Intratumoral CD16+ macrophages are associated with clinical outcomes of patients with metastatic melanoma treated with combination anti-PD-1 and anti-CTLA-4 therapy.
Abstract Purpose: This study characterizes intratumoural macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16) expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex immunohistochemistry in relation to treatment outcomes. Results: Patients who responded to combination ICI contained higher CD16+ macrophage densities than those who did not respond (196 vs 7 cells/mm2; p [...]
Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.
Abstract Background: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma [...]
IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.
Abstract Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor–based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and [...]
Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.
Abstract Background: Metastatic Merkel cell carcinoma (mMCC) is highly responsive to immune checkpoint inhibitors (ICIs); however, durability of response after treatment cessation and response to retreatment in the setting of progression is unknown. Methods: Patients (pts) having mMCC from 10 centres who discontinued ICI treatment for a reason other than progression were studied. Results: Forty patients were included. Median time on treatment was 13.5 months (range 1-35). Thirty-one patients (77.5%) stopped treatment electively while 9 patients (22.5%) stopped due to treatment-related toxicity. After median of 12.3 months from discontinuation, 14 pts (35%) have progressed (PD). Disease progression rate following [...]
Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.
Abstract Background Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. Patients and methods In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), [...]
Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma
Abstract Background The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised. Methods We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age [...]
BRAF inhibitor cessation prior to disease progression in metastatic melanoma: long term outcomes.
Abstract Background: BRAF mutant melanoma treated with BRAF+/-MEK inhibitor (targeted therapy) has a high response rate, however most patients progress (PD). Some patients have durable response, but it is unknown if treatment can be discontinued in these patients. We describe the recurrence risk, progression patterns, response to subsequent treatment, and survival of patients with advanced melanoma who ceased targeted therapy prior to PD. Patients and Methods: Ninety-four patients who ceased targeted therapy without progression were identified retrospectively from 11 centres: 45 were male; 81 V600E; 88 stage IV. Fifty-nine were treated with BRAF+MEK inhibitor, 35 BRAF inhibitor alone. Median [...]
Phase 1b Study of Cobimetinib Plus Atezolizumab in Patients with Advanced BRAFV600 Wild-Type Melanoma Progressing on Prior Anti–Programmed Death-1 Therapy.
Abstract Objective: To evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒programmed death-1 (PD-1) therapy. Patients and Methods: This phase 1b, open-label, global, multicenter study enrolled 3 cohorts. Herein we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Cohort A patients received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Cohort B patients received the same dosing regimen as cohort A except [...]
Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study.
Abstract Purpose: To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma. Patients and methods: This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated. Results: A total of 697 patients were [...]
Obesity is associated with altered tumor metabolism in metastatic melanoma.
Abstract Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 [...]