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Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking.
Methods
At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated.
Results
Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy.
Conclusion
In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
Background
Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment.
Methods
To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT).
Results
SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%).
Conclusion
SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.