Immunometabolic predictive factors in Merkel cell carcinoma (MCC) patients treated with avelumab.

Abstract

e21525 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, associated with a worse prognosis. The link between MCC and immune suppression is well demonstrated. The population of patients with MCC is frequently elderly and frail, making it essential to determine whether the results of clinical trial can be replicated in a real-world setting. Despite the introduction of immune-checkpoint inhibitors (ICIs) has provided great benefit for some patients with advanced MCC (aMCC), it remains a subsets of patients who are refractory to ICIs or develop acquired resistance over time. Thus, there is a clinical need for predictive factors of ICI response. Methods: Twenty patients with aMCC treated with avelumab were included. The treatment was administered as I or II line. Clinical-pathological characteristics, Body Mass Index (BMI), and response to avelumab were analyzed from a MCC System database prospectively collected. An explorative analysis was performed, for available samples, to investigate: i) the plasma levels of soluble PD-1 (sPD-1), and PD-L1 (sPD-L1) collected at baseline, measured using homemade ELISA assays not yet commercially available, and designed according to investigator specifications; ii) IHC for PD-L1 in tumor samples; iii) the presence/absence/class (brisk vs no-brisk) of tumor-infiltrating lymphocytes (TILs) in tumor samples. The primary outcome investigated was the Time to Treatment Failure (TTF). Results: From February 2019 to January 2022, twenty (20) patients were included in the study. The median age was 74 (range 56-83); 10 patients were men (50%) and 10 were women (50%). Seventeen (17) patients (85%) were treated with avelumab as I line, and 3 patients (15%) as II line. The overall response rate was 65% (70.6% in I line patients). One (1) patient (5%) had a complete response (CR), 13 patients (65%) partial response (RP), 4 patients (20%) stable disease (SD), and 2 patients (10%) had a progression disease (PD). Overall median TTF was 22 months (95% confidence interval [CI]: -13.0-30.9). At the time of data analyses, a total of 9 events (progression or death) occurred (45%). Notably, a BMI ≥ 30 was significantly associated with longer TTF (p = 0.004) and objective response rate (p = 0.01). In the explorative biomarker analysis, preliminary data on 6 tumor and plasma samples, showed that plasma sPD-1 > 3.8 ng/ml, and the presence of PD-L1 and brisk TILs on tumor samples, were associated to longer TTF. Conclusions: These finding highlight the complex immune-metabolic interplay in the immunotherapy response. These data extends the previous finding on “obesity paradox” and the role of BMI as predictive factors of ICIs. The data on biomarker analysis warrants further prospective validation.

Identifying Candidates for Immunotherapy among Patients with Non-Melanoma Skin Cancer: A Review of the Potential Predictors of Response

“…In a very recent real-world study involving 20 patients with advanced MCC treated with avelumab, a body mass index (BMI) ≥ 30 was significantly associated with longer time to treatment failure ( p -value = 0.004) and objective RR ( p -value = 0.01). This finding extends the concept of the “obesity paradox” and the role of BMI as a predictive factor for ICIs therapy [ 106 ].…”

“…The results from SPEAR-Merkel, the first study to evaluate real-world clinical outcomes in 94 patients with la-MCC and m-MCC receiving first-line avelumab ( n = 28), non-avelumab immunotherapies ( n = 26, 19 pembrolizumab, 7 nivolumab), or chemotherapy ( n = 40), also highlight the therapeutic value of avelumab with an overall response rate of 64.3% and a median PFS of 11.4 months, compared to 61.5% with a median PFS of 8.1 months in the non-avelumab immunotherapy group and 42.5% with a median PFS of 6.1 months in patients undergoing chemotherapy [ 105 ]. In a similar real-world setting study involving a cohort of 20 patients with advanced MCC, comparable results were reported (overall RR: 65%; overall median time to treatment failure: 22 months) [ 106 ].…”

“…A similar result was found in patients with chemotherapy-refractory MCCs receiving avelumab (cohort A of JAVELIN Merkel 200 study) [ 20 , 103 ]. In addition, in a real-world study, preliminary data analysis on 6 tumoral and plasma samples suggested that serum soluble PD-1 > 3.8 ng/mL, and the presence of PD-L1 and brisk TILs on tumor samples, were associated with a longer time to treatment failure [ 106 ].…”

Tumor response assessment on imaging following immunotherapy

“…Future investigations for a better understanding of immunotherapy response should include imaging, clinical and biological features, e.g. patient BMI or baseline plasma levels for PD-1 and PD-L1 which were previously reported to be associated with time-to-treatment-failure in a recent study involving Merkel cell carcinoma patients treated with avelumab (anti-PD-L1) ( 110 ).…”

Immunosenescence and Skin: A State of Art of Its Etiopathogenetic Role and Crucial Watershed for Systemic Implications

“…Switching to another skin cancer, Merkel cell carcinoma (MCC) is a neuroendocrine cancer that predominantly affects older people with impaired immune status. Its main causative agent is Merkel cell polyomavirus (MCPyV) [89]. Mazziotta et al analyzed the sera of 226 elderly patients for anti-MCPyV IgGs.…”