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Immune checkpoint inhibitors (ICI) represent an exciting new standard of care in selected advanced cancers and are being actively investigated in others. Unfortunately, only a subset of patients benefit from ICI and the current challenge is to transform the majority of non-responders to responders.3 This will likely be improved by combining ICI with other treatment strategies such as small molecules.
Two MEK inhibitors, trametinib and cobimetinib, are already used in the clinical setting, combined with BRAF inhibitors.4 Toxicity (mainly rash, peripheral oedema, cardiac and ocular complications) is one of the obstacles for the development of MEK inhibitors as single agent in patients with cancer but the dual inhibition of MEK and BRAF minimises toxicity. Initial attempts of combining vemurafenib or dabrafenib (anti-BRAF) plus cobimetinib or trametinib (anti-MEK) with ipilimumab (anti CTLA-4) failed due to toxicity. Combination or sequential therapy with anti-PD-(L)1 agents represents a more promising approach and several clinical trials are ongoing (ie, NCT03178851; NCT02908672; NCT02130466; NCT03201458). Therefore, the number of patients exposed to both MEK and PD-(L)1 inhibitors is likely to increase and we are looking forward to see whether more observations of ICI-induced polymyalgia rheumatica (PMR) improved by MEK inhibitors will be reported in the future.
Considering MEK inhibitors as a promising steroid-sparing agent for PMR is a bit provocative, however behind every success story is a first enthusiastic clinical observation and the authors provided solid underlying pathogenesis. Furthermore, there will be always concern of using an anticancer therapy for a non-cancerous disease but one good example comes from methotrexate, as illustrated with the historical perspective of this drug by Weinblatt.5 While the rheumatology community was first reluctant, it has now become the standard of care therapy in patients with rheumatoid arthritis. The observation reported by Chan and Bass suggests that, in ICI-induced PMR, MEK inhibitors could both reinforce the antitumour treatment and control the irAE. As oncologists have wondered whether immunosuppressive therapies given to treat irAEs may reduce the antitumour efficacy of ICI, MEK inhibitors could offer an attractive therapeutic option for such adverse events. On the other hand, this particular situation should be a first step indicating that MEK inhibitors might also represent a possible alternative in case of corticoresistant or corticodependent PMR. Let us see whether or not MEK inhibitors will also become part of our therapeutic arsenal in rheumatology.
Handling editor Josef S Smolen
Contributor FHU-ACRONIM: AQUITAINE’S CARE AND RESEARCH ORGANISATION FOR INFLAMMATORY AND IMMUNE-MEDIATED DISEASES
Contributors MK drafted the manuscript. LD and TS critically reviewed and approved the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.