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Therapeutic management of many cancers has been revolutionised by the development of immune checkpoint inhibitors (ICI) targeting antiprogrammed death 1 (PD-1)/ligand 1 (PDL1) and anticytotoxic T-lymphocyte antigen 4 leading to durable responses.1 ICIs however can induce several immune-related adverse events (irAE) including musculoskeletal irAEs.2 Among them, ICI-related myositis can be severe and sometimes life threatening.3 4 The current management includes permanent discontinuation of ICIs and steroid treatment. To date, very little is known about the risk of irAE recurrence in case of ICI rechallenge,5 6 especially in myositis for which no case of rechallenge has yet been reported. Through two cases, we report the safety of resuming anti-PD-1/PDL1 in patients who experienced severe ICI-related myositis.
An 87-year-old patient with metastatic Merkel cell carcinoma (MCC) received avelumab as first-line treatment. After three infusions, he developed slight head dropped syndrome with increased creatine kinase (CK) level up to 3.5 times the upper limit normal (ULN) range. Electromyography showed myogenic syndrome (left trapezius and right sternocleidomastoid muscles) and 18F-fluorodeoxyglucose-positron emission tomography revealed significant hypermetabolism of axial muscles (table 1). Myositis-specific autoantibodies were negative. Myocarditis was ruled out. At that time the radiologic evaluation showed a partial tumour response. Avelumab was stopped and the patient received prednisone (tapering from 0.5 mg/kg) during 6 weeks, which allowed myositis remission, but MCC recurred 7 months later. Avelumab was resumed and prednisone was preventively given during 3 months, starting at 20 mg/day. With a 9-month follow-up, no irAE, including myositis, occurred and MCC returned in partial response.
A 61-year-old patient with metastatic melanoma developed ptosis, diplopia, dysphagia and muscle weakness 3 weeks after first infusion of ipilimumab combined with nivolumab as first-line treatment. CK levels raised up to 40 ULN. Electromyography showed myogenic pattern of the trapezius, without decrement. Muscular biopsy with focal necrosis/regeneration lesions, HLA-1 and C5b9 positive sarcoplasmic staining of the suffering myofibres and T cell infiltrates confirmed the myositis. Neither myositis-specific nor myasthenia gravis autoantibodies were detected. ICIs were stopped and three pulses of methylprednisolone followed by tapering doses of prednisone were given leading to complete remission within 8 weeks. Because of the lack of efficacy of the single infusion of ICI combination followed by three infusions of dacarbazine, pembrolizumab was introduced 8 months after the myositis episode. The patient presented no irAEs or myositis (table 1) but died due to melanoma progression.
Despite the risk of recurrent irAEs, rechallenging ICIs after discontinuation due to previous irAEs remains critical, when considering their potential benefits in terms of survival.5 These two cases suggest that resuming ICIs can be safe in patients displaying persistent remission of ICI-related myositis.
Contributors JD and FBP analysed the data and drafted the manuscript for intellectual content. SLL, DA, MB and BB had a major role in the acquisition of data. CL and BH interpreted the data and revised the manuscript for intellectual content. All authors approved the submitted version of 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 BH, DA, JD, FBP, MB and SLL had nothing to declare. BB received payments for lectures/boards and travel accommodations from BMS and MSD. CL received research grants or honoraria from Roche, BMS, MSD, GSK, Novartis and Amgen.
Patient consent Obtained.
Ethics approval Local ethics committee.
Provenance and peer review Not commissioned; internally peer reviewed.
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