The nature and management of metastatic melanoma after progression on BRAF inhibitors: Effects of extended BRAF inhibition
Open Access
- 1 July 2014
- Vol. 120 (20), 3142-3153
- https://doi.org/10.1002/cncr.28851
Abstract
BACKGROUND The v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (BRAFi) drugs dabrafenib and vemurafenib have high response rates in BRAF-mutant, metastatic melanoma; however, 50% of patients progress by 7 months. In this study, the authors examined the nature and management of disease progression (PD) on BRAFi treatment, including characteristics and outcomes of patients who received continued BRAFi treatment beyond disease progression (TBP). METHODS Clinicopathologic data at baseline and at the time of PD were collected for all patients with BRAF-mutant metastatic melanoma who received BRAFi monotherapy within clinical trials between July 2009 and September 2012. Management and survival after PD were examined, including continued BRAFi TBP (>28 days beyond Response Evaluation Criteria in Solid Tumor [RECIST]-defined PD). RESULTS Ninety-five of 114 BRAFi-treated patients had PD. Fifty-three of those 95 patients (56%) progressed in extracranial sites alone, 18% (17 of 95 patients) progressed in intracranial and extracranial sites simultaneously, and 16% (15 of 95 patients) progressed in intracranial sites alone. Twenty-nine of the 95 patients (31%) who had PD progressed in a single site or organ, 48% (46 of 95 patients) progressed in existing metastases only, and 18% (17 of 95 patients) had new metastases alone. At the time of PD, 35 of 95 patients (37%) received no subsequent systemic treatment, 20% (19 of 95 patients) changed systemic treatments, and 39% (37 of 95 patients) continued BRAFi TBP for a median of 97 days. BRAFi TBP and known prognostic factors (Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, RECIST sum of the greatest dimensions of target lesions) were associated with overall survival (OS) from the time of PD; however, in multivariable analysis, BRAFi TBP improved OS (hazard ratio, 0.50; 95% confidence interval, 0.27-0.93; P=.029). CONCLUSIONS Most BRAFi-treated patients progressed in existing extracranial sites, and 31% progressed in isolated sites. Compared with cessation, continued BRAFi TBP is associated with prolonged OS even after adjusting for potential prognostic factors at PD. Cancer 2014;120:3142–3153. © 2014 American Cancer Society.Keywords
This publication has 31 references indexed in Scilit:
- Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic MelanomaJournal of Clinical Oncology, 2013
- Intratumoral Molecular Heterogeneity in a BRAF-Mutant, BRAF Inhibitor-Resistant Melanoma: A Case Illustrating the Challenges for Personalized MedicineMolecular Cancer Therapeutics, 2012
- Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 MutationsThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Survival in BRAF V600–Mutant Advanced Melanoma Treated with VemurafenibThe New England Journal of Medicine, 2012
- NRAS mutation status is an independent prognostic factor in metastatic melanomaCancer, 2011
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationThe New England Journal of Medicine, 2011
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of EverolimusClinical Cancer Research, 2007
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000