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Clinical Trial
. 2018 Mar 1;4(3):384-388.
doi: 10.1001/jamaoncol.2017.5029.

Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study

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Clinical Trial

Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study

Eli L Diamond et al. JAMA Oncol. .
Free PMC article

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Abstract

Importance: The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study.

Objective: To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study.

Design, setting, and participants: The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an "other solid tumor" cohort of the VE-BASKET study, and they were enrolled in the present study.

Interventions: Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects.

Main outcomes and measures: The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety.

Results: A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma.

Conclusions and relevance: In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Subbiah reports grants from Roche/Genentech during the conduct of the study; grants from Novartis, Bayer, GSK, Bluprint Medicines, LOXO, Fujifilm, NCI-CTEP, and the NCCN outside the submitted work. Dr Blay reports grants, personal fees and nonfinancial support from Roche, grants from GSK, and grants and personal fees from Novartis during the conduct of the study. Dr Puzanov reports personal fees from Roche during the conduct of the study and personal fees from Amgen outside the submitted work. Dr Chau reports grants and personal fees from Sanofi Oncology, personal fees from Eli-Lilly, Bristol-Myers Squibb, MSD, Bayer, Roche, Five Prime Therapeutics, Taiho, Pfizer, Amgen, and Gilead Science, and grants from Janssen-Cilag, Merck-Serono, and Novartis, outside the submitted work. Dr Wolf reports research grants from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche, BMS, MSD, Novartis, Pfizer, and advisory boards and lecture fees from Roche, outside the submitted work. Dr Lacouture reports research grants and consulting fees from Genentech/Roche, research grants from BMS, personal fees from Foamix, Debio, Janssen, Galderma, and Adgero, outside the submitted work. Dr Martínez-Valle reports grants from Pfizer, outside the submitted work. Dr Pitcher is an employee of F. Hoffmann-La Roche Ltd, Mississauga, Ontario, Canada. Dr Makrutzki is an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Dr Riehl is an employee of F. Hoffmann-La Roche Ltd and owns stock in F. Hoffmann-La Roche Ltd. Dr Hyman reports personal fees from Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, and AstraZeneca; and grants from AstraZeneca, Puma Biotechnology, and Loxo Oncology outside the submitted work. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. Efficacy of Vemurafenib in Individual Patients With BRAF V600–Mutant Erdheim-Chester Disease (ECD) or Langerhans Cell Histiocytosis (LCH)
One patient did not have measurable disease at baseline and was thus not evaluable for response but was included in the intention-to-treat analysis as a nonresponder. The line at −30% represents the cutoff for partial response by RECIST criteria (Response Evaluation Criteria in Solid Tumors); the line at +20% demarcates disease progression, which did not occur in any of the patients in this study.
Figure 2.
Figure 2.. Kaplan-Meier Survival Curves for Patients With BRAF V600–Mutant Erdheim-Chester Disease or Langerhans Cell Histiocytosis

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