Treatment in metastatic melanoma—time to re-think
Authors: D. Schadendorf, E. Livingstone, L. Zimmer
Journal: Annals of Oncology (2019)

After decades of lacking efficacious treatment options for advanced melanoma und regular failure of experimental approaches [1.Schadendorf D. van Akkooi A.C.J. Berking C. et al.Melanoma.Lancet. 2018; 392: 971-984Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar], the success story in melanoma treatment began with the discovery of the B-Raf proto-oncogene serine/threonine-kinase (BRAF) V600 mutation as an oncogenic driver [2.Davies H. Bignell G.R. Cox C. et al.Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8271) Google Scholar]. The subsequent development and fast introduction of BRAF/MEK blockade with small molecules led to improved progression-free survival (PFS) and overall survival (OS) in a large group of patients with BRAF-mutated tumors (reviewed in reference 1). Rather parallel, the success story also unfolded in the field of immunotherapy. Melanoma is a model tumor for immunogenicity and, lacking treatment options, it was the ideal tumor for clinical investigations of checkpoint blockers. The era of checkpoint blockade started with the anti-CTLA4 (cytotoxic T-lymphocyte T-associated protein-4) antibodies; ipilimumab won the race as the first treatment showing a significant OS benefit in advanced melanoma in a prospectively randomized clinical phase III study even before the BRAF inhibitors [3.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11189) Google Scholar]. Ipilimumab treatment, however, came at the cost of a new and, in some cases, also fatal toxicity profile. Clinical trials investigating another class of checkpoint blockers, antibodies directed against the PD1 receptor, started around 2011 in advanced melanoma, initially demonstrating clinical success in pretreated patients [4.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: 908-918Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar, 5.Larkin J. Minor D. D'Angelo S. et al.Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial.JCO. 2018; 36: 383-390Crossref PubMed Scopus (324) Google Scholar], and subsequently also in treatment-naive patients [6.Hodi F.S. Chiarion-Sileni V. Gonzalez R. 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: 1480-1492Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar, 7.Carlino M.S. Long G.V. 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: 236-243Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Apart from a higher response rate, PD1 blockers had the advantage of lower toxicity over ipilimumab making it a preferable treatment option. Since then, the success story of PD1 checkpoint blockade continued with an unprecedented expansion across various cancer entities. The article by Hamid et al. [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar] in this issue reports on the largest phase I trial in advanced melanoma in history with a cohort of 655 patients, Keynote-001. It was one of the first trials investigating a PD1 blocker and started recruiting patients in 2011. Patients have now been monitored for more than 5 years with a median follow-up time of 55 months [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. Objective response rates (41% in the overall patient population) and median OS (in the overall population around 2 years and in treatment-naive around 2.5 years) have not significantly changed after prolonged observation, but it is certainly noteworthy that clinical responses have been ongoing in 73% of all responses and 82% of treatment-naive responses for years with the longest response enduring at 66 months. The 5-year OS rates reported for pembrolizumab (34% in all patients and 41% in treatment-naive patients) are in line with a smaller group of melanoma patients treated with nivolumab [9.Topalian S.L. Sznol M. McDermott D.F. et al.Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.JCO. 2014; 32: 1020-1030Crossref PubMed Scopus (1771) Google Scholar], but significantly higher than for ipilimumab monotherapy [6.Hodi F.S. Chiarion-Sileni V. Gonzalez R. 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: 1480-1492Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar, 10.Schachter J. Ribas A. Long G.V. 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: 1853-1862Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar, 11.Schadendorf D. Hodi F.S. Robert C. 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; 33: 1889-1894Crossref PubMed Scopus (1494) Google Scholar]. It should not be forgotten, however, that the 5-year OS rates for targeted therapy using BRAF-MEK inhibitor combinations in a clinical phase II trial also achieve around 30% in BRAF and MEK inhibitor-naive patients (around 40% were pretreated with chemotherapy or immunotherapy) [12.Long G.V. Eroglu Z. Infante J. et al.Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib.JCO. 2018; 36: 667-673Crossref PubMed Scopus (155) Google Scholar]. The progress the melanoma community has experienced over the last decade is breathtaking; however, one must keep in mind that it is roughly only one-third of advanced melanoma patients recruited into clinical trials who are still alive at 5 years (the number is most likely even smaller in the real-world situation). In other words, two thirds of patients have died. A lot has been achieved, but a lot still needs to be done. We know for some time that several patient and clinical characteristics at and after baseline are associated with clinical outcomes and durable benefit as was shown with targeted treatment in defined patient subsets [13.Long G.V. 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: 1743-1754Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar]. Lactate dehydrogenase und number of organs with metastatic involvement have the strongest predictive value. Unfortunately, Hamid et al. [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar] have not presented any survival curves according to those accepted patient selection criteria. This would have allowed a much better estimate of the patient group deriving long-term benefit [which is not necessarily only differentiation of pretreated and treatment-naive patients as implied in this report (8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar)]. When comparing survival rates at prolonged observation, one also has to keep in mind that these survival rates are—in most cases—not the result of a single therapy. Many patients would have received several lines of therapy, which all may contribute to the extended OS. This can be proven best when comparing 3- to 5-year OS rates of ipilimumab first-line-treated patients from the first trials with rates of about 20% [11.Schadendorf D. Hodi F.S. Robert C. 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; 33: 1889-1894Crossref PubMed Scopus (1494) Google Scholar, 14.Wolchok J.D. Weber J.S. Maio M. et al.Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials.Ann Oncol. 2013; 24: 2174-2180Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar] with those of more recent trials, e.g. KEYNOTE-006 [7.Carlino M.S. Long G.V. 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: 236-243Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 10.Schachter J. Ribas A. Long G.V. 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: 1853-1862Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar] and CheckMate 067 with rates around 30% at 4 years [6.Hodi F.S. Chiarion-Sileni V. Gonzalez R. 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: 1480-1492Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar]. Interestingly, the clinically beneficial effect of MAPK blockade using BRAF-MEK inhibitor combinations on OS rates before or after PD-1 checkpoint blockade over the clinical course (e.g. OS landmarks at 3–5 years) seems to be minimal, since OS rates of BRAF-mutant melanoma patients and those carrying a BRAF wild-type melanoma do not differ significantly in any of the PD1 melanoma trials published so far. If BRAF/MEK blockade is such a potent survival prolonging treatment option (which is missing in BRAF wild-type melanoma patients) should we not expect that melanoma patients carrying a BRAF-mutant tumor survive much longer than others? This raises the question as to whether PD-1 checkpoint blockade and MAPK blockade using BRAF-MEK inhibitor combinations benefit mostly the same patient group and whether these differences that are detected at early observation time points (reviewed in reference 15.Ugurel S. Röhmel J. Ascierto P.A. et al.Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017.Eur J Cancer. 2017; 83: 247-257Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar) are only due to different response kinetics of the two substance classes but do not result in a significant effect on OS landmarks at 3–5 years. Unfortunately, survival analyses based on BRAF status (and BRAF/MEK treatment) are missing in the updated data presented by Hamid et al. [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. The study by Hamid et al. [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar] further evokes five important questions:a.Does OS in PD-1-treated advanced melanoma patients really reach a plateau? Should a drop of 4% to 8% between months 24 and 60 in the overall population or a drop between 3% and 10% per year in the treatment-naive cohort be considered relevant? Is the drop from 38% (at 4 years) to 34% (at 5 years) survival rate in the overall treatment population, and from 48% (at 4 years) to 41% (at 5 years, only 12 patients in total were under observation!) in the pretreatment-naive subset real or is it an "artifact of small numbers" OR does it have to attributed to analyzing OS instead of melanoma-specific survival?b.What is the scientific basis of late treatment failures such as relapse after 3 years or even later? And what are the best treatment strategies for these patients? With terms such as long-term clinical benefit and long duration of response which are both mostly associated with and attributed to checkpoint blockade, we need a much better description and (molecular) understanding of the mechanism. Additionally, concepts are required that help to develop models which can anticipate treatment failures early and predict the best subsequent treatment option for those relapsing patients. It is good to know that two out of four patients responded to PD1 re-exposure. But two out of four did not. Even though KEYNOTE-001comprises a large cohort of 655 patients, this report does not aid in developing such a model [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar], neither does another recent analysis. In an evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials, tumor mutational burden and T-cell-inflamed gene expression profiles were investigated and were reported to exhibit joint predictive utility in identifying responders and non-responders to pembrolizumab [16.Cristescu R. Mogg R. Ayers M. et al.Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Science. 2018; 362: eaar3593.Crossref PubMed Scopus (1085) Google Scholar]. However, whether these biomarkers have real utility in clinical patient selection or guidance is highly unlikely at this moment, since there are various open questions at this stage including agreement on methodology and cut-offs for tumor mutational burden or which of the inflammatory gene expression profiles should by implemented.And this leads to a another burning question:c.What are readily available biomarkers that predict response as well as early and late treatment failure to checkpoint blockade? Two more questions remain:d.PD 1 blockers have—compared with conventional chemotherapy and CTLA4-blocking agents—a favorable safety profile. Yet, patients can experience severe (and sometimes fatal) adverse events after only one infusion. The pathomecha-nisms behind these checkpoint-inhibitor induced adverse events need to be better understood. This would also aid in identifying patients at a higher risk for certain adverse events and in better choosing causal treatment rather than simply treating using unspecific immunosuppression with corticosteroids. Exploration of biomarkers that can predict adverse events in this data set would be of great interest.e.For how long do we need to treat? Is it safe to stop treatment in patients with response or possibly also in patients with long-term stable disease (SD)? As demonstrated herein, patients can have long-term response after treatment cessation: 72 patients stopped treatment at complete response (CR) or partial remission (PR), and only 7 patients (10%) experienced subsequent progressive disease (PD). Similar results were reported in Keynote 006 (17.Long G.V. Schachter J. Ribas A. et al.4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006.JCO. 2018; 36: 9503Crossref Google Scholar). In this study, estimated PFS in patients with PR or CR who completed 2 years of treatment with pembrolizumab was 91% and 96%, respectively, at 18 months after the last dose of pembrolizumab. In contrast, in patients with SD who stopped treatment after two years, PFS was only 67%. We must bear in mind that adverse events can also occur after long-term treatment, and the financial burden of potentially unnecessary treatment continuation for the patients and the society should not be forgotten. It would have been useful if adverse events had not only been listed by their frequency but also by the time since start of treatment to see which adverse events occurred after long-term pembrolizumab treatment, e.g. for more than 2 years. Taken together, the updated Keynote-001 report by Hamid et al. [8.Hamid O. Robert C. Daud A. et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar] continues to describe the success of PD-1 blockade in advanced melanoma. And it is certainly a great success that was achieved in only a few years. However, this does not allow us to sit back and relax. Around two-thirds of initially treated melanoma patients have died within 5 years, clearly indicating that we have achieved only a few steps toward our final aim of providing long-lasting clinical benefit to most of our melanoma patients. Particularly, patients with a poor prognosis profile such as high lactate dehydrogenase, multiple organ sites and/or high tumor load still have a very high medical need; their chance of achieving a (complete) clinical and durable response is low for any currently available drug. Clinical trials are urgently needed that focus on those patients in need and which test more vigorously already established drugs (in different sequences) as well as new agents. None declared.