ASCO 2013—treatment of metastatic melanoma: is it still a story of success?
- First Online:
- Cite this article as:
- Weinlich, G. memo (2013) 6: 244. doi:10.1007/s12254-013-0114-8
- 103 Views
‘There is a light at the end of the tunnel in the treatment of metastatic melanoma’ was the slogan of enthusiastic dermatologists around the world in 2010, when two new substances were approved by the Food and Drug Association in the United States and later on, the European Medicines Agency in Europe. Ipilimumab (Yervoy®) is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4, which switches off the mechanism of immune suppression and enables continuous, unrestrained stimulation of T-cells by dendritic cells. The objective response rates are only 10–15 %, but most of them are long lasting. The second approved substance is vemurafenib (Zelboraf®), a selective BRAF inhibitor. BRAF is a member of the Raf family, which is part of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway. Approximately 40–60 % of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signalling through the MAPK pathway. However, the duration of response has been limited, as resistance to BRAF inhibitors develops within months after initiation of treatment. So in 2013 the question arises, whether the story of success in the treatment of metastatic melanoma is prolonged and whether there are some new promising substances in the treatment pipeline. At American Society of Clinical Oncology 2013, actual data of studies with other immune checkpoint molecules, such as programmed death-1 antibodies or antibodies against its ligand programmed death ligand 1, were presented, as well as data from downstream molecules of the MAPK pathway (e.g. MEK inhibitors). The most promising response rates, however, can be observed by combining these new substances.
This year’s American Society of Clinical Oncology (ASCO) news in the field of metastatic melanoma can be divided into three groups: BRAF/MEK inhibitors, ‘immune checkpoint molecules’ cytotoxic T-lymphocyte antigen-4 (CTLA-4)/programmed death-1 (PD-1)/programmed death ligand 1 (PDL1) and combination therapies of checkpoint molecules with kinase inhibitors.
Since 2011, ipilimumab can be used as a first-line treatment in patients with metastatic melanoma in the United States and as a second-line therapy in Europe. This antibody blocks the CTLA-4 on T-cells and enhances the T-cell-mediated response. Objective response rates (ORRs) can be observed in only 10–15 %, but are often long lasting. Most of the side effects are immune-related (IrSAEs); grade 3–5 IrSAEs can be seen in up to 20 % of patients.
This year at ASCO, Hodi et al.  presented data of a phase II study, in which they compared the combination of ipilimumab and the cytokine granulocyte macrophage colony-stimulating factor GM-CSF (sargramostim) with an ipilimumab monotherapy. The ORRs and the progression-free survival (PFS) were similar in both treatment arms, whereas there was a significant difference in the overall survival (OS): 12.7 months with ipilimumab alone versus 17.5 months in the combination with GM-CSF (p = 0.014). Interestingly, the addition of GM-CSF reduced the immune-related side effects of the ipilimumab therapy, especially the gastrointestinal colitis.
In the past years, other ‘immune-checkpoint’ antibodies against T-cell-inhibiting receptors, the PD-1-antibody and an antibody against its ligand PDL1 were tested in clinical studies. Sznol et al.  presented data, in which the therapy with the PD-1-antibody nivolumab led to an ORR of 31 %; the median OS was 16.8 months. As nivolumab was given as a second-line or later-line treatment, the 2-year OS of 43 % is astonishing.
A trial with another PD-1 antibody lambrolizumab (Ribas et al. ) demonstrated that even in ipilimumab-pretreated melanoma patients, the median ORR was 38 % [3, 4]. In ipilimumab-naive patients, who were treated with lambrolizumab in a dose of 10 mg/kg every 2 weeks, the ORR increased to 52 %.
In both studies, the substance was well tolerated; the rate of immune-related colitis, in contrast to ipilimumab, was very low; and in 4.4 % of cases, immune-related pneumonitis could be observed.
In a phase I trial with the antibody against the ligand of PD-1 (MPDL3280A), even ocular melanoma patients could be recruited, but none of them showed a response to this agent. In cutaneous melanoma patients, the ORR of 29 % was comparable with those with PD1-antibodies. In contrast, treatment with the PDL1-antibody was not associated with the typical immune-related side effects of ipilimumab. The most common side effects were fatigue, headache, diarrhoea and in 9 %, hyperglycaemia.
The biggest highlight at ASCO 2013 was presented by Wolchock et al. [5, 6]: the combination therapy of ipilimumab with the PD-1-antibody nivolumab in a phase I trial. In the cohort of ipilimumab 3 mg/kg and nivolumab 1 mg/kg, the ORR reached 53 %. In contrast to an ipilimumab monotherapy, the majority of patients showed a tumour reduction of more than 80 % within the first 12 weeks of treatment. This effect was long lasting, as the 1-year OS was 82 %. Side effects were observed a little more frequently than in a monotherapy but were manageable. The most common side effects were pruritus, exanthemas and changes in liver and pancreatic parameters.
In recent years, genetic and molecular studies and a number of somatic mutations playing a key role in melanoma pathogenesis have been identified. BRAF is a member of the Raf family, which is part of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway. Activation of the MAPK pathway results in increased transcription of genes required for cell cycle entry, cell proliferation and prolonged cell survival. Approximately 40–60 % of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signalling through the MAPK pathway. The BRAF inhibitor, vemurafenib, has demonstrated improved PFS and OS compared with chemotherapy in randomised trials, and represents a new standard of care in patients with advanced melanoma harbouring a BRAF-V600 mutation and was approved in 2012 as a first-line treatment in BRAF-mutated melanoma patients. However, in the meantime, it is also clear that most patients develop resistance to vemurafenib, manifested by progressive disease within 6–8 months after initiation of the therapy.
For approval by the Food and Drug Administration (FDA) in the BRIM3 trial, vemurafenib was studied as the first-line treatment in metastatic melanoma patients with BRAF V600E mutation, with an ORR of 57 % and an OS of 13.2 months [9.6 months in the dacarbazine (DTIC) control arm]. At ASCO 2013, Hauschild et al.  gave an update on the BREAK-3 trial data, a study with the BRAF inhibitor dabrafenib versus DTIC monotherapy. The PFS in the dabrafenib group was 6.9 months versus 2.7 months with DTIC, but the median OS in 20 % of the continuously dabrafenib-treated patients, although they showed a progression of their disease, reached 18.2 months.
As active cerebral metastases are exclusion criteria in most of the studies, the efficacy of BRAF inhibitors was still unclear. In an excellent talk, Georgina Long presented data that approximately 50 % of melanoma patients with brain metastasis, even when untreated, will benefit from a treatment with a BRAF inhibitor, and the OS will be doubled to 30 weeks [8–10].
As we are aware of the common progression of the melanoma disease 6–8 months after beginning of a treatment with BRAF inhibitors due to resistances, in the past years, other kinase inhibitors in the downstream of Ras/Raf/MEK/ERK MAPK signal transduction pathway were tested, especially MEK inhibitors. Sosman et al.  presented data of a phase I/II trial with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. In untreated patients, the ORR was 41 %, PFS was 10.8 months and the 1-year OS was approximately 80 %, whereas in BRAF-resistant patients, the ORR was only 4 % and the PFS was 3.6 months. The most common side effects were pyrexia in approximately 70 % and rashes. Both substances, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, got the approval of the FDA during the congress of ASCO 2013.
In the poster discussion session, the preliminary results from a phase Ib/II, open-label, dose-escalation study of another BRAF inhibitor LGX818 in combination with an oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumours were presented. In a small cohort of 16 metastatic melanomas, a complete response was observed in one of seven (14 %) BRAF inhibitor-naive melanoma patients and partial responses were observed in five of seven (71 %) BRAF inhibitor-naive melanoma patients, but even in two of nine (22 %) BRAF inhibitor-pretreated patients .
Combination therapies of checkpoint molecules with kinase inhibitors
As most of the vemurafenib-treated patients will show a progression of their disease after several months, many tumour centres tried to change the therapy in this situation to ipilimumab. What could be observed was a very rapid progression, and the vast majority of patients died. A continuous treatment of both substances, on the other hand, often is limited due to the increased hepatotoxicity .
So an Italian group (Ascierto et al. ) retrospectively investigated the sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma, and Hodi et al.  started a phase II study of vemurafenib followed by ipilimumab in patients with BRAF V600-mutated advanced melanoma. Both groups reported similar preliminary results, which suggest that in BRAF-mutated patients, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence.
After decades of frustration in the treatment of metastatic melanoma, the past 2 years were characterised by the hype due to the new drugs ipilimumab and vemurafenib. In the meantime, we are aware of the strengths and failings of these substances, but two new drugs were approved by the FDA already, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. Due to the convincing data, especially in the trial of the combination of ipilimumab with the PD-1 antibody nivolumab, the board of the European Association of Dermato Oncology decided to contact the European Medicines Agency to reconsider their decision about ipilimumab as a first-line treatment in metastatic melanoma.
Furthermore, ASCO 2013 proved that actually more promising agents are under development and are tested in clinical trials. The data of all these presented trials are convincing and optimistic. So in the near future, clinical oncologists probably will be able to offer not only palliative but also curative treatment options to metastatic melanoma patients.
Conflict of interest
The author Georg Weinlich has no conflict of interest.