Overview

Rationale: The randomized trial NADINA has demonstrated that neoadjuvant treatment with nivolumab with ipilimumab improves event-free survival (EFS) in patients with macroscopic resectable stage III melanoma. In this study, therapeutic lymph node dissection (TLND) was standard of care, showing that patients achieving a major pathological response (MPR, i.e., ≤10% residual viable tumor bed) have an excellent outcome (EFS and Distant Metastasis Free Survival (DMFS)). The PRADO trial indicated that the MPR definition can also be revealed from a surrogate lymph node response, the index lymph node (ILN), allowing sparing the extensive surgery in MPR patients. In these MPR patients the DMFS was 100% after 1 year and 98% after 2 years, and recurrence-free survival (RFS) was 95% after 1 year and 93% after 2 years. Given that TLND is associated with morbidity and has a significant impact on health-related quality of life (HR-QoL) and healthcare costs, this study aims to prospectively investigate the safety of omitting TLND in patients who have an MPR within the ILN after neoadjuvant immunotherapy.

Objectives: To investigate whether TLND can be safely omitted in patients with macroscopic resectable stage III (B/C/D) melanoma achieving an MPR within the ILN upon neoadjuvant treatment with immune checkpoint inhibitors (ipilimumab and nivolumab).

Study design: This study is a prospective, single-arm phase 2 nationwide multicenter trial.

Study population:

Inclusion criteria for study participants are as follows:

• Patients must be eligible for neoadjuvant treatment
• Patients must have a histologically confirmed diagnosis of macroscopic resectable stage III melanoma (stage III B/C/D) with one or more macroscopic lymph node metastasis
• The patient must have a measurable tumor burden that qualifies (according to clinical practice) for neoadjuvant therapy

Intervention: Omitting TLND in patients who achieve an MPR in the ILN following neoadjuvant ipilimumab and nivolumab.

Main study endpoints: The two coprimary endpoints are 2-year Local Recurrence Free Survival (LRFS) and 2-year DMFS.

Eligibility

Inclusion Criteria:

• Patients must be eligible for neoadjuvant treatment (ipilimumab and nivolumab)
• Patients must be 16 years of age or older.
• Patients must have a histologically confirmed diagnosis of macroscopic resectable stage III melanoma (stage III B/C/D) with one or more macroscopic lymph node metastase defined as either one:
• a palpable node, confirmed as melanoma by pathology; a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology;
• a PET scan positive lymph node of any size confirmed as melanoma by pathology;
• The patient must have a measurable tumor burden that qualifies (according to clinical practice) for neoadjuvant therapy with immune checkpoint inhibitors
• Patients in whom ILN marking is feasible
• Written informed consent

Exclusion Criteria:

• Uveal/ocular or mucosal melanoma
• WHO performance status of two or more
• In-transit metastases only (without cytological or histological proven lymph node involvement)
• Prior targeted therapy targeting BRAF and/or MEK for melanoma
• Prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 for melanoma
• Patients with (history of) distant metastasis (stage IV melanoma)