TY - JOUR
T1 - Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies
T2 - Association with overall survival?
AU - Mangana, Joanna
AU - Cheng, Phil F.
AU - Schindler, Katja
AU - Weide, Benjamin
AU - Held, Ulrike
AU - Frauchiger, Anna L.
AU - Romano, Emanuella
AU - Kähler, Katharina C.
AU - Rozati, Sima
AU - Rechsteiner, Markus
AU - Moch, Holger
AU - Michielin, Olivier
AU - Garbe, Claus
AU - Hauschild, Axel
AU - Hoeller, Christoph
AU - Dummer, Reinhard
AU - Goldinger, Simone M.
N1 - Funding Information:
O.M. has a consultant or advisory board relationship with Novartis, Merck Sharp & Dhome, Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Amgen. J.M., P.F.C., K.S, U.H., A.F., E.R., M.R., and H.M. did not declare any conflicts of interest or funding. B.W. received research funding, travel grants, and honoraria from Bristol-Myers Squibb, and travel grants and honoraria from Roche. K.C.K. declares speakers fees and travel grants from BMS, Roche, and MSD. S.R. declares a compensated research fellowship. C.G. reports grants and personal fees from BMS, during the conduct of the study; grants and personal fees from GSK; personal fees from MSD, personal fees from Novartis; grants and personal fees from Roche; personal fees from Philogen; and personal fees from Amgen, outside the submitted work. A.H. reports consultancies for Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche Pharma. He receives honoraria from Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma and receives trial grants (clinical trials) from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche Pharma. C.H. reports advisory positions at BMS, Roche, GSK and speakers honoraria at BMS, Roche, GSK, MSD, Amgen, and Novartis. R.D. receives research funding from Astra Zeneca, Novartis, Cephalon, Merck Sharp & Dhome, Transgene, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Bayer, and has a consultant or advisory board relationship with Astra Zeneca, Novartis, Cephalon, Merck Sharp & Dhome, Transgene, Genta, Bayer, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Spirig, and Amgen. S.M.G. receives research funding from the University Hospital Zurich, has advisory board relationship with Merck Sharp & Dhome and received travel grant support from MSD and BMS. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2015 Mangana et al.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Ipilimumab and tremelimumab are humanmonoclonal antibodies (Abs) against cytotoxic Tlymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti- CTLA-4 antibodies from December 2006 until August 2012. Themedian overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78- 13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). Themedian OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to themedian OS of BRAFmutated patients (n = 38, mOS = 8.03months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.
AB - Ipilimumab and tremelimumab are humanmonoclonal antibodies (Abs) against cytotoxic Tlymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti- CTLA-4 antibodies from December 2006 until August 2012. Themedian overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78- 13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). Themedian OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to themedian OS of BRAFmutated patients (n = 38, mOS = 8.03months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.
UR - http://www.scopus.com/inward/record.url?scp=84947285069&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947285069&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0139438
DO - 10.1371/journal.pone.0139438
M3 - Article
C2 - 26426340
AN - SCOPUS:84947285069
SN - 1932-6203
VL - 10
JO - PLoS One
JF - PLoS One
IS - 10
M1 - e0139438
ER -