Vemurafenib Achieves ‘Prolonged Efficacy’ For BRAF-Mutated Erdheim–Chester Disease

Final analysis of the VE-BASKET trial suggests long-term survival benefit for vemurafenib in select patients with Erdheim–Chester disease or Langerhans cell histiocytosis

medwireNews: Long-term survival findings of the VE-BASKET trial support the use of vemurafenib in adults with Erdheim–Chester disease (ECD) or Langerhans cell histiocytosis (LCH) shown to have a BRAF V600 mutation.

“As BRAF V600 mutations occur in more than 50% of patients with ECD and LCH, these findings have the potential to change the standard of care for a majority of patients with these orphan disorders”, write Eli Diamond, from the Memorial Sloan Kettering Cancer Center in New York, USA, and co-investigators. 

The open-label basket trial of the BRAF V600 kinase inhibitor included 22 patients with BRAF-mutated ECD and four with BRAF-mutated LCH in the “other solid tumor” group, all of whom were assigned to receive vemurafenib 960 mg twice daily until disease progression, intolerable side effects or study withdrawal.

The primary endpoint of a RECIST objective response rate was achieved by 61.5% of the patients, including 54.5% of the ECD patients, but all evaluable patients achieved at least stable disease during vemurafenib therapy. Responses to vemurafenib were observed at all disease sites including the brain, bone, soft tissues, skin, lungs, eyes and kidneys.

The median time to response was 5.5 months and the researchers note that this is longer than previously reported for melanoma.

At trial closure, after a median of 28.8 months, median overall survival (OS) and progression-free survival (PFS) had not been reached, with 2-year estimated rates of 96% and 86%, respectively.

Indeed, 24 of the 26 patients in the cohort remained free from disease progression during treatment, the authors report in JAMA Oncology.

And all 15 of the patients who underwent 18F-fluorodeoxyglucose–positron-emission tomography showed a metabolic response to vemurafenib, with a complete response achieved by 80% and a partial response in 20%.

Adverse events reported included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma and hyperkeratosis. Two LCH patients developed noncutaneous primary malignancies, only one of which was thought to be associated with vemurafenib therapy.

All patients had at least one adverse event leading to dose interruption and/or modification and 31% of the patients discontinued treatment because of side effects.

Hypertension and dermatological side effects both occurred at higher rates among the ECD and LCH patients than previously reported for vemurafenib-treated patients with metastatic melanoma, the researchers observe.

Discussing their findings, Eli Diamond et al say the lack of a control or true historic control cohort “makes interpretation of the PFS and OS data challenging” and admit that the trial does not address the optimal dose or duration of vemurafenib therapy.

“The maintenance of responses, despite dose reductions in all patients, suggests that doses below the currently indicated dose for melanoma (960 mg, twice daily) may be sufficient to maintain therapeutic responses”, the investigators say. 

While stopping vemurafenib has previously been linked to relapse, intermittent therapy or treatment interruption with monitoring may also be feasible, they write. 

 “Based on these results, the US Food and Drug Administration has approved vemurafenib for patients with BRAF V600–mutant ECD”, the team observes, adding that the agent “warrants consideration as a new standard of care for these patients.” 


Diamond EL, Subbiah V, Lockhart AC, et al. 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. JAMA Oncol; Advance online publication 29 November 2017. doi:10.1001/jamaoncol.2017.5029

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