scholarly journals Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248097
Author(s):  
Patricia M. LoRusso ◽  
Aleksandar Sekulic ◽  
Jeffrey A. Sosman ◽  
Winnie S. Liang ◽  
John Carpten ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Treatment Options ◽  
Standard Of Care ◽  
Wild Type ◽  
Drug Classes ◽  
Pathway Activation ◽  
Comprehensive Genomic Profiling ◽  
Melanoma Patients ◽  
Post Trial ◽  
Selection Of

Although combination BRAF and MEK inhibitors are highly effective for the 40–50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.

Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 138-138
Author(s):  
Jesus Vera Aguilera ◽  
Jonas Paludo ◽  
Jarrett Failing ◽  
Robert R. McWilliams ◽  
Lisa A. Kottschade ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Efficacy And Safety ◽  
Wild Type ◽  
Lung Cancer Patients ◽  
Melanoma Patients

138 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]

scholarly journals TNS1- ALK Fusion in a Recurrent, Metastatic Uterine Mesenchymal Tumor Originally Diagnosed as Leiomyosarcoma

2019 ◽  
Vol 48 (1) ◽  
pp. 116
Author(s):  
Jessica Lee ◽  
Arun Singh ◽  
Siraj M. Ali ◽  
Douglas I. Lin ◽  
Samuel J. Klempner
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Standard Of Care ◽  
Genomic Profiling ◽  
Curative Intent ◽  
Case Identification ◽  
Complementary Role ◽  
Comprehensive Genomic Profiling ◽  
Standard Of Care Treatment

<p><strong>Objective.</strong> We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care.</p><p><strong>Case Report.</strong> The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP) identifying an TNS1-ALK fusion.</p><p><strong>Conclusion. </strong>In this case, identification of the ALK kinase fusion permitted enrollment in a matched mechanism driven clinical trial after exhausting standard of care treatment options. CGP raises the possibility of uterine inflammatory myofibroblastic tumor as an alternative diagnosisto leiomyosarcoma, highlighting the complementary role of CGP beyond immunohistochemical analyses.</p>

scholarly journals Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

Neoplasia ◽  
2017 ◽  
Vol 19 (4) ◽  
pp. 255-260 ◽  
Author(s):  
Arthur E. Frankel ◽  
Ugur Eskiocak ◽  
Jennifer G. Gill ◽  
Stacy Yuan ◽  
Vijayashree Ramesh ◽  
...  
Keyword(s):  
Disease Control ◽  
Metastatic Melanoma ◽  
Wild Type ◽  
Melanoma Patients

Sonography as a Prognostic Indicator of Breslow Depth: Primary Malignant Melanoma of the Auricular Helix

2021 ◽  
pp. 875647932098102
Author(s):  
Shirly Payano-Griffin
Keyword(s):  
Malignant Melanoma ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Prognostic Indicator ◽  
Primary Malignancy ◽  
Irregular Border ◽  
Current Therapies ◽  
Melanoma Patients

Malignant melanoma is a cellular cancer that produces pigmentation of the skin. The tendency toward melanoma may be inherited, and risk factors are increased with overexposure to the sun and ultraviolet radiation. Melanomas commonly present as a dark, asymmetrical, mole-like spot that spreads, with an irregular border. It is uncommon to find a melanoma in the auricular regions and even rarer for it to be a primary malignancy of the auricles. Utilizing sonography to evaluate melanoma lesions could serve as a prognostic indicator, regarding Breslow’s depth, an aide in staging, as well as surgical planning. However, utilizing multiple diagnostic imaging modalities is essential in the proper evaluation and staging of a melanoma. Currently there are revolutionary, effective systemic therapies available for patients with a metastatic melanoma. Current therapies are focused on immunotherapy and checkpoint inhibitors. These treatment options provide an opportunity for selected metastatic melanoma patients to achieve healthy long-term success.

The Option Value of Innovative Treatments for Metastatic Melanoma

2018 ◽  
Vol 21 (1) ◽  
Author(s):  
Julia Thornton Snider ◽  
Seth Seabury ◽  
Mahlet Gizaw Tebeka ◽  
Yanyu Wu ◽  
Katharine Batt
Keyword(s):  
Metastatic Melanoma ◽  
Treatment Options ◽  
Standard Of Care ◽  
Tumor Control ◽  
Option Value ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Using Data ◽  
Additional Value ◽  
Survival Extension

Abstract Background Treatment options in oncology have increased in recent years due to the quick pace of innovation. In the cancer care landscape, therapies that enable patients to live to the next innovation have additional value, “option value,” from the benefit of surviving to the next innovation. In such disease areas, providers and payers should consider this value when gauging the value of new therapies. The purpose of this study is to develop a model to estimate the additional survival patients attain from a therapy that allows them to live to benefit from further advances in care, and to apply the model to immunotherapy for metastatic melanoma. Methods The benefit of a therapy extends beyond immediate tumor control; it can also allow patients to live to benefit from further advances in care. This is a therapy’s option value. Using data from the SEER cancer registry and clinical trial publications, we developed a model to estimate option value and applied it to ipilimumab, the first immune checkpoint modulator used to treat metastatic melanoma. Because ipilimumab extends survival, select patients benefited from survival extension to live to benefit from the introduction of PD-1 inhibitors (i.e. pembrolizumab and nivolumab). We calculated the option value of ipilimumab in terms of additional life-months patients gained by living to become potential candidates for PD-1 inhibitors, discounting at 3% per year. Results Patients taking ipilimumab as a second-line therapy for metastatic melanoma gained 10.5 months compared to patients taking the prior standard of care. Patients diagnosed in 2011, 2012, and 2013 gained an additional 1.6, 2.8, and 5.1 months of life expectancy, respectively, by living to see the introduction of PD-1 inhibitors. This equates to an option value of 15%, 27%, and 49%, respectively, of the conventionally calculated survival gain from ipilimumab. Ipilimumab had greater option value for patients diagnosed in later years who were more likely to live to the introduction of PD-1 inhibitors. Conclusions Therapies that enable patients to see further advances in care have option value. Option value is particularly important to patients with disease areas undergoing rapid innovation.

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 Tyrosyl-DNA phosphodiesterase 1 and topoisomerase I activities as predictive indicators for Glioblastoma susceptibility to genotoxic agents

2019 ◽  
Author(s):  
Wenjie Wang ◽  
Monica Rodriguez-Silva ◽  
Arlet M. Acanda de la Rocha ◽  
Aizik L. Wolf ◽  
Yanhao Lai ◽  
...  
Keyword(s):  
Cell Lines ◽  
Topoisomerase I ◽  
Activity Ratio ◽  
Ectopic Expression ◽  
Standard Of Care ◽  
Wild Type ◽  
Repair Enzyme ◽  
Protein Levels ◽  
Predictive Indicator ◽  
Selection Of

AbstractBackgroundGlioblastoma (GBM) patients have an estimated survival of ∼15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan, currently in clinical trials for GBM, targets topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex (TOP1cc) inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan.MethodsWe treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. TOP1 and TDP1 protein levels from each cell type as well as GBM patient tumors were determined by Western blot analysis, while activity levels were ascertained by specific enzymatic assays. Cellular TDP1 was elevated by ectopic expression of wild-type or mutant TDP1.ResultsAfter comparing cellular susceptibility to TDP1 and TOP1 concentrations and activities, we found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.92) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by ectopic expression of wild-type TDP1 increased in irinotecan IC50, while expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan.ConclusionsTDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for selection of individual patients for irinotecan treatment based on risk-benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.Key PointsTDP1/TOP1 activity ratio correlates with irinotecan sensitivity in GBM cell lines.TDP1 and TOP1 protein levels are not reliable predictors for irinotecan activity.TDP1 inhibition is a plausible approach to improve irinotecan effectiveness in GBM.Importance of the StudyThe current standard of care (surgery, radiation, and chemotherapy) for GBM patients modestly enhances survival beyond ∼15 months. Thus, there is a great need for effective therapies and biomarkers that address personalized variations in GBM tumors to improve treatment outcome. Topoisomerase I (TOP1) is the target of irinotecan. The repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is known to excise irinotecan-induced TOP1-DNA cleavage complexes (TOP1ccs). Consequently, this study examines the relationship between TOP1 and TDP1 expression and activities in GBM cells and their correlation with irinotecan sensitivity. The results reveal that the TDP1/TOP1 activity ratio predicts irinotecan vulnerability in GBM cell lines. TDP1/TOP1 activity ratio was found to vary among GBM patient tumors. This potential predictive indicator may permit selection of patients responsive to irinotecan based on the capacity to repair TOP1cc. Moreover, inhibitors of TDP1 may represent a promising approach to enhance irinotecan efficacy in GBM patients.

Digoxin plus trametinib therapy of BRAF wild type metastatic melanoma patients.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 9527-9527
Author(s):  
Arthur E. Frankel ◽  
Ugur Eskiocak ◽  
Thomas W. Froehlich ◽  
Chul Ahn ◽  
Amanda Joy Hoelscher ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Wild Type ◽  
Melanoma Patients

Phase II study of ceralasertib (AZD6738), in combination with durvalumab in patients with metastatic melanoma who have failed prior anti-PD-1 therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9514-9514
Author(s):  
Minsuk Kwon ◽  
Seung Tae Kim ◽  
Simon Smith ◽  
Claire Smith ◽  
Peter G. Mortimer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Study Drug ◽  
Standard Of Care ◽  
Phase 2 Trial ◽  
Tumor Mutational Burden ◽  
Melanoma Patients ◽  
Grade 3 ◽  
Tumor Biopsies ◽  
Anti Tumor Activity

9514 Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with metastatic melanoma (MM) who had failed to anti-PD-1 therapy. The study drug schedule was: ceralasertib at 240 mg BD on days 15 to 28 in combination with durvalumab at 1500 mg on day 1 in a 28-day cycle. The primary end point was overall response rate (ORR) by RECIST (v1.1). To investigate markers predictive of clinical outcome, fresh tumor biopsies were obtained from all enrolled patients before treatment. Results: From August 2019 to May 2020, 30 MM patients (median # of lines, 2; range, 2 - 5) were enrolled. All enrolled patients were exposed to prior anti-PD-1 treatment (immediate failure, n = 23). The ORR was 30.0% (9 PRs, 10 SDs, 10 PDs), DCR 63.3%, median PFS 7.1 months (95% confidence interval (CI), 3.6-10.6), and median OS was 14.2 months (95% CI, 9.3-19.1). Common adverse events of any grade were anemia (n = 23, 76.7%), anorexia (n = 20, 66.7%) and thrombocytopenia (n = 19, 63.3%). Common adverse events of grade 3 or more included anemia (n = 10, 33.3%). One death occurred due to febrile neutropenia in a patient with a pre-existing wound infection. Conclusions: Ceralasertib in combination with durvalumab demonstrated a promising anti-tumor activity, particularly in melanoma patients who failed to standard of care including anti-PD1 treatment. Clinical trial information: NCT03780608.

scholarly journals Clinicopathological characteristics, diagnosis and treatment of melanoma in Serbia: The Melanoma Focus Study

2015 ◽  
Vol 72 (4) ◽  
pp. 312-316 ◽  
Author(s):  
Lidija Kandolf-Sekulovic ◽  
Nada Babovic ◽  
Mirjana Balic ◽  
Borislava Nikolin ◽  
Dejan Nikolic ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Clinical Studies ◽  
Treatment Options ◽  
Stage Iv ◽  
Second Line ◽  
First Line ◽  
Stage Iiic ◽  
First Line Therapy ◽  
Line Therapy ◽  
Melanoma Patients

Background/Aim. Treatment options for metastatic melanoma in Serbia are limited due to the lack of newly approved biologic agents and the lack of clinical studies. Also, there is a paucity of data regarding the treatment approaches in different tertiary centers and efficacy of available chemotherapy protocols. The aim of this study was to obtain more detailed data about treatment protocols in Serbia based on structured survey in tertiary oncology centers. Methods. Data about the melanoma patients treated in 2011 were analyzed from hospital databases in 6 referent oncology centers in Serbia, based on the structured survey, with the focus on metastatic melanoma patients (unresectable stage IIIC and IV). Results. A total of 986 (79-315 in different centers) patients were treated, with 320 (32.45%) newly diagnosed patients. There were 317 patients in stage IIIC/IV, 77/317 aged < 50 years. At the time of diagnosis 47.3% of patients were < 60 years of age (24.2% < 40 years, 23% 50-59 years, 52.6% > 60 years). At initial diagnosis 12.5% of patients were in stage III and 4.5% in stage IV. The most common type was superficial spreading melanoma (50-66%), followed by nodular melanoma (23.5-50%). Apart from the regional and distant lymph node metastases, the most frequent organs involved in stage IV disease were distant skin and soft tissues (12-55%), lungs (19-55.5%), liver (10-60%), and bones (3-10%). The first line therapy in stage IV metastatic melanoma was dacarbazine (DTIC) dimethyl-triazeno-imidozole-carboxamide in 61-93% of the patients, while the second line varied between the centers. Disease control (complete response + partial response + stable disease) was achieved in 25.7% of the patients treated with the first line chemotherapy and 23.1% of the patients treated with the second line therapy, but the duration of response was short, in first-line therapy 6.66 ? 3.36 months (median 6.75 months). More than 90% of patients were treated outside the clinical trials. Conclusion. Based on this survey, there is a large unmet need for the new treatment options for metastatic melanoma in Serbia. The development of national guidelines, and greater involvement in international clinical studies could lead to widening of treatment options for this chemotherapy resistant disease.

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