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Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, Romano E, Kähler KC, Rozati S, Rechsteiner M, Moch H, Michielin O, Garbe C, Hauschild A, Hoeller C, Dummer R, Goldinger SM - PLoS ONE (2015)

Bottom Line: 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).The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

ABSTRACT
Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte 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. The median 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). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) 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.

No MeSH data available.


Related in: MedlinePlus

Overview of all anti-CTLA-4 patients according to treatment duration and treatment with BRAF or MEK inhibitors either prior or after anti-CTLA-4Abs.Each bar represents one patient.
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pone.0139438.g001: Overview of all anti-CTLA-4 patients according to treatment duration and treatment with BRAF or MEK inhibitors either prior or after anti-CTLA-4Abs.Each bar represents one patient.

Mentions: Fifteen patients (15%) received anti-CTLA-4 Abs as first line treatment. The median TD in the complete study cohort (n = 101) was 2.38 months. Sixty-nine patients (69%) were able to complete 4 cycles of anti-CTLA-4 treatment. After completion of anti-CTLA-4 treatment, nine patients were subsequently treated with BRAF or MEK inhibitors. Sixteen patients received either a BRAF or MEK inhibitor prior to anti-CTLA-4 treatment with only eight of them (50%) being able to finish 4 cycles of treatment; two of the patients were re-exposed to BRAF or MEK inhibition treatment upon progression to anti-CTLA-4 Abs. The rest of the patients (n = 8) discontinued the treatment either due to progression (n = 7) or due to adverse events (n = 1) (Fig 1).


Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, Romano E, Kähler KC, Rozati S, Rechsteiner M, Moch H, Michielin O, Garbe C, Hauschild A, Hoeller C, Dummer R, Goldinger SM - PLoS ONE (2015)

Overview of all anti-CTLA-4 patients according to treatment duration and treatment with BRAF or MEK inhibitors either prior or after anti-CTLA-4Abs.Each bar represents one patient.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591284&req=5

pone.0139438.g001: Overview of all anti-CTLA-4 patients according to treatment duration and treatment with BRAF or MEK inhibitors either prior or after anti-CTLA-4Abs.Each bar represents one patient.
Mentions: Fifteen patients (15%) received anti-CTLA-4 Abs as first line treatment. The median TD in the complete study cohort (n = 101) was 2.38 months. Sixty-nine patients (69%) were able to complete 4 cycles of anti-CTLA-4 treatment. After completion of anti-CTLA-4 treatment, nine patients were subsequently treated with BRAF or MEK inhibitors. Sixteen patients received either a BRAF or MEK inhibitor prior to anti-CTLA-4 treatment with only eight of them (50%) being able to finish 4 cycles of treatment; two of the patients were re-exposed to BRAF or MEK inhibition treatment upon progression to anti-CTLA-4 Abs. The rest of the patients (n = 8) discontinued the treatment either due to progression (n = 7) or due to adverse events (n = 1) (Fig 1).

Bottom Line: 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).The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

ABSTRACT
Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte 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. The median 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). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) 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.

No MeSH data available.


Related in: MedlinePlus