Omitting Therapeutic Lymph Node Dissection in Patients with Melanoma (stage 3) and Major Pathological Response in the Index Lymph Node

Not Applicable

Not yet recruiting

• Conditions: Melanoma, Skin

• Registration Number: NCT06754904
• Lead Sponsor: D.J. (Dirk) Grünhagen

Brief 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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-13
• Study First Submitted QC: 2024-12-23
• Last Update Submitted: 2024-12-23
• Study First Posted: 2025-01-01
• Last Update Posted: 2025-01-01
• Study Start: 2025-04-01
• Primary Completion: 2027-04-01
• Study Completion: 2032-04-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 213

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Local Recurrence Free Survival (LRFS)	2 years after inclusion	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)	2 years after inclusion	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

Secondary Outcome Measures

Name	Time	Method
Evaluation of health-related quality of life (HRQoL), EORTC QLQ C30	3 years after inclusion	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	3 years after inclusion	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	1 year after inclusion	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	2 year after inclusion	Description of the incidence and severity of post-surgical complications according to CTCAE v5
Evaluation of the surgical morbidity, Clavien Dindo	2 year after inclusion	Description of the incidence and severity of post-surgical complications according to Clavien Dindo
Radiological evaluation of the index lymph node	1 year after inclusion	Calculate Concordance rates between radiological and pathological response (pCR, pPR, pNR) in the ILN
Proportion of patients undergoing therapeutic lymph node dissection (TLND)	5 years after inclusion	Description of the proportion of patients undergoing TLND stratified by MPR and non-MPR status
Melanoma specific survival	5 years after inclusion	Description of the Melanoma specific survival, as calculated time from the date of start of neoadjuvant therapy to the date of death due to melanoma
Overall survival	5 years after inclusion	Description of the overall survival, as calculated time from the date of start of neoadjuvant therapy to the date of death due to melanoma or any cause