Efficacy of Vemurafenib Treatment in 43 Metastatic Melanoma Patients with BRAF Mutation. Single-Institute Retrospective Analysis, Early Real-Life Survival Data

2017 ◽  
Vol 25 (1) ◽  
pp. 45-50 ◽  
Author(s):  
Kata Czirbesz ◽  
Eszter Gorka ◽  
Tímea Balatoni ◽  
Gitta Pánczél ◽  
Krisztina Melegh ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Retrospective Analysis ◽  
Survival Data ◽  
Braf Mutation ◽  
Real Life ◽  
Melanoma Patients

The impact of BRAF mutation status on clinical outcomes with single-agent PD-1 inhibitor versus combination ipilimumab/nivolumab.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10024-10024
Author(s):  
Vincent The-Luc Ma ◽  
Stephanie Daignault ◽  
Jessica Waninger ◽  
Leslie Anne Fecher ◽  
Michael Green ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Retrospective Analysis ◽  
Braf Mutation ◽  
Univariate Analysis ◽  
Single Agent ◽  
Mutation Status ◽  
Melanoma Patients ◽  
The Impact ◽  
Braf Mutant ◽  
Braf V600 Mutation

10024 Background: Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for BRAF mutant metastatic melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens. Our aim was to better assess if BRAF mutation status has any impact on survival to combination ipilimumab/nivolumab (I/N) versus single-agent PD-1 inhibitor (PD-1i). Methods: We performed a single center, retrospective analysis on a cohort of patients diagnosed with metastatic or unresectable melanoma from 2012 to 2019 at the University of Michigan who were treated with standard I/N or PD-1i (nivolumab or pembrolizumab). A univariate analysis of progression free survival (PFS) and overall survival (OS) was stratified by treatment type and BRAF mutation status. A multivariate Cox regression of survival was used to compare the effects of the treatment groups adjusted by BRAF status, age, gender, pre-treatment LDH level, prior treatment status, and brain metastases status. Results: 323 patients were identified. 132 had BRAF V600 mutation and 191 had BRAF wildtype (WT) status. 138 patients received I/N and 185 patients received PD-1i. In our univariate analysis, there was no difference in PFS [HR: 0.72, 95% CI, 0.46 – 1.13] or OS [HR: 0.78, 0.44 – 1.38] with I/N versus PD-1i in the BRAF mutant cohort, but there was improved PFS [HR: 0.55, 0.35 – 0.88) and OS [HR: 0.52, 0.28 – 0.95] with I/N compared to PD-1i in the BRAF WT group. In the multivariate analysis, the BRAF WT group continued to show PFS benefit with I/N compared to PD-1i [HR: 0.57, 95% CI, 0.35 – 0.95], but the OS benefit no longer achieved statistical significance [HR: 0.54, 0.28 – 1.03]. Conclusions: Our study results were discordant with the observation in the landmark CheckMate 067 trial, which noted improved PFS and OS with I/N compared to nivolumab alone in the BRAF mutant group and no difference in the BRAF WT group. In our real-world retrospective analysis, I/N over PD-1i should be considered as initial immunotherapy for metastatic melanoma patients regardless of BRAF mutation status, but even more favorably in BRAF WT.

scholarly journals Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

2019 ◽  
Vol 11 ◽  
pp. 175883591984887 ◽  
Author(s):  
Lorena Incorvaia ◽  
Giuseppe Badalamenti ◽  
Gaetana Rinaldi ◽  
Juan Lucio Iovanna ◽  
Daniel Olive ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Survival Rate ◽  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Primary Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Enzyme Linked Immunosorbent Assay ◽  
Melanoma Patients ◽  
Infiltrating Lymphocytes

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. Patients and Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients’ overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis.

scholarly journals Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4164
Author(s):  
Gabriele Madonna ◽  
Giuseppe V. Masucci ◽  
Mariaelena Capone ◽  
Domenico Mallardo ◽  
Antonio Maria Grimaldi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Metastatic Melanoma ◽  
Learning Algorithm ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Previous Treatment ◽  
Clinical Decision ◽  
Neutrophil Lymphocyte Ratio ◽  
Real World Evidence ◽  
Melanoma Patients

The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy (INT-NA). To compare patients’ clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm—survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9048-9048
Author(s):  
Tulasi Gummadi ◽  
Roxana Stefania Dronca ◽  
Chul Kim ◽  
Lisa A. Kottschade ◽  
Rajendar K Mittapalli ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Retrospective Analysis ◽  
Braf Mutation ◽  
Braf Inhibitor ◽  
Preclinical Studies ◽  
Braf Inhibitors ◽  
Intracranial Disease ◽  
Extracranial Disease ◽  
The Brain

9048 Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.

scholarly journals Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2329
Author(s):  
Nethanel Asher ◽  
Guy Ben-Betzalel ◽  
Shaked Lev-Ari ◽  
Ronnie Shapira-Frommer ◽  
Yael Steinberg-Silman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Real World ◽  
Real Life ◽  
Response Rates ◽  
Immune Checkpoints ◽  
World Population ◽  
Induction Phase ◽  
Treatment Naïve ◽  
Melanoma Patients

Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database—a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-naïve. The median follow-up was 12 months. The response rates for treatment-naïve and previously-treated patients were 61% and 25%, respectively; median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-naïve patients was 58% (95% CI 42–65). At data cutoff, 22% were still on-treatment. Grade 3–4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%); AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.

Pretreatment features and risk of death from BRAF-positive metastatic melanoma patients treated with vemurafenib.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21028-e21028
Author(s):  
Dorota Malgorzata Kwapisz
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Performance Status ◽  
Elevated Serum ◽  
Braf Inhibitor ◽  
Poor Performance ◽  
Poor Performance Status ◽  
Disease Symptoms ◽  
Risk Of Death ◽  
Melanoma Patients

e21028 Background: Clinicopathologic features of BRAF-positive metastatic melanoma patients were identified. No study to date has examined influence on risk of death features at baseline before starting treatment with vemurafenib. The purpose of the study is to identify demographic, clinical, biochemical, and tumor-related features at baseline before treatment with vemurafenib that are related with increase risk of death in BRAF-positive metastatic melanoma patients. Methods: 323 consecutive patients with metastatic melanoma tested for BRAF mutation were analysed. The presence of BRAF gene V600 mutation was evaluated by the cobas 4800 BRAF V600 Mutation Test. The pretreatment features were collected prospectively after inclusion patients for BRAF inhibitor treatment but before treatment was started. Results: 204 patients had a BRAF mutation. Of these, 115 were treated with vemurafenib. The median time of treatment with vemurafenib was 198 days. Death occurred more frequently among patients with: pretreatment disease symptoms (p = 0.003), ECOG PS ≥1 (p = 0.03), CNS metastases at baseline (p = 0.049) [χ2 test]. The pretreatment elevated serum LDH level (p < 0.0005), leukocytosis (p = 0.042), and hipoalbuminemia (p = 0.002) had an impact on higher incidence of death. AJCC stage 3 was reported more frequently in patients who have died (AJCC 1-2 vs. AJCC 3; p = 0.025, χ2 test). Higher incidence of death in patients with ≥4 localisations of metastases (different organs) was noted (1-3 vs 4-8; p = 0.001, χ2test). The maximum metastasis dimension was greater in the group of patients who have died (p = 0.009; Mann-Whitney test). In the analysed population, all patients whose pretreatment metastasis dimension exceeded 56 mm have died. Age, BMI, and sex were not related with higher risk of death. Conclusions: Pretreatment features may identify patients at higher risk of death. Those with features at baseline such as: disease symptoms, poor performance status, elevated LDH, leukocytosis, hipoalbuminemia, increased metastatic tumor burden, especially when brain is one of the metastatic localisation are in higher risk of death among all patients treated with vemurafenib.

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