Reply to: Letter comments on: Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers

2021 ◽  
Author(s):  
Dirk Schadendorf
Keyword(s):  
Clinical Trials ◽  
Braf Mutant

scholarly journals Treatment Sequencing in Advanced BRAF-Mutant Melanoma Patients: Current Practice in the United States

2017 ◽  
Vol 34 (1) ◽  
pp. 17-23
Author(s):  
Céline Audibert ◽  
Mark Stuntz ◽  
Daniel Glass
Keyword(s):  
United States ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Online Survey ◽  
The United States ◽  
Community Based ◽  
Academic Center ◽  
Melanoma Patients ◽  
To Receive ◽  
Braf Mutant

Background: Treatment of advanced BRAF-mutant melanoma has changed dramatically in the past 3 years thanks to the approval of new immunotherapy and targeted therapy agents. Objectives: The goal of our survey was to investigate when immunotherapy and targeted therapy are used in the management of advanced melanoma patients and whether differences exist between the types of setting. Methods: Oncologists from academic centers, community-based centers, and private clinics were invited to participate in an online survey. Survey questions addressed the proportion of BRAF-mutant patients per treatment line, proportion of patients on targeted therapy and immunotherapy available in the United States, and reasons for prescribing each drug class. Results: A total of 101 physicians completed the survey, of which 47 worked in a private clinic, 33 in an academic center, and 21 in a community-based center. Academic center participants tended to see more severe patients ( P < .001) and had more patients in second-line treatment than participants from other setting types. In addition, academic center physicians had more patients in clinical trials ( P < .001), and they prescribed the ipilimumab and nivolumab combination more frequently. In terms of sequencing, all participants used targeted therapy for severe or rapidly progressing patients and immunotherapy for those who were less severe or slowly progressing. Conclusions: The findings illustrate the differences in treatment approach per type of setting, with patients in academic centers more likely to receive recently approved products or to be enrolled in clinical trials than those in community-based settings.

219 Long-term clinical outcomes associated with sequential treatment of BRAF mutant advanced melanoma patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A238-A238
Author(s):  
Ahmad Tarhini ◽  
David McDermott ◽  
Apoorva Ambavane ◽  
Agnes Benedict ◽  
Cho-Han Lee ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Randomized Clinical Trials ◽  
Advanced Melanoma ◽  
Lifetime Horizon ◽  
Mek Inhibitors ◽  
Life Years ◽  
Braf Mutant ◽  
Treatment Sequences

BackgroundPatients with BRAF mutant advanced melanoma can be treated sequentially with immunotherapies (IO) and BRAF+MEK inhibitors. We evaluated the clinical outcomes associated with various treatment sequences for BRAF mutant advanced melanoma based on the 5-year follow-up data from clinical trials.MethodsIn the absence of head-to-head trial data, a matching-adjusted indirect comparison (MAIC) was conducted for IO vs. BRAF+MEK inhibitors, using the longest follow-up available in the published literature. Multivariate risk equations were developed to predict time-to-event outcomes based on patient-level data from pooled CheckMate-067 &-069 trials. Risk equations were inserted into a discrete event simulation to estimate the average life-years (LYs) and quality-adjusted life-years (QALYs) that can be gained with various treatment sequences over a lifetime horizon. Treatment sequences and corresponding efficacy data sources are presented below (table 1). Utility weights for quality-adjustment of LYs were obtained from published literature.ResultsTreatment sequences starting with IO followed by BRAF+MEK were associated with 2.9–4.3 years of additional survival and 2.2–3.3 years of quality-adjusted survival versus sequences starting with BRAF+MEK followed by anti-PD-1. After 1L IO, the time spent in the treatment-free interval (TFI) is 3.3–5.0 years. LYs, QALYs, and time spent in TFI were higher with sequences starting with anti-PD-1+anti-CTLA-4 vs. anti-PD-1 alone.ConclusionsIn this sequencing model with 5-year data from randomized clinical trials, initiating 1L treatment with IO provided prolonged survival compared to initiating 1L treatment with BRAF+MEK. Time spent in TFI represents a significant proportion of survival time for patients on IO initiating sequences. Limitations of the study are the reliance on published information for BRAF+MEK, which could lead to biases due to unmeasured differences in the patient populations or trial conduct and the absence of data on 2L combination IO. Anti-PD-1+anti-CTLA-4 as second line option has not been included because of a lack of clinical evidence. Findings from this analysis will require validation in ongoing prospective randomized clinical trials.Abstract 219 Table 1Clinical outcomes on treatment sequences for BRAF MT melanoma

scholarly journals Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers

2021 ◽  
Vol 153 ◽  
pp. 234-241
Author(s):  
Dirk Schadendorf ◽  
Caroline Robert ◽  
Reinhard Dummer ◽  
Keith T. Flaherty ◽  
Hussein A. Tawbi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Braf Mutant

scholarly journals Targeting BRAF-Mutant Biliary Tract Cancer: Recent Advances and Future Challenges

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482098301
Author(s):  
Alessandro Rizzo ◽  
Alessandro Di Federico ◽  
Angela Dalia Ricci ◽  
Giorgio Frega ◽  
Andrea Palloni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Targeted Therapies ◽  
Ampulla Of Vater ◽  
Braf Mutations ◽  
Extrahepatic Cholangiocarcinoma ◽  
New Era ◽  
Tract Cancer ◽  
Future Challenges ◽  
Braf Mutant

Background: Biliary tract cancers (BTCs) represent a heterogeneous group of aggressive solid tumors with limited therapeutic options, and include gallbladder cancer (GBC), ampulla of Vater cancer (AVC), intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). Methods & Results: In the current review, we will discuss recent results of clinical trials testing targeted therapies in BRAF-mutant BTCs, with a particular focus on the recently published Phase II ROAR trial and ongoing active and recruiting clinical trials. Conclusions: Although the extended use of molecular profiling has paved the way toward a new era in BTC management, targeted therapies are limited to iCCA so far, and the prognosis of patients with metastatic disease has substantially not changed in the last decade. In this discouraging scenario, BRAF inhibition is currently emerging as a novel treatment option in patients harboring BRAF mutations.

scholarly journals Significance of BRAF Kinase Inhibitors for Melanoma Treatment: From Bench to Bedside

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1342 ◽  
Author(s):  
Taku Fujimura ◽  
Yasuhiro Fujisawa ◽  
Yumi Kambayashi ◽  
Setsuya Aiba
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Hdac Inhibitors ◽  
Asian Population ◽  
Phase Iii ◽  
Braf Inhibitors ◽  
Mek Inhibitors ◽  
Braf Mutant

According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. In addition, drug resistance sometimes abrogates the persistent efficacy of combined therapy with BRAF and MEK inhibitors. Therefore, recent pre-clinical study-based clinical trials have attempted to identify optimal drugs (e.g., immune checkpoint inhibitors or histone deacetylase (HDAC) inhibitors) that improve the anti-melanoma effects of BRAF and MEK inhibitors. In addition, the development of novel protocols to avoid resistance of BRAF inhibitors is another purpose of recent pre-clinical and early clinical trials. This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors.

Generalizability of clinical trials in metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21004-e21004
Author(s):  
Davis Sam ◽  
Gillian K. Gresham ◽  
Winson Y. Cheung
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Progressive Disease ◽  
Population Based ◽  
Wild Type ◽  
Exclusion Criteria ◽  
Eligibility Criteria ◽  
Receive Treatment ◽  
Treatment Policies ◽  
Braf Mutant

e21004 Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.

Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

1973 ◽  
Vol 31 ◽  
pp. 404-405
Author(s):  
D. C. Swartzendruber ◽  
Norma L. Idoyaga-Vargas
Keyword(s):  
Clinical Trials ◽  
Soft Tissue ◽  
Tumor Tissue ◽  
Soft Tissue Tumors ◽  
Clinical Usefulness ◽  
Electron Microscopic ◽  
Normal Cells ◽  
Electron Microscopic Autoradiography ◽  
Peritoneal Cells ◽  
Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

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