (2) post locoregional recurrence (LR) state; (3) post distant recurrence (DR) first-line treatment (1 L DR) state; (4) post DR second-line treatment (2 L DR) state; and (5) dead state. The efficacy data and health utilities were mined from the COMBI AD trial. The costs were mined from a USA payer perspective. Delea et al construed that patients on dabrafenib and trametinib experience 2.34 more total LYs and 2.15 additional QALYs (both discounted) compared with patients on best supportive care (BSC). This effect was in principal attributed to an increase of QALY reported in patients at the RFS. The cost of the combination exceeded the corresponding cost of the BSC by $74,518. As expected, the increase in costs occurred in the RFS, in line with the increased utilities. These perpetuate to an incremental cost-effectiveness ratio (ICER) for dabrafenib and trametinib versus observation, of $34,689 per QALY gained, which is rendered as a favourable cost-effectiveness ratio. The reported ICER was primarily sensitive to medication costs, the hazard rate for first-line progression-free survival and follow-up and monitoring costs. The reduction of the time horizon, exerted a negative effect on the ICER, while the use of log-logistic restricted cure distribution for the RFS, would render ICER well above the acceptability level, at $136,308. On the contrary, the use of a gamma unrestricted cure distribution would demonstrate a beneficial effect on ICER, trimming it down to $12,458.

This is the first study to assess the cost-effectiveness of the combination of dabrafenib and trametinib vs BSC. Dabrafenib was the scope of two economic evaluations, albeit in a deviating background. A study in Switzerland elucidated the efficiency parameters of the combination therapy of trametinib plus dabrafenib compared to vemurafenib. They deduced that trametinib plus dabrafenib yielded an ICER of CHF 385,603 per QALY, which extends well beyond the acceptability level in Switzerland. Nevertheless, this study utilised US market prices⁸.

A second study evaluated the cost effectiveness of dabrafenib versus dacarbazine and vemurafenib as first-line treatments in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a Canadian healthcare system perspective. They reported that dabrafenib is superior to dacarbazine, albeit the marginal cost extends above the acceptability curve, thus comprising dabrafenib a non-cost-effective modality compared to dacarbazine, while no explicit results could be reached contingent to comparison with vemurafenib⁹.

Conclusion

This paper underpins the importance of properly performed economic evaluations, which can compound uncertainty and may extenuate irrational decision making by streamlining the decision-making process with the broader financial context of the country through the utilization of the willingness to pay threshold. In this manner, this is the first study to explore and also corroborate the establishment of the combination as a cost-effective therapy for melanoma. Τhe health policy context can be endowed with these findings, while this result is further bolstered by the high quality of this work. Nevertheless, the extrapolation in other health care settings should be performed with caution due to disparities in drug prices, as attested by the results of the sensitivity analysis. Moreover, and in light of the engulfed uncertainty of the melanoma area, more economic evaluations are imperative in other countries as well, to crystallise costs and benefit, especially in an era blatantly hallmarked by a meteoric ascent of pharmaceutical expenditure. Finally, the bandwidth of available managed entry agreements (MEA) could help compound uncertainty for payers, which primarily stems out of price and hazard of progression. MEA can serve twofold by safeguarding timely access of patients to the necessary treatment modality.

P. Petrou
School of Sciences and Engineering, Pharmacy School, Pharmacoepidemiology-Pharmacovigilance,
University of Nicosia, Nicosia, Cyprus
[email protected]; [email protected]

Transparency

Declaration of funding

This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer.

Declaration of financial/other relationships

The author and peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

None.