omitting therapeutic lymph node dissection in patients with melanoma (stage 3) and major pathological response in the index lymph node

Conditions: Melanoma, Skin

Summary: 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 criteria:
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)

Keywords: neoadjuvant ipilimumab nivolumab immunotherapy index node therapeutic lymph node dissection omitting