MelPRO-0322 (CRISTINA Trial) [miCrobiome pRedIctS aPD1 effecTivnes In melaNoma pAtietns]

Neoadjuvant Monotherapy With Anti-PD1 Agents in Patients With Resectable Stage IIIB-D Melanoma: Analysis of Novel Biomarkers

The goal of this observational study is to learn about if new biomarkers such as gut microbiota and molecular genetics melanoma features could predict clinical radiological and pathological response to neoadjuvant monotherapy with anti-PD1 agents in patients with resectable stage IIIB-D melanoma. The main questions it aims to answer are:

• radiological and pathological response rate to three doses of antiPD1 agents;
• do radiological and pathological responses correlate with gut microbiota and melanoma molecular genetics features Participants will receive three doses of aPD1 monotherapy as per center routine practice and will undergo regional lymphadenectomy. Before treatment initiation patients will be asked to bring faeces probes and fill out dietary questionnaire as well as just before the surgery.

After sugery adjuvant therapy will be prescribed for 12 month and patients will be followed up according to institutional routine practice for 5 years.

The clinical efficacy of PD1 inhibitors on the 2-year recurrence-free survival of patients with resectable stage III B-D melanoma will be assessed. This indicator will be compared with a historical control group using adjuvant PD1 immunotherapy and targeted therapy. Various factors will be analyzed for their potential impact on immunotherapy effectiveness, including demographics, disease stage and sub-stage, molecular-genetic status of the tumor, composition of the tumor's lymphoid infiltrate, LDH levels, gut microbiome composition, radiological and pathological response to treatment, and the development of immune-mediated adverse events. These findings may help optimize treatment by implementing neoadjuvant therapy for stage III B-D cutaneous melanoma.

Inclusion Criteria:

• Patients aged 18 years and older.
• Performance status according to the Eastern Cooperative Oncology Group (ECOG) of 0-1.
• Patients who have not previously received immunotherapy with anti-PD1, anti-PDL1, or anti-CTLA4 agents.
• Clinical stage III (B-D), i.e., with clinically or radiologically determined metastatic changes in lymph nodes.
• Histologically confirmed involvement of regional lymph nodes.
• Lesions assessable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Exclusion Criteria:

• Patients with melanoma of non-skin localizations.
• Patients with active autoimmune diseases.
• Patients with active infectious diseases.
• Patients with severe concomitant diseases with an ECOG status >1.
• Pregnant or lactating patients.
• Patients requiring the intake of glucocorticoids at a dose greater than 10 mg of prednisone (or equivalent) per day.
• Patients requiring the use of, or having received, systemic antibiotics within 4 weeks prior to the start of the study.