> ## Content Index > Fetch the complete content index at: https://www.theplasticsfella.com/llms.txt > Use this file to discover other available public pages before exploring further. # Oncological Adjuvant Trials in Melanoma - URL: https://www.theplasticsfella.com/oncological-adjuvant-trials-in-melanoma/ - Published: 2021-03-17T11:54:38.000Z - Updated: 2024-07-24T18:51:00.000Z - Description: Major adjuvant oncological trials in melanoma show a significant survival benefit in patients with completely resected stage III disease, as discussed here. - Author: PlasticsFella - Tags: Skin and Soft Tissue ## 5 Key Points > These major adjuvant oncological trials in melanoma, which were based on the previous AJCC 7th Edition for Staging Melanoma, showed a significant survival benefit in patients with completely resected stage III disease. This can be summarised in 5-Key Points. 1. **EORT 18,201** showed a significant survival benefit with adjuvant ipilimumab. 2. **CheckMate 238** showed a significant survival benefit of adjuvant nivolumab over ipilimumab. 3. **Combi-AD** showed a significant survival benefit of adjuvant dabrafenib + trametinib in BRAF+ disease. 4. **EORTC 1325/KeyNote 054** showed a significant survival benefit of adjuvant Pembrolizumab. 5. **BRIM-8​** showed a modest survival benefit of adjuvant vemurafenib in Stage 2C-3C disease. --- ## EORTC 18,701 > Eggermont et al​1​ phase 3 trial in 2016 showed significant survival benefit at 5-years for adjuvant ipilimumab (checkpoint inhibitor) in Stage 3A-3C disease. ### Background - A phase 3 study following up from the data of a phase 2 trial( ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram) - This phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. ### Methods - Patients had undergone complete resection of stage III cutaneous melanoma - Random assignment to ipilimumab (475 patients) or placebo (476) medication. - For up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. - Primary Endpoint: Recurrence-free survival. - Secondary Endpoints: overall survival, distant metastasis–free survival, and safety. ### Results - Median follow-up of 5.3 years, - **Recurrence-free survival**: Ipilimumab was 40.8%, placebo was 30.3%. - **Overall survival**: Ipilimumab was 65.4%, placebo was 54.4%. - **Rate of distant metastasis**: Ipilimumab was 48.3%, placebo was 38.9%. - 1.1% treatment related death in the Ipilimumab group. ### Conclusion Ipilimumab adjuvant therapy results in significantly higher rates of - Recurrence-free survival - Overall survival - Distant metastasis–free survival. There were more immune-related adverse events with ipilimumab than with placebo. --- ## CheckMate 238 > Webster et al​2​ in 2018 showed a significant relapse-free survival benefit of nivolumab over ipilimumab in resected Stage 3b-4 disease. ### Methods - Patients were ≥15 yrs with complete resection of stage IIIB/C or IV melanoma, - 906 patients were randomised to treat nivolumab over ipilimumab. - Primary endpoint was relapse free survival. ### Results - 24-month follow-up - **Relapse-Free Surviva**l: NIVO 171/453, IPI 221/453 - **Distant Metastasis-Free Survival**: NIVO 70.5% and IPI 63.7% ### Conclusion - NIVO demonstrated a sustained efficacy benefit vs IPI in pts with resected stage III/IV melanoma at high risk of recurrence, regardless of disease stage, PD-L1 expression, or **BRAF* mutation status. - Adjuvant Nivolumab is approved by the EMA and by NICE for patients with resected 3A-4 disease. --- ## Combi-AD > The Combi-AD study​3​ showed a 47% reduction in risk of developing metastasis, or death in the group treated with dabrafenib + trametinib. This was adjuvant treatment for BRAF positive resected 3A-3C disease. ### Background - Combination therapy with BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in advanced BRAF+ melanoma. - Aim is to determine if adjuvant dabrafenib+trametinib improve outcomes in resected, stage III BRAF+ melanoma ### Methods - Double-blind, placebo-controlled, phase 3 trial, - Patients had completely resected, stage III melanoma with BRAF V600E or V600K mutations. - Primary endpoint: relapse-free survival - Secondary endpoints: overall survival, distant metastasis–free survival, freedom from relapse, and safety. ### Results - Median follow-up of 2.8 years with 840 randomised patients. - 3-year relapse-free survival: 59% in combination therapy, 39% placebo - 3-year overall survival: 86% in combination therapy, 77% placebo. - Safety profile of dabrafenib plus trametinib was consistent with normal standards. ### Conclusion - Adjuvant use of dabrafenib + trametinib significantly lowers risk of recurrence in patients with stage III melanoma with **BRAF* V600E or V600K mutations. - It was not associated with new toxic effects --- ## EORTC 1325/KeyNote 054 > This study​4​ showed the role of Pembrolizumab (a PD-1 inhibitor) to increase relapse free survival in high-risk completely resected stage III melanoma patients. ### Background - Pembrolizumab (programmed death 1 (PD-1) inhibitor) prolongs progression-free and overall survival among patients with advanced melanoma. - Aim to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma in a phase 3 double-blind trial. ### Methods - Patients with completely resected stage III melanoma were randomly assigned to pembrolizumab (514 patients) or placebo (505 patients) - Primary endpoints: Recurrence-free survival ### Results - Median follow-up of 15 months, - Recurrence-free survival: Pembrolizumab 75.4%, placebo 61%. - 14.7% of the patients in the pembrolizumab group had adverse effects, with one treatment-related death due to myositis in the pembrolizumab group. ### Conclusion - As adjuvant therapy for high-risk stage III melanoma, pembrolizumab significantly increases recurrence-free survival than placebo, with no new toxic effects identified. --- ## Brim-8 Study > The BRIM8 study​5​ examined the role of the adjuvant vemurafenib in Stage 2C-3C disease. This showed a modest impact on RFS and is not being taken forward. ### Background - Hypothesis: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. - Aim: Evaluate adjuvant vemurafenib monotherapy in patients with resected, **BRAF* V600 mutation-positive melanoma. ### Methods - Phase 3, international, double-blind, randomised, placebo-controlled study - 498 adults with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) **BRAF* V600 mutation-positive melanoma that was fully resected. - Patients were randomly assigned to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). - Primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. ### Outcome - The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival must be considered exploratory only. - 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. --- ## References 1. 1\. Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. **N Engl J Med*. November 2016:1845-1855\. doi:[10.1056/nejmoa1611299](https://doi.org/10.1056/nejmoa1611299?ref=theplasticsfella.com) 2. 2\. Weber JS, Mandalà M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). **JCO*. May 2018:9502-9502\. doi:[10.1200/jco.2018.36.15\_suppl.9502](https://doi.org/10.1200/jco.2018.36.15%5Fsuppl.9502?ref=theplasticsfella.com) 3. 3\. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage IIIBRAF-Mutated Melanoma. **N Engl J Med*. November 2017:1813-1823\. doi:[10.1056/nejmoa1708539](https://doi.org/10.1056/nejmoa1708539?ref=theplasticsfella.com) 4. 4\. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. **N Engl J Med*. May 2018:1789-1801\. doi:[10.1056/nejmoa1802357](https://doi.org/10.1056/nejmoa1802357?ref=theplasticsfella.com) 5. 5\. Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected, BRAF V600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. **The Lancet Oncology*. April 2018:510-520\. doi:[10.1016/s1470-2045(18)30106-2](https://doi.org/10.1016/s1470-2045%2818%2930106-2?ref=theplasticsfella.com)