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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 7/2020

01-07-2020 | Melanoma | Melanoma

The Landmark Series: Neoadjuvant Systemic Therapy (NAST) for Stage 3 Melanoma Patients – A Potential Paradigm Shift in Management

Authors: Andrew J. Spillane, MD, Alexander M. Menzies, MBBS, PhD, Alexander C. J. van Akkooi, MD, PhD

Published in: Annals of Surgical Oncology | Issue 7/2020

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Abstract

Since the advent of effective systemic therapy, quantum changes have occurred in the multidisciplinary management strategies used for patients with American Joint Committee on Cancer stages 3 and 4 melanoma. For high-risk stage 3 patients, neoadjuvant immune checkpoint blockade (ICB) and targeted therapies present a promising novel approach to improving survival outcomes. In particular, patients who respond to ICB have an excellent prognosis, and clinical trials are ongoing to investigate whether those with a pathologic complete response (pCR) or near-pCR in a single node may avoid therapeutic lymph node dissection and adjuvant therapy. Toxicities currently are acceptably low, but when toxic events occur, they can have an enduring impact on a patient’s quality of life. To date, nearly all patients evaluated after treatment with neoadjuvant dabrafenib plus trametinib have some clinical and pathologic response. Patients who achieve pCR have improved prognosis, but pCR is not as reliable a predictor of improved outcome as pCR or near-pCR after neoadjuvant ICB. Ongoing studies should ideally be coordinated through the International Neoadjuvant Melanoma Consortium to ensure maximal efficiency at improving outcomes for melanoma patients.
Literature
1.
Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472–92.PubMedPubMedCentralCrossRef
2.
Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2019;5:187–94.PubMedCrossRef
3.
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.CrossRef
4.
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;32:1020–30.PubMedPubMedCentralCrossRef
5.
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;16:375–84.PubMedCrossRef
6.
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;390:1853–62.PubMedCrossRef
7.
Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18:611–22.PubMedCrossRef
8.
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.PubMedPubMedCentralCrossRef
9.
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.PubMedCrossRef
10.
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68.PubMedPubMedCentralCrossRef
11.
Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–92.PubMedCrossRef
12.
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.PubMedPubMedCentralCrossRef
13.
Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.PubMedPubMedCentralCrossRef
14.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56.PubMedPubMedCentralCrossRef
15.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.PubMedPubMedCentralCrossRef
16.
Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19:1315–27.PubMedCrossRef
17.
Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19:603–15.PubMedCrossRef
18.
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.PubMedCrossRef
19.
Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, 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;28:1631–9.PubMedPubMedCentralCrossRef
20.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.PubMedCrossRef
21.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.PubMedCrossRef
22.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.PubMedCrossRef
23.
24.
Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34:871–8.PubMedCrossRef
25.
26.
Robert C, Karaszewska B, Schachter J, et al. Two-year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Eur J Cancer. 2015;51:3301.
27.
Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Ann Oncol. 2016;6: 27.
28.
Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.PubMedPubMedCentralCrossRef
29.
Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–30.PubMedCrossRef
30.
Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019;119:1–10.PubMedCrossRef
31.
Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): preliminary safety and efficacy of the ipilimumab arms. J Clin Oncol. 2017; 35 (Suppl):9500.
32.
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35.PubMedCrossRef
33.
Weber J, Grob J, Margolin KA, et al. A phase III study (CheckMate 238) of adjuvant immunotherapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage IIIb/c or stage IV melanoma (MEL) in patients (pts) at high risk for recurrence. J Immunother Cancer 2015 2:3.
34.
Weber JS, Mandalà M, Vecchio MD, Gogas H, Arance AM, Cowey CL, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238). J Clin Oncol. 2018;36(Suppl):9502.CrossRef
35.
Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801.PubMedCrossRef
36.
Maio M, Lewis K, Demidov L, Mandala M, Bondarenko I, Ascierto PA, et al. Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2018;19:510–20.PubMedCrossRef
37.
Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalà M, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018;36:3441–9.PubMedPubMedCentralCrossRef
38.
Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.PubMedCrossRef
39.
Amaria RN, Menzies AM, Burton EM, Scolyer RA, et al. Shaping the future of neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium (INMC). Lancet Oncol. 2019 20:e378–89.PubMedCrossRef
40.
Tetzlaff MT, Messina JL, Stein JE, Xu X, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol. 2018;29:1861–8.PubMedPubMedCentralCrossRef
41.
Blank C, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24:1655–61.PubMedCrossRef
42.
Liu et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease Cancer Discov. 2016;6:1382–99.PubMedCrossRef
43.
Rozeman EA, Menzies AM, van Akkooi ACJ, Adhikari C, et al. Identification of the optimal combination scheme of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma: a multicentre randomized phase 2 study (OpACIN-neo). Lancet Oncol. 2019;20:948–60.PubMedCrossRef
44.
45.
Huang AC et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nature Med. 2019;25:454–61.PubMedCrossRef
46.
Fridman, WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.PubMedCrossRef
47.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.PubMedCrossRef
48.
49.
Kamphorst AO, et al. Proliferation of PD-1 + CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A. 2017;114:4993–8.PubMedCrossRef
50.
Amaria RN, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018;19:30015–9.CrossRef
51.
Metadata
Title
The Landmark Series: Neoadjuvant Systemic Therapy (NAST) for Stage 3 Melanoma Patients – A Potential Paradigm Shift in Management
Authors
Andrew J. Spillane, MD
Alexander M. Menzies, MBBS, PhD
Alexander C. J. van Akkooi, MD, PhD
Publication date
01-07-2020
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 7/2020
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-08566-8

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