Melanoma, Skin
Conditions
Keywords
Neoadjuvant, Ipilimumab, Nivolumab, Immunotherapy, Index node, Therapeutic lymph node dissection, Omitting
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.
Interventions
PROCEDUREOmitting TLND
Omitting TLND in patients who achieve an MPR in the index node following neoadjuvant ipilimumab and nivolumab.
PROCEDUREIndex node procedure
Index node procedure
Sponsors
D.J. (Dirk) Grünhagen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Omitting TLND in patients who achieve an MPR in the ILN following neoadjuvant ipilimumab and nivolumab.
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
| 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 |
| 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. |
Countries
Netherlands
Contacts
Primary ContactDrik Grünhagen, MD, PhD
Outcome results
None listed