Complete response of merkel cell carcinoma with brain metastases to pembrolizumab and radiotherapy: A case report

Merkel cell carcinoma is a rare, but highly malignant and fast growing skin-cancer with high recurrence-rates, deriving from endothelial and neuroendocrine tissues. For advanced Merkel cell carcinoma prognosis is poor [1] and even under cytotoxic chemotherapy there is only a median progressionfree survival of only 3 months [2,3]. Even though Merkel cell carcinoma frequently shows lymphatic metastases, it almost never shows cerebral involvement [1]. To our knowledge there are only twelve reported cases of cerebral metastases. Furthermore this is the fi rst reported case of complete response in a patient with advanced Merkel cell carcinoma Stage IV with brain metastases under combined treatment with pembrolizumab and radiotherapy.


Introduction
Merkel cell carcinoma is a rare, but highly malignant and fast growing skin-cancer with high recurrence-rates, deriving from endothelial and neuroendocrine tissues. For advanced Merkel cell carcinoma prognosis is poor [1] and even under cytotoxic chemotherapy there is only a median progressionfree survival of only 3 months [2,3]. Even though Merkel cell carcinoma frequently shows lymphatic metastases, it almost never shows cerebral involvement [1]. To our knowledge there are only twelve reported cases of cerebral metastases. inactivates p53 and Rb [2]. Affected patients were found to produce MCPyV T-antigen-specifi c T cells and antibodies in relation to disease severity [4][5][6]. Virus-associated Merkel cell carcinoma showed signifi cant lower mutation rates than MCPyV-negative Merkel cell carcinoma [7]. The detected low mutational rate and the absence of typical driver mutations in the presented patient are in line with a MCPyV infection positive Merkel cell carcinoma. Positive expression of PD-L1 on tumor cells and PD-1 on tumor-infi ltrating lymphocytes suggests an endogenous tumor reactive immune response that might be unleashed by anti-PD-1 or anti-PD-L1 drugs [7][8][9]. Recently immunotherapy has been shown to be a highly effective and well tolerated treatment. A phase 2 -study with 26 patients with advanced Merkel cell carcinoma undergoing anti-PD1 treatment, showed a response rate of 56% [10]. Two clinical studies demonstrated a response rate as high or even higher as in melanoma [9,11]. Corresponding cases with advanced courses, especially with cerebral metastases, and therapeutic options have not been reported so far.

Case presentation
A 60-year-old man was referred to our outpatient clinic in After extra-cerebral complete response it was decided to  Figure 1B). Corresponding documentation of the upper body with huge dermal metastases, pre-treatment assessment ( Figure 1C). After initiation of pembrozulimab therapy the next follow up examination reveals at least partial response with remaining fi brotic tissue in place of the soft tissue metastases on the right cheek and nuchal as depicted by contrast enhanced whole body multi detector computed tomography (Figure 1d). The soft tissue component of the bone metastases located in the second left rib has completely disappeared and the bone texture transformed from lytic to sclerotic indicating healing of the bone after disappearance of the metastases ( Figure 1E). Documentation of the upper body with residual scars, post-treatment assessment ( Figure 1F). Six months later the patient developed severe autoimmune pneumonitis and increasing neurological defi cits. Cerebral MRI raised suspicion of carcinomatous meningitis which was confi rmed by cerebrospinal fl uid puncture. Within a few days the patient's condition deteriorated drastically and he died of respiratory insuffi ciency.

Discussion
Immune checkpoint inhibition is a promising new therapy for metastatic Merkelcell carcinoma, which has good response rates and an improved long-term response to therapy. In our case of a refractory Merkelcell carcinoma under chemotherapy, a complete response was achieved after switching to immune checkpoint inhibition. The novelty of the case presented here is due to several respects: it is one of the very few cases of Merkel cell carcinoma with cerebral metastases that regressed under therapy with checkpoint inhibition and whole brain radiotherapy and even showed complete response.
Possible mechanisms leading to treatment resistance in brain metastases could be hyperactivation of AKT (p-AKT) and loss of PTEN expression [15]. In our particular case, brain metastases derived from combined radiotherapy and continuing immunotherapy. Effectivness is as well described for brain metastases in advanced melanoma [16]. It was shown that radiotherapy has the ability to prime an endogenous antigenspecifi c immune response by increasing the percentage of antigen-experienced T cells and effector memory T cells in mouse model using the small animal radiation research platform [17].
Due to improved treatment options and prolonged survival, serial therapies are gaining importance. Whole exom sequencing could be recommended to evaluate further therapy options, even if in our case no therapeutic consequences resulted from the analysis.

Conclusion
The here presented case is of special interest since it impressively illustrates the possible therapeutic effects of combined treatment with check point inhibition and radiotherapy in advanced Merkel cell carcinoma with brain metastases.  Fig. 2A and B, arrows). After irradiation the cerebral metastases disappeared completely thus restoring a state of complete response ( Fig. 2 C and D). The differences in the MRI images are due to a slightly different tilt in the examination planning. reports grants from Novartis, grants from BMS Stiftung Immunonkologie, outside the submitted work. Dr. Eigentler reports personal fees from Bristol Myers Squibb, personal fees from Roche Pharma AG, personal fees from MSD, personal fees from Pierre Fabre, personal fees from LEO Pharma, personal fees from Sanofi /Regeneron, personal fees from Novartis, outside the submitted work. Dr. Lomberg has nothing to disclose. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi , outside the submitted work. Dr.
Leiter has nothing to disclose. The authors declare that there is no confl ict of interest regarding the publication of this article.
Ethical approval is not required at our institution to publish an anonymous case report. There were no grants supporting this work. Informed consent was obtained.