72MO Concurrent BRAF targeted therapy (TT) with dabrafenib and trametinib and anti-PD-1 agent pembrolizumab (PD1) increased B cell signalling and inflammatory pathways more effectively than when given sequentially or with anti-PD-1 alone
Background Long duration TT prior to immunotherapy(IO) is inferior to IO upfront for patients with advanced BRAFV600 mutant melanoma while short duration TT continues to be investigated. The previously presented results of the neoadjuvant(NA) NeoTrio clinical trial (NCT02858921) demonstrated concurrent TT with PD1 yielded the highest pathologic response rates compared to 1 week of TT followed by PD1 or PD1 alone, although durability of pathological response was better with PD1 alone. We sought to characterise longitudinal changes to the tumour microenvironment induced by treatment. Methods In NeoTrio, 60 patients with BRAFV600 mutant stage IIIB/C/D melanoma were randomised to 6 weeks of [...]
The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort
Abstract Background: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. Methods: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. Results: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of [...]
Predicting sentinel node positivity in patients with primary cutaneous melanoma: an international multicentre study validating and refining the MIA risk calculator
Background: The Melanoma Institute Australia (MIA) sentinel node (SN) metastasis risk-prediction online calculator[Lo2020] is now widely used around the world. The tool comprises eight models that variously use between three and six input parameters. However, the full (six-parameter) model has only been validated in the US population, the model with missing mitoses was validated for the Dutch and Swedish populations. Furthermore, some confidence intervals (CIs) of the tool are large due to uncommon input parameter values. This study further validated the tool in other populations and improved the precision of the risk estimates. Methods: Validation data were pooled from the Danish [...]
Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial.
Abstract Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAFV600-mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome [...]
Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.
Abstract Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy. Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival. Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% [...]
Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas
Abstract Background: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA. Methods: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively. Results: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group [...]
The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort
Abstract Background: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. Methods: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. Results: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of [...]
Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma
Abstract Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. Patients and methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), [...]
Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator
Abstract Purpose: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. Methods: Data were extracted [...]
ASO Author Reflections: Lymphoedema Related to Inguinal and Ilioinguinal Lymphadenectomy for Melanoma.
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