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Published in: Clinical and Translational Oncology 1/2017

01-01-2017 | Research Article

Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma

Authors: F. Aya, A. Fernandez-Martinez, L. Gaba, I. Victoria, M. Tosca, E. Pineda, P. Gascon, A. Prat, A. Arance

Published in: Clinical and Translational Oncology | Issue 1/2017

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Abstract

Purpose

Immunotherapy (IT) agents and BRAF inhibitors (BRAFi) are effective treatments for patients with advanced BRAF-mutant melanoma although the optimal sequence remains to be elucidated. The aim of this study was to compare the outcomes of two different cohorts of patients treated with BRAFi first, then IT or the reverse sequence.

Patients and methods

This is a retrospective study on two groups of patients: a cohort was treated first with BRAFi followed by immunotherapy (BRAFi-IT) and the other cohort with the reverse sequence (IT-BRAFi). Baseline characteristics and clinical outcomes were compared between the two cohorts.

Results

A total of 25 patients were included in the study. Sixteen patients were given BRAFi-IT sequence and nine received IT-BRAFi sequence. No differences were observed in the characteristics of patients prior to each treatment between cohorts. Objective response rate (ORR) achieved by BRAFi were not different among groups. ORR achieved by IT was higher when administered after BRAFi (43.8 vs 0 %). Survival rates at 1–2 years were similar in both cohorts and median overall survival was not different for BRAFi-IT and IT-BRAFi (log rank test p = 0.97).

Conclusions

No differences were observed in OS between the two cohorts. These results support the indistinct use of IT or BRAFi as initial treatment in patients with metastatic BRAF-mutant melanoma, although higher rate of response to IT was observed when administered after BRAFi. Prospective randomized clinical trials are needed on this issue.
Literature
1.
go back to reference Korn EL, Liu P-Y, Lee SJ, Chapman J-AW, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:527–34.CrossRef Korn EL, Liu P-Y, Lee SJ, Chapman J-AW, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:527–34.CrossRef
2.
go back to reference Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.CrossRefPubMed Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.CrossRefPubMed
3.
go back to reference Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–8.CrossRefPubMed Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–8.CrossRefPubMed
4.
go back to reference Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7.CrossRefPubMedPubMedCentral Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7.CrossRefPubMedPubMedCentral
5.
go back to reference Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol (CB). 2005;15:249–54.CrossRef Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol (CB). 2005;15:249–54.CrossRef
6.
go back to reference Willmore-Payne C, Holden JA, Tripp S, Layfield LJ. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol. 2005;36:486–93.CrossRefPubMed Willmore-Payne C, Holden JA, Tripp S, Layfield LJ. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol. 2005;36:486–93.CrossRefPubMed
7.
go back to reference Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16:267–73.CrossRefPubMed Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16:267–73.CrossRefPubMed
8.
go back to reference Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentral Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentral
9.
go back to reference Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.CrossRefPubMed Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.CrossRefPubMed
10.
go back to reference Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47.CrossRefPubMedPubMedCentral Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47.CrossRefPubMedPubMedCentral
11.
go back to reference McDermott D, Lebbé C, Hodi FS, Maio M, Weber JS, Wolchok JD, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40:1056–64.CrossRefPubMed McDermott D, Lebbé C, Hodi FS, Maio M, Weber JS, Wolchok JD, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40:1056–64.CrossRefPubMed
12.
go back to reference Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRefPubMed Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRefPubMed
13.
go back to reference Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.CrossRefPubMed Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.CrossRefPubMed
14.
go back to reference Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.CrossRefPubMed Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.CrossRefPubMed
15.
go back to reference Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentral Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentral
16.
go back to reference Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.CrossRefPubMedPubMedCentral Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.CrossRefPubMedPubMedCentral
17.
go back to reference Jarkowski A, Norris L, Trinh VA. Controversies in the management of advanced melanoma: “gray” areas amid the “black and blue”. Ann Pharmacother. 2014;48:1456–68.CrossRefPubMed Jarkowski A, Norris L, Trinh VA. Controversies in the management of advanced melanoma: “gray” areas amid the “black and blue”. Ann Pharmacother. 2014;48:1456–68.CrossRefPubMed
18.
go back to reference Cooper ZA, Frederick DT, Ahmed Z, Wargo JA. Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma. Oncoimmunology. 2013;2:e24320.CrossRefPubMedPubMedCentral Cooper ZA, Frederick DT, Ahmed Z, Wargo JA. Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma. Oncoimmunology. 2013;2:e24320.CrossRefPubMedPubMedCentral
19.
go back to reference Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6.CrossRefPubMed Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6.CrossRefPubMed
20.
go back to reference Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695–701.CrossRefPubMed Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695–701.CrossRefPubMed
21.
go back to reference Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31.CrossRefPubMedPubMedCentral Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31.CrossRefPubMedPubMedCentral
22.
go back to reference Ascierto PA, Simeone E, Sileni VC, Del Vecchio M, Marchetti P, Cappellini GCA, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32:144–9.CrossRefPubMed Ascierto PA, Simeone E, Sileni VC, Del Vecchio M, Marchetti P, Cappellini GCA, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32:144–9.CrossRefPubMed
23.
go back to reference Fisher R, Ali Z, Edmonds K, Turajlic S, Gore M, Larkin J. Clinical behaviour of metastatic melanoma after progression on vemurafenib [abstract]. Pigment Cell Melanoma Res. 2012;25:856. Fisher R, Ali Z, Edmonds K, Turajlic S, Gore M, Larkin J. Clinical behaviour of metastatic melanoma after progression on vemurafenib [abstract]. Pigment Cell Melanoma Res. 2012;25:856.
24.
go back to reference Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be more beneficial than vice versa for the majority of patients with advanced melanoma. Cancer. 2014;120:1617–9.CrossRefPubMed Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be more beneficial than vice versa for the majority of patients with advanced melanoma. Cancer. 2014;120:1617–9.CrossRefPubMed
25.
go back to reference Grob JJ, Long GV, Schadendorf D, Flaherty K. Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials. Lancet Oncol. 2015;16:e522–6.CrossRefPubMed Grob JJ, Long GV, Schadendorf D, Flaherty K. Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials. Lancet Oncol. 2015;16:e522–6.CrossRefPubMed
Metadata
Title
Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma
Authors
F. Aya
A. Fernandez-Martinez
L. Gaba
I. Victoria
M. Tosca
E. Pineda
P. Gascon
A. Prat
A. Arance
Publication date
01-01-2017
Publisher
Springer International Publishing
Published in
Clinical and Translational Oncology / Issue 1/2017
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-016-1514-0

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