scholarly journals Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression

2021 ◽  
Author(s):  
Gabriela Marsavela ◽  
Ashleigh C. McEvoy ◽  
Michelle R. Pereira ◽  
Anna L. Reid ◽  
Zeyad Al-Ogaili ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Validation Cohort ◽  
Positron Emission Tomography Imaging ◽  
Radiological Progression ◽  
Positron Emission ◽  
Braf Inhibition ◽  
Treatment Naïve ◽  
Melanoma Patients ◽  
Ctdna Analysis

Abstract Background The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. Methods Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. Results ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15). Conclusions These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.

Blood mRNA signature to predict survival in patients with metastatic melanoma treated with tremelimumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9080-9080 ◽  
Author(s):  
Yvonne M. Saenger ◽  
Jay Magidson ◽  
Bobby Chi-Hung Liaw ◽  
Karl Wassmann ◽  
William Barker ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Risk Score ◽  
Peripheral Blood ◽  
Validation Cohort ◽  
Risk Groups ◽  
Phase Iii ◽  
Gene Model ◽  
Training Cohort ◽  
Melanoma Patients

9080 Background: Tremelimumab (Ticilimumumab, Pfizer), a monoclonal antibody targeting CTLA-4, a T cell inhibitory molecule, has shown activity in metastatic melanoma. Ipilimumab (Yervoy, BMS), another antibody targettingCTLA-4, improves survival relative to a peptide vaccine and is now FDA approved. A minority of patients will achieve durable tumor control with CTLA-4 blockade and biomarkers are urgently needed to identify those patients. Methods: 170 inflammatory, melanoma-specific and CTLA4-pathway related mRNA transcripts were measured using RT-PCR in pre-treatment peripheral blood samples from 218 patients with refractory melanoma receiving tremelimumab in a multi-center phase II study. A 2-class latent model yielded a risk score based on 4-genes that was highly predictive of survival (p<0.001), and was used to categorize patients into low, medium and high-risk groups. An independent cohort of 260 treatment naïve melanoma patients receiving tremelimumab as part of a multi-center phase III study was then used to validate the risk score as well as the 3 risk groups defined using the pre-specified cut-points. Results: There was no significant difference between the two cohorts in terms of age, gender, stage of disease or ECOG status. Median time of follow up was 297 days for the training cohort and 386 days for the validation cohort. 67% of patients in the training cohort and 70% of patients in the validation died during time of follow-up. Collectively, the ability of the 170 genes to predict survival exhibited a high degree of consistency across the cohorts (p < 0.001). A 4-gene model including cathepsin D (CTSD), Phopholipase A2 group VII (PLA2G7), Thioredoxin reductase 1 (TXNRD-1) and Interleukin 1 receptor associated kinase 3 (IRAK3) predicted survival in the validation cohort (p=0.001 by log rank test). Multivariable cox analysis showed that the 4-gene model added to the predictive value of clinical predictors (p<0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in melanoma patients treated with ticilimumab (αCTLA-4). Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

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.

scholarly journals Serum CEACAM1 Correlates with Disease Progression and Survival in Malignant Melanoma Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sapoznik Sivan ◽  
Faranesh Suzan ◽  
Ortenberg Rona ◽  
Hamburger Tamar ◽  
Barak Vivian ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Malignant Melanoma ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Skin Test ◽  
Metastatic Disease ◽  
Prognostic Value ◽  
Serum Samples ◽  
Melanoma Patients

The search for melanoma biomarkers is crucial, as the incidence of melanoma continues to rise. We have previously demonstrated that serum CEACAM1 (sCEACAM1) is secreted from melanoma cells and correlates with disease progression in metastatic melanoma patients. Here, we have used a different cohort of melanoma patients with regional or metastatic disease (N=49), treated with autologous vaccination. By monitoring sCEACAM1 in serum samples obtained prior to and after vaccination, we show that sCEACAM1 correlates with disease state, overall survival, and S100B. The trend of change in sCEACAM1 following vaccination (increase/decrease) inversely correlates with overall survival. DTH skin test is used to evaluate patients’ anti-melanoma immune response and to predict response to vaccination. Importantly, sCEACAM1 had a stronger prognostic value than that of DTH, and when sCEACAM1 decreased following treatment, this was the dominant predictor of increased survival. Collectively, our results point out the relevance of sCEACAM1 in monitoring melanoma patients.

BKM120 combined with vemurafenib in vemurafenib-refractory BRAF mutant metastatic melanoma: Two cases.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20010-e20010 ◽  
Author(s):  
Alain Patrick Algazi ◽  
Christian Posch ◽  
Susana Ortiz-Urda ◽  
Alyson Cockerill ◽  
Pamela N. Munster ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Braf Inhibitor ◽  
Study Drug ◽  
Braf V600e ◽  
Response To Treatment ◽  
Mixed Response ◽  
Pi3k Activation ◽  
Melanoma Patients ◽  
Braf Mutant

e20010 Background: PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause of acquired resistance to BRAF inhibitors. Two vemurafenib refractory were treated with the potent BRAF inhibitor, vemurafenib, and the pan-class I PI3K inhibitor BKM120. Methods: The study enrolled BRAF-V600E/K mutant metastatic melanoma patients with an ECOG PS ≥ 2 and adequate organ function. Vemurafenib refractory BRAF-V600E/K mutant melanoma patients started both vemurafenib twice daily and BKM120 daily on cycle 1, day 1 after a vemurafenib washout of at least 14 days. Serial biopsies prior to treatment, on cycle 1 day 15, and at progression were obtained for pharmacodynamics analysis in patients with visible or palpable tumors. Results: 3 BRAF inhibitor refractory patients were treated on study with vemurafenib 720 mg PO bid and BKM120 60 mg PO daily. One patient was inevaluable due to non-compliance and had minimal exposure to study drug. Pre-treatment biopsy specimens were available in the remaining 2 vemurafenib-refractory patients. Both patient expressed PTEN at baseline and had demonstrable pAKT and pS6 staining. One patient had a mixed response to treatment with a 35.9% reduction in target lesions and two new small subcutaneous lesions. This patient also developed dose limiting febrile neutropenia on trial. The second patient tolerated treatment well but had widespread disease progression at 8 weeks. Conclusions: Combination therapy with vemurafenib and BKM120 in BRAF-V600E/K mutant melanoma led to substantial regression of several tumors in a PTEN+ patient with prior disease progression on vemurafenib alone. A phase I dose escalation trial in ongoing. Clinical trial information: NCT01512251.

scholarly journals Single Center Experience Study with Pembrolizumab in Patients with BRAF Mutant Negative Metastatic Melanoma

2018 ◽  
Vol 35 (4) ◽  
pp. 267-272
Author(s):  
Ivica Pejčić ◽  
Ivan Petković ◽  
Ana Cvetanović ◽  
Irena Conić
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Performance Status ◽  
Progression Free Survival ◽  
Complete Response ◽  
Wild Type ◽  
Free Survival ◽  
Good Performance Status ◽  
Melanoma Patients ◽  
Braf Mutant

Abstract The aim of the paper was to determine the efficacy, toxicity and progression free survival with anti-PD-1 immunotherapy pembrolizumab in BRAF wild type metastatic melanoma patients with good performance status (ECOG PS 0-1). From February 2017 to April 2018, 17 patients with BRAF mutant wild type metastatic melanoma were enrolled in the study. Only 3/17 patient had received chemotherapy previously. The aim of the study was to confirm the efficacy of pembrolizumab immunotherapy in patients with good performance status (ECOG 0-1). Treatment consisted of pembrolizumab 2 mg/kg Q3 weeks continued until disease progression or intolerable toxicity. Secondary end points included toxicity and progression-free survival (defined as the time from randomization to documented disease progression according to RECIST). The overall response rate (ORR) was 11/17 (53.0 %), with complete response (CR) 0, partial response (PR) 3 (18 %), stable disease (SD) 8 (47%), and progressive disease (PD) 6 (35%). A total number of 97 consecutive cycles were administered. Adverse effects were mild. The most common toxicity was pneumonitis grade 1. None of the patients in the study demonstrated grade 2, 3 and 4 toxicity. No treatment-related deaths occurred. The median time to disease progression was 5.8 months. Anti-PD-1 pembrolizumab immunotherapy appeared to be a beneficial therapeutic approach with less toxicity for metastatic BRAF wild type melanoma patients with good PS.

scholarly journals Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab – real-world experience

2020 ◽  
Vol 54 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Nezka Hribernik ◽  
Marko Boc ◽  
Janja Ocvirk ◽  
Jasna Knez-Arbeiter ◽  
Tanja Mesti ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Metastatic Melanoma ◽  
Retrospective Analysis ◽  
Real World ◽  
Hospital Data ◽  
Real World Data ◽  
Treatment Naïve ◽  
Melanoma Patients ◽  
Metastatic Involvement

AbstractBackgroundBased on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question remains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials.Patients and methodsThis observational retrospective cohort study included 138 consecutive metastatic treatment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019.ResultsThe estimated median overall survival (OS) was 25.1 months (95% CI, 14.6–35.6) and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.9–15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3–4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment.ConclusionsOur real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients.

A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9046-9046
Author(s):  
Everett J Moding ◽  
Mohammad Shahrokh Esfahani ◽  
Barzin Nabet ◽  
Yufei Liu ◽  
Jacob J. Chabon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Validation Cohort ◽  
Residual Disease ◽  
Risk Index ◽  
Training Cohort ◽  
Independent Validation ◽  
Risk Of Progression ◽  
Ctdna Analysis ◽  
Model Features

9046 Background: Circulating tumor DNA (ctDNA) molecular residual disease after curative intent therapy predicts disease progression in localized lung cancer. We hypothesized that integrating pre-CRT features and ctDNA levels during chemoradiation therapy (CRT) can predict patient outcomes earlier to enable response-adapted therapy. Methods: We identified pre-CRT features prognostic of disease progression after CRT for Stage II-III non-small cell lung cancer (NSCLC) in a historical “pre-CRT” training cohort of 109 patients. In addition, we applied CAPP-Seq ctDNA analysis pre-CRT and a median of 21 days into CRT (mid-CRT) to a “ctDNA” training cohort of 42 patients treated at MD Anderson and an independent validation cohort of 21 patients treated at Stanford. Prognostic pre-CRT features and mid-CRT ctDNA concentration were integrated using a Bayesian proportional hazards approach to generate a Continuous Individualized Risk Index (Kurtz et al. Cell 2019) for NSCLC (CIRI-NSCLC) to predict freedom from progression (FFP). Results: Adenocarcinoma histology (HR 2.6, P = 0.0005) and KEAP1 mutation (HR 2.7, P = 0.002) but not stage (P = 0.16), age (P = 0.60), or gender (P = 0.98) were significantly associated with FFP in the pre-CRT training cohort. Mid-CRT ctDNA concentration as a continuous variable was significantly associated with FFP in the ctDNA training cohort (HR 1.6, P = 0.04), and applying an optimal threshold identified in the training cohort (3.2 hGE/ml) significantly stratified FFP in the independent ctDNA validation cohort (HR 4.8, P = 0.02). CIRI-NSCLC enabled individualized real-time updating of the probability of FFP as model features became available over the course of CRT. CIRI-NSCLC outperformed individual model features in the independent validation cohort when compared by C-statistic (CIRI-NSCLC: 0.85; mid-CRT ctDNA: 0.76; histology: 0.66; KEAP1: 0.60). Across the whole cohort, patients with a greater than 66% risk of progression predicted by CIRI-NSCLC (n = 10) had an FFP of 10.0% at 12 months while patients with a less than 33% risk of progression predicted by CIRI-NSCLC (n = 22) had an FFP of 79.7% at 12 months (HR 15.0, P < 0.001). Conclusions: Our results suggest that CIRI-NSCLC can identify patients at very high and low risk of progression. Prospective evaluation will be necessary to test the potential utility of adapting treatment based on CIRI-NSCLC.

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