Hyperprogression of Merkel cell carcinoma after avelumab treatment

Dear Editor, Merkel cell carcinoma (MCC) is a rare but aggressive skin tumour with high rates of local recurrence. Up to 40% of patients also develop distant metastasis.1 The pathophysiology of MCC is well investigated. Contributing to MCC development are chronic UVexposure, old age, immunosuppression and the Merkel cell polyomavirus (MCPyV).2 MCC is considered an immunogenic tumour with high response rates to immunecheckpoint inhibition. To date, antibodies against the programmed death 1 receptor or its ligand (PD(L)1) are the gold standard for patients with advanced MCC.3 Antitumor activity is observed in up to 60% of patients. Particularly, treatment naïve patients typically respond well to checkpoint inhibition (CPI), with significant improvement of progressionfree and overall survival compared with patients receiving cytotoxic therapies.4 Despite these advances, primary and secondary resistance to CPI treatment remain clinical challenges. A rare form of primary resistance is hyperprogressive disease (HPD), in which patients not only fail CPI, but treatment appears to trigger rapid worsening of the disease. Hyperprogression has to be distinguished from pseudoprogression, where an initial increase in tumour size due to immunecellinflux mimics progressive disease. However, pseudoprogression is followed by a response to therapy.5 Little is known about immunologic and tumourcellintrinsic mechanisms underlying HPD. Thus far, it has been described in different tumour entities following CPI, including head and neck squamous cell carcinomas (HNSCC), nonsmall lung cell cancer (NSCLC) and metastatic melanoma.6 To our knowledge, this is the first reported case of MCC hyperprogression after PDL1 inhibition. In July 2021, an 80yearold man was diagnosed with a MCPyV negative MCC on the right cheek (pT2N0M0, 8th edition AJCC). The tumour was resected with a safety margin of 2 cm. Histology not only confirmed complete resection but also reported on perineural tumourcell invasion and lymphangiotropism. Two sentinel lymph nodes (mandibular region and parotid region) were tumour free. The patient received postoperative radiotherapy (48 Gy in 2 Gy fractions, 5 cm safety margin) at the tumour site. A routine PET/CT staging 3 months later was suspicious for a new regional cervical lymph node and one bone metastasis. Histology of the lymph node confirmed metastatic MCC. The patient was immediately treated with the PDL1 antibody avelumab at 800 mg IV q2w. Due to bone metastasis, he also received the RANKL antibody denosumab. Treatment was well tolerated. Four weeks into systemic treatment and just before his third treatment cycle, routinely performed blood testing showed a fourfold increase in GOT, and a slight increase in GPT. Analysis also revealed thrombocytopenia (48 G/L; reference value 150– 400 G/L) and a more than fivefold increase in creatinine kinase (CK). Myositis autoantibodies and screening Received: 28 September 2022 | Accepted: 16 January 2023