First experiences with the use of targeted and immunotherapy in the treatment of cutaneous melanoma: a single Centre experience
Abstract
Background / Aim: Up until ten years ago stage four melanoma was considered a disease with extremely poor prognosis. Standard therapy during this period of time was dacarbazine chemotherapy. Patients with better performance status were treated with immunotherapy cytokine IL-2. In the last ten years eight medications have been approved by the FDA for the therapy of melanoma. The goal of this study was to determine objective response rate (ORR), median overall survival (OS), median progression free survival (PFS) and safety in patients with advanced and metastatic cutaneous melanoma treated with targeted therapy and immunotherapy at the University Clinical Centre of the Republic of Srpska (Centre).
Methods: A non-randomised observational retrospective/prospective trial was conducted to investigate first experiences with the use of targeted therapy and immunotherapy at the Centre and compare the results with the literature data. A total of 23 patients received BRAF targeted therapy for the treatment of metastatic cutaneous melanoma in the first line of treatment. Nine patients received vemurafenib, fourteen patients received a combination of BRAF/MEK inhibitor. Nine patients were treated with pembrolizumab immunotherapy. The trial was performed in a period from May 2017 until December 2020.
Results: In patients receiving vemurafenib ORR was 44.4 %, median PFS was 5 months (95 % CI, 1 to 11) and the median OS was 9 months (95 % CI, 2 to 17). In the vemurafenib/cobimetinib group ORR was 71.4 %. Median PFS was 9 months and median OS was 12 months. ORR in patients receiving pembrolizumab was 22.9 %, median PFS was 3 months (95 % CI, 1 to 11) and the median OS was 4.5 months (95 % CI, 2 to 12).
Results in all three groups were inferior compared to the results from the literature except for ORR in patients receiving vemurafenib and vemurafenib/cobimetinib. Adverse events were tolerable and manageable and were similar to those described in the literature.
Conclusion: Based on the experience with the targeted and immunotherapy in the Centre, which was presented in this study, it was concluded that in conditions when there is limited access to drugs, the greatest benefit have the patients who meet the inclusion criteria in clinical trials.
References
Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 2017 Aug;14(8):463-82.
Luke JJ, Schwartz GK. Chemotherapy in the management of advanced cutaneous malignant melanoma. Clin Dermatol 2013;31:290–7.
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999 Jul;17(7):2105-16.
Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016 Sep;17(9):1248-60.
Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017 Oct 21;390(10105):1853-62.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jun 27;417(6892):949-54.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011 Jun 30;364(26):2507-16.
McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014 Mar;15(3):323-32.
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 2014 Aug;15(9):954-65.
Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014 Nov 13;371(20):1867-76.
McArthur G, Larkin J, Dréno B, Ascierto P. Impact of baseline genetic heterogeneities on progression-free survival (PFS) in patients (pts) with advanced BRAFV600 mutated melanoma treated with cobimetinib (COBI) + vemurafenib (VEM) in the phase 3 coBRIM study [abstract 25LBA]. Eur J Cancer 2015;51 Suppl 3:S722–S723.
Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther 2015;37(4):764–82.
Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase ii and phase iii trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015 Jun 10;33(17):1889-94.
Merck Sharp & Dohme Corp. KEYTRUDAVR (Pembrolizumab) for injection, for intravenous use. Whitehouse Station, NJ: Merck & Co. Inc; 2018.
Bristol-Myers Squibb Company. OPDIVOVR (Nivolumab) injection, for intravenous use. Princeton, NJ: Bristol-Myers Squibb Company 2018.
Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol 2016; 34(Suppl 15): 9503.
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015 Aug;16(8):908-18.
Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 2016;315(15):1600–9.
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(26):2521–32.
Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016;34(13):1510–7.
Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, et al. Final analysis of a randomized trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer 2017;86:37–45.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32(10):1020–30.
Hodi FS, Kluger H, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. Presented at AACR Annual Meeting, April 16–20, 2016, New Orleans, LA.
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(4):320–30.
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16(4):375–84.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009 Jan;45(2):228-47.
National Cancer Institute [Internet]. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. May 29,2009 Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Cited: 2020 May 1.
Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014 Apr;15(4):436-44.
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, at al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2019 Apr 1;30(4):582-8.
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