Garbe C, Eigentler TK, Keilholz U, et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011;16:5–24.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wolchock JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.

Article  Google Scholar 

Hodi FS, O’Day SJ, McDermotte DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Robert C, Schachter J, Long GV, et al. KEYNOTE-006 Investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

Article  CAS  PubMed  Google Scholar 

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.

Article  CAS  PubMed  Google Scholar 

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.

Article  CAS  PubMed  Google Scholar 

Weber JS, D’Angelo SP, Minor D, 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.

Article  CAS  PubMed  Google Scholar 

Robert C, Ribas A, Hamid O, et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol. 2018;36:1668–74.

Article  CAS  PubMed  Google Scholar 

Ribas A, Hamid O, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600–9.

Article  CAS  PubMed  Google Scholar 

Robert C, Ribas A, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. JCO. 2016;34(Suppl 15):9503.

Article  Google Scholar 

Schachter J, Ribas A, 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(10105):1853–62.

Article  CAS  PubMed  Google Scholar 

Hamid O, Puzanov I, et al. Final analysis of a randomized trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractor advanced melanoma. Eur J Cancer. 2017;86:37–45.

Article  CAS  PubMed  Google Scholar 

Hamid O, Robert C, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019;30(4):582–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hodi FS, Chiarion-Sileni V, 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(11):1480–92.

Article  CAS  PubMed  Google Scholar 

Larkin J, Chiarion-Sileni V, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535–46.

Article  CAS  PubMed  Google Scholar 

•• Wolchok JD, Chiarion-Sileni V, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127–37. These 6.5-year CheckMate 067 results showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and with the combination over nivolumab monotherapy.

Article  CAS  PubMed  Google Scholar 

•• Robert C, Marabelle A, et al. Immunotherapy discontinuation — how, and when? Data from melanoma as a paradigm. Nat Rev Clin Oncol. 2022;17:707–15. For the first time in the management of patients with metastatic cancer, considering stopping therapy has become possible for patients who had considerable benefit from treatment. These observations first became apparent in patients with melanoma and are now beginning to be described for several other cancer types. Today, the best marker for long-term survival and a minimal risk of disease relapse after stopping therapy is the achievement of a CR, which should, therefore, become a new crucial end point for clinical trials.

Article  Google Scholar 

Robert C, Ribas A, 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;20:1239–51.

Article  CAS  PubMed  Google Scholar 

Tawbi HA, Forsyth PA, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12):1692–704.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Di Giacomo AM, Chiarion-Sileni V, et al. Primary analysis and 4-year follow-up of the phase III NIBIT-M2 trial in melanoma patients with brain metastases. Clin Cancer Res. 2021;27:4737–45.

Article  PubMed  Google Scholar 

Long GV, Atkinson V, et al. Five-year overall survival from Anti-PD1 Brain Collaboration (ABC study): randomised phase 2 study of nivolumab or nivolumab+ipilimumab in patients with melanoma brain metastases. American Society of Clinical Oncology (ASCO) Congress; 2021. (abstr 9508)

Google Scholar 

•• Robert C, Carlino M, et al. Seven-year follow-up of the phase 3 KEYNOTE-006 study: pembrolizumab versus ipilimumab in advanced melanoma. JCO. 2023; In press. The results of this long-term follow-up showed that the survival benefits previously observed with pembrolizumab in advanced melanoma remain stable over time, with a 7-year OS of 37.8% for all patients and 41.2% for those who received first-line pembrolizumab, and a 7-year PFS of 23.8%. An OS benefit was seen regardless of BRAF-mutation status and receipt of prior BRAF/MEK-inhibitor therapy and poor prognostic characteristics.

Schadendorf D, Wolchok J, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807–14.

Article  CAS  PubMed  PubMed Central  Google Scholar 

. Robert C, Hwu WJ, et al. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: a landmark analysis in patients with advanced melanoma. Eur J Cancer. 2021;144:182–91. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.

Article  CAS  PubMed  Google Scholar 

Weber JS, Hodi FS, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92.

Article  CAS  PubMed  Google Scholar 

Freeman-Keller M, Kim Y, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Canc Res. 2016;22(4):886–94.

Article  CAS  Google Scholar 

Jansen YJL, Rozeman EA, et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann Oncol. 2019;30(7):1154–61.

Article  CAS  PubMed  Google Scholar 

Dimitriou F, Zaremba A, et al. Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response. Eur J Cancer. 2021;149:37–48.

Article  CAS  PubMed  Google Scholar 

Reck M, Rodriguez-Abreu D, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol. 2021;39(21):2339–49.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sholl M, L. Biomarkers of response to checkpoint inhibitors beyond PD-L1 in lung cancer. Mod Pathol. 2022;35(Suppl 1):66–74.

Article  CAS  PubMed  Google Scholar 

Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, et al. Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res. 2018;28:1–236.

Article  Google Scholar 

Tan AC, Emmett L, et al. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol. 2018;29(10):2115–20.

Article  CAS  PubMed  Google Scholar 

Vilain RE, Menzies AM, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res. 2017;23(17):5024–33.

Article  CAS  PubMed  Google Scholar 

Dall'Olio FG, Marabelle A, et al. Tumour burden and efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2022;19(2):75–90.

Article  CAS  PubMed  Google Scholar 

Lee JH, Menzies AM, et al. Longitudinal monitoring of ctDNA in patients with melanoma and brain metastases treated with immune checkpoint inhibitors. Clin Cancer Res. 2020;26(15):4064–71.

Article  CAS  PubMed  Google Scholar 

Marsavela G, Lee J, et al. Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy. Clin Cancer Res. 2020;26(22):5926–33.

Article  CAS  PubMed