BACKGROUND: Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. METHODS: This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. RESULTS: Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. CONCLUSIONS: Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

Department of Clinical Radiotherapy and Oncology University Hospital in Hradec Kralove Hradec Kralove Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Dermatovenereology 3rd Faculty of Medicine Charles University and Kralovske Vinohrady University Hospital Prague Czech Republic

Department of Oncology County Hospital České Budějovice Czech Republic

Department of Oncology Faculty of Medicine and Dentistry Palacký University and University Hospital Olomouc Czech Republic

Zobrazit více v PubMed

Ascierto P. SECOMBIT: the best sequential approach with combo immunotherapy [ipilimumab (I)/nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with BRAF mutated metastatic melanoma: a phase II randomized study. Ann Oncol. 2021;32(Suppl_5):S1283‐S1346. doi:10.1016/S0923-7534(21)04227-7 DOI

Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial—ECOG‐ACRIN EA6134. J Clin Oncol. 2021;39(36_suppl):356154. doi:10.1200/JCO.2021.39.36_suppl.356154 DOI

Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF‐mutant melanoma: the DREAMseq trial‐ECOG‐ACRIN EA6134. J Clin Oncol. 2023;41(2):186‐197. doi:10.1200/jco.22.01763 PubMed DOI PMC

Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24‐34. doi:10.1056/NEJMoa2109970 PubMed DOI PMC

Wolchok JD, Chiarion‐Sileni V, Gonzalez R, et al. Long‐term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2021;40:127‐137. doi:10.1200/JCO.21.02229 PubMed DOI PMC

Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE‐006): post‐hoc 5‐year results from an open‐label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239‐1251. doi:10.1016/s1470-2045(19)30388-2 PubMed DOI

Zhong JH, Huang DH, Chen ZY. Prognostic role of systemic immune‐inflammation index in solid tumors: a systematic review and meta‐analysis. Oncotarget. 2017;8(43):75381‐75388. doi:10.18632/oncotarget.18856 PubMed DOI PMC

Hu K, Lou L, Ye J, Zhang S. Prognostic role of the neutrophil‐lymphocyte ratio in renal cell carcinoma: a meta‐analysis. BMJ Open. 2015;5(4):e006404. doi:10.1136/bmjopen-2014-006404 PubMed DOI PMC

Kou J, Huang J, Li J, Wu Z, Ni L. Systemic immune‐inflammation index predicts prognosis and responsiveness to immunotherapy in cancer patients: a systematic review and meta‐analysis. Clin Exp Med. 2023;23:3895‐3905. doi:10.1007/s10238-023-01035-y PubMed DOI

Gambichler T, Mansour R, Scheel CH, Said S, Abu Rached N, Susok L. Prognostic performance of the derived neutrophil‐to‐lymphocyte ratio in stage IV melanoma patients treated with immune checkpoint inhibitors. Dermato. 2022;2(2):14‐20.

Capone M, Giannarelli D, Mallardo D, et al. Baseline neutrophil‐to‐lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer. 2018;6(1):74. doi:10.1186/s40425-018-0383-1 PubMed DOI PMC

Zhang F, Gong W. Prognostic value of the platelet‐to‐lymphocyte ratio in patients with melanoma: a meta‐analysis. Front Oncol. 2020;10:1116. doi:10.3389/fonc.2020.01116 PubMed DOI PMC

Wan L, Wu C, Luo S, Xie X. Prognostic value of lymphocyte‐to‐monocyte ratio (LMR) in cancer patients undergoing immune checkpoint inhibitors. Dis Markers. 2022;2022:3610038. doi:10.1155/2022/3610038 PubMed DOI PMC

Kopecky J, Kubecek O, Priester P, Vosmikova H, Cermakova E, Kyllarova A. Prognostic value of blood cell count‐derived ratios in BRAF‐mutated metastatic melanoma. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2021;166:393‐404. doi:10.5507/bp.2021.053 PubMed DOI

Liszkay G, Gogas H, Mandalà M, et al. Update on overall survival in COLUMBUS: a randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600–mutant melanoma. J Clin Oncol. 2019;37(15_suppl):9512. doi:10.1200/JCO.2019.37.15_suppl.9512 DOI

Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30‐39. doi:10.1056/NEJMoa1412690 PubMed DOI

Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF‐mutated melanoma. N Engl J Med. 2014;371(20):1867‐1876. doi:10.1056/NEJMoa1408868 PubMed DOI

Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711‐723. doi:10.1056/NEJMoa1003466 PubMed DOI PMC

Larkin J, Chiarion‐Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23‐34. doi:10.1056/NEJMoa1504030 PubMed DOI PMC

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521‐2532. doi:10.1056/NEJMoa1503093 PubMed DOI

Donia M, Kimper‐Karl ML, Høyer KL, Bastholt L, Schmidt H, Svane IM. The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials. Eur J Cancer. 2017;74:89‐95. doi:10.1016/j.ejca.2016.12.017 PubMed DOI

Betof Warner A, Tarhini A, Kang B, et al. Real‐world outcomes of different lines and sequences of treatment in BRAF‐positive advanced melanoma patients. Melanoma Res. 2023;33(1):38‐49. doi:10.1097/cmr.0000000000000856 PubMed DOI

Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K‐mutant melanoma: long‐term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631‐1639. doi:10.1093/annonc/mdx176 PubMed DOI PMC

Robert C, Grob JJ, Stroyakovskiy D, et al. Five‐year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381:626‐636. doi:10.1056/NEJMoa1904059 PubMed DOI

Dummer R. 5‐year update on COLUMBUS: a randomized phase III trial of encorafenib (enco) + binimetinib (bini) versus enco or vemurafenib (vem) in patients (pts) with BRAF V600‐mutant melanoma. Ann Oncol. 2021;32(Suppl_5):S867‐S905. doi:10.1016/S0923-7534(21)04227-7 DOI

Ascierto PA, Dréno B, Larkin J, et al. 5‐year outcomes with Cobimetinib plus vemurafenib in BRAF (V600) mutation‐positive advanced melanoma: extended follow‐up of the coBRIM study. Clin Cancer Res. 2021;27:5225‐5235. doi:10.1158/1078-0432.ccr-21-0809 PubMed DOI PMC

Robert C, Long GV, Brady B, et al. Five‐year outcomes with nivolumab in patients with wild‐type BRAF advanced melanoma. J Clin Oncol. 2020;38(33):3937‐3946. doi:10.1200/jco.20.00995 PubMed DOI PMC

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320‐330. doi:10.1056/NEJMoa1412082 PubMed DOI

Carlino MS, Long GV, Schadendorf D, et al. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE‐006: a randomised clinical trial. Eur J Cancer. 2018;101:236‐243. doi:10.1016/j.ejca.2018.06.034 PubMed DOI

Kim SI, Cassella CR, Byrne KT. Tumor burden and immunotherapy: impact on immune infiltration and therapeutic outcomes. Front Immunol. 2021;11:629722. doi:10.3389/fimmu.2020.629722 PubMed DOI PMC

Joseph RW, Elassaiss‐Schaap J, Kefford R, et al. Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab. Clin Cancer Res. 2018;24(20):4960‐4967. doi:10.1158/1078-0432.Ccr-17-2386 PubMed DOI PMC

Tarantino P, Marra A, Gandini S, et al. Association between baseline tumour burden and outcome in patients with cancer treated with next‐generation immunoncology agents. Eur J Cancer. 2020;139:92‐98. doi:10.1016/j.ejca.2020.08.026 PubMed DOI

Long GV, Grob J‐J, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17(12):1743‐1754. doi:10.1016/S1470-2045(16)30578-2 PubMed DOI

Schadendorf D, Long GV, Stroiakovski D, et al. Three‐year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45‐55. doi:10.1016/j.ejca.2017.05.033 PubMed DOI

Lewis KD, Larkin J, Ribas A, et al. Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM‐2, BRIM‐3, BRIM‐7 and coBRIM. Br J Cancer. 2019;121(7):522‐528. doi:10.1038/s41416-019-0546-y PubMed DOI PMC

Parvathareddy SK, Siraj AK, Al‐Badawi IA, et al. Differential expression of PD‐L1 between primary and metastatic epithelial ovarian cancer and its clinico‐pathological correlation. Sci Rep. 2021;11(1):3750. doi:10.1038/s41598-021-83276-z PubMed DOI PMC

Placke JM, Kimmig M, Griewank K, et al. Correlation of tumor PD‐L1 expression in different tissue types and outcome of PD‐1‐based immunotherapy in metastatic melanoma–analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM. EBioMedicine. 2023;96:104774. doi:10.1016/j.ebiom.2023.104774 PubMed DOI PMC

Robinson AV, Keeble C, Lo MCI, et al. The neutrophil‐lymphocyte ratio and locoregional melanoma: a multicentre cohort study. Cancer Immunol Immunother. 2020;69(4):559‐568. doi:10.1007/s00262-019-02478-7 PubMed DOI PMC

Wang Z, Peng S, Wang A, et al. Platelet‐lymphocyte ratio acts as an independent predictor of prognosis in patients with renal cell carcinoma. Clin Chim Acta. 2018;480:166‐172. doi:10.1016/j.cca.2018.02.014 PubMed DOI

Cassidy MR, Wolchok RE, Zheng J, et al. Neutrophil to lymphocyte ratio is associated with outcome during ipilimumab treatment. EBioMedicine. 2017;18:56‐61. doi:10.1016/j.ebiom.2017.03.029 PubMed DOI PMC

Zaragoza J, Caille A, Beneton N, et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol. 2016;174(1):146‐151. doi:10.1111/bjd.14155 PubMed DOI

Ferrucci PF, Ascierto PA, Pigozzo J, et al. Baseline neutrophils and derived neutrophil‐to‐lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol. 2016;27(4):732‐738. doi:10.1093/annonc/mdw016 PubMed DOI

Bartlett EK, Flynn JR, Panageas KS, et al. High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy. Cancer. 2020;126(1):76‐85. doi:10.1002/cncr.32506 PubMed DOI PMC

Fujisawa Y, Yoshino K, Otsuka A, et al. Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population. Br J Dermatol. 2018;179(1):213‐215. doi:10.1111/bjd.16427 PubMed DOI

Matsumura Y, Kawarada Y, Matsuo M, et al. Retrospective analysis of neutrophil‐to‐lymphocyte ratio in patients with melanoma who received ipilimumab monotherapy or ipilimumab in combination with nivolumab in Japan. Biol Pharm Bull. 2023;46(3):427‐431. doi:10.1248/bpb.b22-00750 PubMed DOI

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860‐867. doi:10.1038/nature01322 PubMed DOI PMC

Uribe‐Querol E, Rosales C. Neutrophils in cancer: two sides of the same coin. J Immunol Res. 2015;2015:983698. doi:10.1155/2015/983698 PubMed DOI PMC

Goubran HA, Burnouf T, Radosevic M, El‐Ekiaby M. The platelet‐cancer loop. Eur J Intern Med. 2013;24(5):393‐400. doi:10.1016/j.ejim.2013.01.017 PubMed DOI

Olingy CE, Dinh HQ, Hedrick CC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol. 2019;106(2):309‐322. doi:10.1002/jlb.4ri0818-311r PubMed DOI PMC

Ascierto PA, Mandalà M, Ferrucci PF, et al. Phase II study SECOMBIT (sequential combo immuno and target therapy study): a subgroup analysis with a longer follow‐up. J Clin Oncol. 2022;40(16_suppl):9535. doi:10.1200/JCO.2022.40.16_suppl.9535 DOI

Reddy SM, Reuben A, Wargo JA. Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr Oncol Rep. 2016;18(7):42. doi:10.1007/s11912-016-0531-z PubMed DOI PMC

Adams R, Coumbe JEM, Coumbe BGT, et al. BRAF inhibitors and their immunological effects in malignant melanoma. Expert Rev Clin Immunol. 2022;18(4):347‐362. doi:10.1080/1744666x.2022.2044796 PubMed DOI

Jung T, Haist M, Kuske M, Grabbe S, Bros M. Immunomodulatory properties of BRAF and MEK inhibitors used for melanoma therapy‐paradoxical ERK activation and beyond. Int J Mol Sci. 2021;22(18):9890. doi:10.3390/ijms22189890 PubMed DOI PMC

Cooper ZA, Reuben A, Spencer CN, et al. Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma. Onco Targets Ther. 2016;5(3):e1136044. doi:10.1080/2162402x.2015.1136044 PubMed DOI PMC

Frederick DT, Piris A, Cogdill AP, 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(5):1225‐1231. doi:10.1158/1078-0432.ccr-12-1630 PubMed DOI PMC

Daud A, Ribas A, Robert C, et al. Long‐term efficacy of pembrolizumab (pembro; MK‐3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE‐001. J Clin Oncol. 2015;33(15_suppl):9005. doi:10.1200/jco.2015.33.15_suppl.9005 DOI

Puzanov I, Ribas A, Robert C, et al. Association of BRAF V600E/K mutation status and prior BRAF/MEK inhibition with pembrolizumab outcomes in advanced melanoma: pooled analysis of 3 clinical trials. JAMA Oncol. 2020;6(8):1256‐1264. doi:10.1001/jamaoncol.2020.2288 PubMed DOI PMC

Ascierto PA, Mandala M, Ferrucci PF, et al. LBA40 SECOMBIT: the best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with BRAF mutated metastatic melanoma: a phase II randomized study. Ann Oncol. 2021;32:S1316‐S1317. doi:10.1016/j.annonc.2021.08.2118 DOI

Trojaniello C, Sparano F, Cioli E, Ascierto PA. Sequencing targeted and immune therapy in BRAF‐mutant melanoma: lessons learned. Curr Oncol Rep. 2023;25(6):623‐634. doi:10.1007/s11912-023-01402-8 PubMed DOI PMC

Ferrucci PF, Di Giacomo AM, Del Vecchio M, et al. KEYNOTE‐022 part 3: a randomized, double‐blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF‐mutant melanoma. J Immunother Cancer. 2020;8(2):e001806. doi:10.1136/jitc-2020-001806 PubMed DOI PMC

Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first‐line treatment for unresectable advanced BRAF (V600) mutation‐positive melanoma (IMspire150): primary analysis of the randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet. 2020;395(10240):1835‐1844. doi:10.1016/s0140-6736(20)30934-x PubMed DOI

Dummer R, Long GV, Robert C, et al. Randomized phase III trial evaluating Spartalizumab plus dabrafenib and trametinib for BRAF V600‐mutant unresectable or metastatic melanoma. J Clin Oncol. 2022;40(13):1428‐1438. doi:10.1200/jco.21.01601 PubMed DOI PMC