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.
Patients must be eligible for neoadjuvant treatment (ipilimumab and nivolumab)
Patients must be 16 years of age or older.
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;
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
Single group
Omitting TLND
Procedure/SurgeryOmitting TLND in patients who achieve an MPR in the index node following neoadjuvant ipilimumab and nivolumab.
Index node procedure
Procedure/SurgeryIndex node procedure
Local Recurrence Free Survival (LRFS)
LRFS, as defined as time from removal of the index lymph node (ILN) until local (in basin) recurrence in the MPR group. Accepting a local relapse of 20%.
Distant Metastasis Free Survival (DMFS)
DMFS assessed in the MPR group, as defined as time from the start of neoadjuvant immunotherapy, nivolumab with ipilimumab, until the first occurrence of distant metastasis. Accepting DMFS 3% lower than the 2 years DMFS of the NADINA trial
Evaluation of health-related quality of life (HRQoL), EORTC QLQ C30
Description of the changes in HR-QoL scores from baseline to follow-up visits, measured by validated questionnaires using EORTC Quality of Life Questionnaire-core 30 (EORTC QLQ C30). The EORTC QLQ C30 is scored on 4 point Likert-scales: "Not at all", "A little", "Quite a bit", and "Very much."
Evaluation of health-related quality of life (HRQoL), FACT-M
Description of the changes in HR-QoL scores from baseline to follow-up visits, measured by validated questionnaires using Melanoma Surgery Specific subscale of the FACT-M. The FACT-M is scored on a 5 point Likert-scale: "Not at all", "A little bit", "Somewhat", "Quite a bit", and "Very much."
Description of the pathological response rates in the ILN
The pathologic response rate is categorized into pathologic complete response (pCR), near-pCR, major pathologic response (MPR), pathologic partial response (pPR), pathologic no response (pNR), according to International Neoadjuvant Melanoma Consortium (INMC) criteria.
Evaluation of the surgical morbidity, CTCAE v5
Description of the incidence and severity of post-surgical complications according to CTCAE v5
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D.J. (Dirk) Grünhagen
Lead sponsor
Erasmus Medical Center
Sponsor institution
