Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases.
Abstract Purpose: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). Patients and Methods: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial [...]
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), [...]
Genomic profiling of metastatic basal cell carcinoma reveals candidate drivers of disease and therapeutic targets.
Abstract Basal cell carcinomas (BCCs) are human beings’ most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal [...]
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 [...]
Clinical features associated with outcomes and biomarker analysis of dabrafenib plus trametinib treatment in patients with BRAF-mutant melanoma brain metastases.
Abstract Purpose: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunological changes associated with dabrafenib in MBMs and extracranial (ECM) metastases. Patients and methods: Post-hoc analysis was performed for baseline features of patients (n=125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with ICRR, PFS, and overall survival (OS). [...]
The effect of organ-specific tumor microenvironments on response patterns to immunotherapy.
Abstract Immunotherapy, particularly immune checkpoint inhibitors, have become widely used in various settings across many different cancer types in recent years. Whilst patients are often treated on the basis of the primary cancer type and clinical stage, recent studies have highlighted disparity in response to immune checkpoint inhibitors at different sites of metastasis, and their impact on overall response and survival. Studies exploring the tumor immune microenvironment at different organ sites have provided insights into the immune-related mechanisms behind organ-specific patterns of response to immunotherapy. In this review, we aimed to highlight the key learnings from clinical studies across [...]
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 [...]