Breaking avelumab resistance with combined ipilimumab and nivolumab in metastatic Merkel cell carcinoma?
Authors: V Glutsch, H Kneitz, M Goebeler, A Gesierich, B Schilling
Journal: Annals of Oncology (2019)

Immune-checkpoint blockade (ICB) shows significant activity in metastatic Merkel cell carcinoma (MCC) but primary resistance remains a major clinical challenge [1.Nghiem P.T. Bhatia S. Lipson E.J. et al.PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma.N Engl J Med. 2016; 374: 2542-2552Crossref PubMed Scopus (728) Google Scholar, 2.Kaufman H.L. Russell J. Hamid O. et al.Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 1374-1385Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar]. Here, we report a complete response to combined ipilimumab and nivolumab in a patient with metastatic MCC and primary resistance to the PD-L1 inhibitor avelumab. A 60-year-old male with a known history of stage III MCC (UICC 2017, Merkel cell poliomavirus positive; Figure 1A) relapsed with limited retroperitoneal lymph node metastases and was treated with avelumab (10 mg/kg, q2w). He, however, experienced progressive disease (PD, RECIST 1.1; Figure 1B) after 3 months of treatment. Four months after salvage surgery of the retroperitoneal tumor mass, a CT scan showed a relapse again. A new adrenal metastasis was then treated with palliative radiation therapy. Unfortunately, the patient was hospitalized 4 months later with a painful new lymph node metastasis in the left axilla. A CT scan of chest and abdomen revealed new soft tissue, peritoneal, perihepatic, interenteric and retrosternal metastases (Figure 1C). At this point, a grand round recommended off-label combined immunotherapy with ipilimumab and nivolumab according to the ongoing CheckMate-358 study (NCT02488759). The patient received four applications of a combined immunotherapy (ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, q3w). Apart from grade 1 fatigue (CTCAE 4.03) the patient did not experience any toxicity. A CT scan of chest and abdomen 4 weeks after the last dose of ipilimumab and nivolumab showed a complete remission (CR, RECIST 1.1; Figure 1C) without any signs of residual disease. Due to the complete response and the lack of clinical data for the treatment of MCC with combined immunotherapy we refrained from a maintenance monotherapy with nivolumab recommended in metastatic melanoma [3.Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (4165) Google Scholar]. In patients with disseminated MCC refractory to PDL-1 blockade with avelumab, systemic treatment options are limited to chemotherapy known to induce only short-lived responses [4.Nghiem P. Kaufman H.L. Bharmal M. et al.Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.Future Oncol. 2017; 13: 1263-1279Crossref PubMed Scopus (71) Google Scholar]. Although we cannot provide data on the durability of the response observed, combined ipilimumab/nivolumab might be considered as a treatment of metastatic MCC showing primary resistance to avelumab. We think that this initial observation warrants further investigations to unravel the underlying mechanisms and its clinical significance in the treatment of metastatic MCC. None declared.