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Melanoma - Paper of the month
This section contains a monthly selection of papers selected by the editors of the Melanoma Resource Centre.
Aug / Sep 2015
Spranger S, Bao R, Gajewski TFNature. 2015 Jul 9;523(7559):231-5. doi: 10.1038/nature14404. Epub 2015 May 11
Editorial Comment by Dr. James Larkin
The systemic treatment of advanced melanoma and a number of other tumour types is changing rapidly as a consequence of the development of immune checkpoint inhibitors such as antibodies to CTLA4, PD1 and PD-L1. Nevertheless even in melanoma, the malignancy most sensitive to these drugs, only a minority of patients benefit from single agent therapy and it may be that this minority is characterised by is a pre-existing T-cell response against the tumour, as evidenced by a baseline CD8+ T-cell tumour infiltration. Thus understanding the basis of a spontaneous T-cell response to the tumour may allow the development of therapies for tumours lacking a T-cell infiltrate. Spranger and colleagues in this work identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltrate. Specifically, analysis of human metastatic melanoma samples showed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. In mouse models a mechanism was identified by which tumour-intrinsic active β-catenin signalling resulted in T-cell exclusion and resistance to anti-CTLA-4/anti-PD-L1 therapy. The authors conclude that specific oncogenic signals can mediate resistance to immunotherapies, opening up the possibility of developing therapeutic strategies to counteract such resistance.
June / July 2015
James Larkin, M.D., Ph.D., Vanna Chiarion-Sileni, M.D., Rene Gonzalez, M.D., Jean Jacques Grob, M.D., C. Lance Cowey, M.D., Christopher D. Lao, M.D., M.P.H., Dirk Schadendorf, M.D., Reinhard Dummer, M.D., Michael Smylie, M.D., Piotr Rutkowski, M.D., Ph.D.Background Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] checkpoint inhibitor) have...
Caroline Robert, M.D., Ph.D., Jacob Schachter, M.D., Georgina V. Long, M.D., Ph.D., Ana Arance, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., Laurent Mortier, M.D., Ph.D., Adil Daud, M.D. et al.Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell...
Editors’ comment: Dr. Paolo Ascierto
Immunotherapy represents one of the fastest growing areas in oncology. The two main inhibitory checkpoint pathways involve signaling through CTLA-4 or PD-1. Ipilimumab, an anti-CTLA-4 monoclonal antibody, is approved for treatment of advanced melanoma; pembrolizumab is an anti PD-1 monoclonal antibody approved for treatment of unresectable or metastatic melanoma progressed following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. In this phase III trial (KEYNOTE-006) pembrolizumab, used at dosage of 10 mg/kg every 2 or every 3 weeks, was compared with ipilimumab every 3 weeks for the treatment of unresectable stage III or IV melanoma which received no more than one previous systemic therapy for advanced disease, not previously treated with anti CTLA-4 and anti PD-1/PD-L1 antibodies. The two regimens of pembrolizumab, as compared with ipilimumab, improved both progression-free and overall survival. Benefits provided by pembrolizumab were extended to most subgroups that were assessed, except for overall survival in patients with PD-L1–negative melanoma; however, considering the many factors which could influence this data (insufficient sample sizes, different levels of expression), is not possible to make conclusions regarding the possible use of PD-L1 as predictive marker. Moreover, the presence of BRAF V600 mutation did not affect the benefit of pembrolizumab over ipilimumab. In conclusion, this study demonstrates that pembrolizumab used in ipilimumab naïve patients is superior to ipilimumab in all subgroups of patients, with a favorable toxicity profile. On the basis of these results, pembrolizumab could be a valid option for patient with advanced melanoma ipilimumab-naïve.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037)
A randomised, controlled, open-label, phase 3 trial04/09/2015 - 09:44Jeffrey S Weber et al. Lancet Oncol 2015;16:375–84
Editorial comment by Prof. R. Dummer:
The treatment of patients who progressed after ipilimumab and/or targeted therapy is a major challenge. These patients typically receive chemotherapy. However the treatment success is limited and chemotherapy still has a number of serious adverse reactions. The results of this study show a triple benefit for the immunotherapy in comparison to the chemotherapy. There are more responses, there is a longer response duration, and the number and the severity of the adverse reactions was and more significant in the chemotherapy group. The exploratory analysis of the responses in predefined patients subgroups, demonstrated benefit for the anti PD1-therapie for BRAF mutant patients and even in patients, that did not express PD-L1 in the tumor biopsy. This study will definitely have an impact on treatment recommendations for patients with pretreated advanced metastatic melanoma.
Editorial comment by Dr. J. Larkin:
Whole-exome sequencing was undertaken on tumours and matched blood samples of 64 patients with melanoma treated with the anti-CTLA4 agents ipilimumab or tremelimumab. Somatic mutations and candidate neoantigens were characterised. Neoantigen peptides were tested for their ability to activate lymphocytes from ipilimumab-treated patients.
A discovery set consisted of 11 patients with long-term clinical benefit and 14 patients without such benefit. Mutational load was associated with the degree of clinical benefit but was insufficient alone to predict this whereas a neoantigen signature specifically present in tumours with a good response to CTLA-4 blockade was reported and validated in a second set of 39 patients. Furthermore predicted neoantigens activated T cells from patients treated with ipilimumab.
These findings provide a genetic basis for efficacy from CTLA-4 blockade in melanoma and whilst confirmation in other datasets is required, suggest a potential means of prospectively defining patients most likely to benefit from this treatment.
Alexandra Snyder, M.D., Vladimir Makarov, M.D., Taha Merghoub, Ph.D., et al.N Engl J Med 2014; 371:2189-2199December 4, 2014DOI: 10.1056/NEJMoa1406498
Editor's comments: Prof Paolo A. Ascierto
Nivolumab is a fully human IgG4 anti PD-1 antibody that selectively blocks the interaction of the PD-1 receptor with its two ligands, PD-L1 and PD-L2, disrupting the negative signal which regulates T-cell activation and proliferation. In a phase I study nivolumab was associated with promising antitumor activity in patients with solid tumors, including advanced melanoma. In this manuscript were reported data of a randomized phase 3 double-blind study where nivolumab was compared to dacarbazine to verify whether it’s able to improve overall survival of previously untreated patients with advanced melanoma BRAF wild type. The study was largely positive showing a significant improvement of ORR (40 % vs 13.9%), PFS (5.1 vs 22 months) and 1-year OS (72.95 vs 42.1%) for the group of patients treated with nivolumab respect to those treated with dacarbazine. In addition to an high response rate, it was also found a long duration of responses (median DOR in the patients treated with nivolumab was not found yet), and a rapid time to response (2.1 months) with a good toxicity profile. Nivolumab treated patients had improved ORR as compared with dacarbazine treated patients both in PD-L1 positive and PD-L1 negative groups. In the subgroup with PD-L1 positive, the ORR was 52.7% in the nivolumab group versus 10.8% in the dacarbazine group. In the subgroup with PD-L1 negative, the ORR was 33.1% in the nivolumab group versus 15.7% in the dacarbazine group. The 1-year OS rate for the nivolumab PD-L1 positive, nivolumab PD-L1 negative, dacarbazine PD-L1 positive, and dacarbazine PD-L1 negative was of 82.1%, 67.8, 52.7, and 37.4 respectively. These data evidenced that PD-L1 positive status is related with a better survival but also PD-L1 negative patients had an higher OS respect to the control arm.
When this study was planning ipilimumab wasn't still approved as first-line of treatment. Currently is ongoing a three-arms phase III study which is evaluating the combination of ipilimumab and nivolumab with nivolumab and ipilimumab monotherapy in previously untreated advanced melanoma patients.
Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D., Et alN Engl J Med 2014, E-pub November 16, 2014,
Editorial comment by Prof. R. Dummer:
This month we have decided to present two papers. Both papers were published in the New England Journal of Medicine and report on two prospective randomized trials investigating the clinical outcome of a monotherapy with a BRAF inhibitor versus a combination therapy using a BRAF inhibitor and a MEK inhibitor in patients with BRAF mutated advanced melanoma. In both studies there is a clear advantage for the combination therapy with an increase in progression free survival resulting in an improvement of approximately 40% with an improved response rate. The phase III clinical trial presented by Long reached its primary endpoint progression free survival and the secondary endpoint overall survival. Taking together these studies clearly support combination therapy with a BRAF and MEK inhibitor as the standard of care for BRAF mutated melanoma.
Georgina V. Long, M.D., Ph.D., Daniil Stroyakovskiy, M.D., Helen Gogas, M.D., Evgeny Levchenko, M.D., Filippo de Braud, M.D., James Larkin, M.D., Claus Garbe, M.D., Ph.D., Thomas Jouary, M.D., Axel Hauschild, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., V11/14/2014 - 10:44N Engl J Med 2014; 371:1877-1888November 13, 2014DOI: 10.1056/NEJMoa1406037
James Larkin, M.D., Ph.D., Paolo A. Ascierto, M.D., Brigitte Dréno, M.D., Ph.D., Victoria Atkinson, M.D., Gabriella Liszkay, M.D., Michele Maio, M.D., Mario Mandalà, M.D., Lev Demidov, M.D., Daniil Stroyakovskiy, M.D., Luc Thomas, M.D., Ph.D., Luis de la11/14/2014 - 10:35N Engl J Med 2014; 371:1867-1876November 13, 2014DOI: 10.1056/NEJMoa1408868
Lise Boussemart, Hélène Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingsson, Gorana Tomasic, Marina Thomas, Christine Basmadjian, Nigel Ribeiro, Frédéric Thuaud, Christina Mateus, Emilie Routier, Nyam Kamsu-Kom, Sandrine Agoussi, AlexanderNature 513, 105–109 (04 September 2014) doi:10.1038/nature13572
Editorial comment by professor Reinhard G. Dummer:
A French research group headed by Dr. Vagner has investigated molecular alterations associated drug resistance in V600E mutated tumor cells treated with targeted therapies. The eIF4F translation initiation complex was identified as a central intersection node to generate resistance against B raf inhibitors. and MEK inhibitors as well as the combination of both. This complex, that is a key regulator of mRNA translation, is a central mechanism of resistance in melanoma and also in other cancer types such as colon and thyroid cancers. Interestingly, an in-situ test system was developed to demonstrate the functioning of this pathway in human tumor tissue.
Combination of vemurafenib and cobimetinib in patients with advanced BRAF V600-mutated melanoma: a phase 1b study
Antoni Ribas, Rene Gonzalez, Anna Pavlick, Omid Hamid, Thomas F Gajewski, Adil Daud, Lawrence Flaherty, Theodore Logan, Bartosz Chmielowski, Karl Lewis, Damien Kee, Peter Boasberg, Ming Yin, Iris Chan, Luna Musib, Nicholas Choong, Igor Puzanov, Grant A McOriginal Research Article The Lancet Oncology, Volume 15, Issue 9, August 2014, Pages 954-965
This is a dose-escalation phase I trial which enrolled 129 patients with advanced melanoma BRAFV600 mutant; all these patients were divided in two different cohorts: the previously treated with BRAF inhibitors and the naive to BRAF inhibitors treatment. They received vemurafenib and cobimetinib at progressively increasing doses in the different cohorts and the maximum tolerated dose established for the combination corresponds to that of the two drugs in monotherapy. The toxicity profile was acceptable with the reduction of some peculiar side effects of BRAF inhibitors, such as squamous cell carcinomas, compared with data from studies of vemurafenib monotherapy. This was probably due to the attenuation of the paradoxal BRAF-induced activation of the MAPK pathway in normal tissues, induced by the simultaneous inhibition of MEK. The combination therapy in vemurafenib-naive patients has given encouraging results. The most significant data is certainly the PFS of 13 months much higher than that of 6-7 months obtained with vemurafenib monotherapy. Of course this finding requires confirmation in the ongoing phase III trial.
Matthew G. Field, J. William Harbour
Cancer Cell, 6, 25, pages 714 - 715
By Prof. Reinhard Dummer: Finally a target for the treatment of Uveal melanoma? Ocular melanomas are the most common malignancy of the eye. Approximately 50% of the effected individuals metastasize most commonly in the lever. In contrast to other melanomas ocular melanomas do not present mutations for BRAF or RAS. However they present inactivating mutations for GNAQ and GNA11, which result in increased activity of protein kinase C and the MAP kinase pathway and as now described the hippo tumor suppresser pathway including the phosphorylation of YAP. The YAP inhibitor verteporfin together with protein kinase C and MEK inhibitors might be a promising approach for this difficult to treat malignancy.
- Field MG et al., Cancer Cell 2014;25:714-715
- Feng X et al., Cancer Cell 2014;25:831-845
- Yu FX et al., Cancer Cell 2014;25:822-830
Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study.
Corrie PG, Marshall A, Dunn JA, Middleton MR, Nathan PD, Gore M, Davidson N, Nicholson S, Kelly CG, Marples M, Danson SJ, Marshall E, Houston SJ, Board RE, Waterston AM, Nobes JP, Harries M, Kumar S, Young G, Lorigan P.Lancet Oncol. 2014 May;15(6):620-30
The effectiveness of anti-angiogenic factors in the treatment of melanoma is currently the subject of many clinical trials. Especially the activity of bevacizumab in the treatment of patients with advanced melanoma looks promising. The AVAST-M trial is a phase III trial designed to evaluate the efficacy of adjuvant treatment with bevacizumab in patients at high risk of recurrence. The primary end point was the OS. The 1343 patients enrolled were randomized to receive bevacizumab 7.5 mg every 3 weeks for a year or to observation. The results of the interim analysis showed no benefit in terms of OS, and neither of distant metastasis-free interval. A statistically significant difference was found in terms of disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70 -0 • 98, p = 0.03). Treatment with bevacizumab was well tolerated. We will need to wait for the results of the follow-up to 5 years to identify an effect on the OS.
Sun C et al.Nature 508,118–122 (03 April 2014)
This is another paper focusing on BRAF resistance mechanism. It shows that BRAF inhibitors can cause a loss of melanocytic differentiation which is associated with increased EGFR and TGF-β signaling as it was predicted by the phenotype switching model (Hoek et al., Cancer Research 2008). Sox10 is a transcription factor essential for neural crest differentiation and controls melanocytic differentiation via MITF. As we are gathering more and more information about resistance mechanisms, we will be able to design therapeutic solutions hopefully.
Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials
Keith T Flaherty, Michael Hennig, Sandra J Lee, Paolo A Ascierto, Reinhard Dummer, Alexander M M Eggermont, Axel Hauschild, Richard Kefford, John M Kirkwood, Georgina V Long, Paul Lorigan, Andreas Mackensen, Grant McArthur, Steven O'Day, Poulam M Patel,The Lancet Oncology, Volume 15, Issue 3, Pages 297 - 304, March 2014
Since decades, overall survival was the one and only primary endpoint of important multicenter randomized trial investigating the treatment outcome for metastatic melanoma. Prof. Schadendorf, Flaherty and co-workers have now provided a systematic analysis of many randomized controlled trials including more than 4000 patients that have used the cover sign in the control arm. The careful analysis of this large dataset revealed that progression-free survival is a powerful surrogate marker for overall survival. This is particularly true for studies investigating targeted therapy. It holds also true for immunotherapy. Within the evolving landscapes of treatment options for advanced melanoma, this analysis is extremely helpful in order to justify progression-free survival as a primary endpoint in the next generation of clinical trials.
Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells
Paul F Robbins, Yong-Chen Lu, Mona El-Gamil, Yong F Li, Colin Gross, Jared Gartner, Jimmy C Lin, Jamie K Teer, Paul Cliften, Eric Tycksen, Yardena Samuels & Steven A RosenbergNature Medicine 19, 747–752 (2013)
Which antigens facilitate tumor rejection during successful immunotherapy The successful outcome of an immunotherapy is associated with the infiltration of tumor-specific T-killer lymphocytes in the tumor tissue. These lymphocytes are able to detect various antigens presented in the HLA class I molecules including melanocytic differentiation antigens, cancer/testis antigens and other antigens. Robbins PF and Rosenberg SA and colleagues have developed a new screening approach that allows to find mutated proteins of individual tumor cells. The respective T-cell epitopes were synthesized. The authors have elegantly shown that private mutations in the tumor cells are strong antigens that facilitate tumor rejection by adoptive T-cell transfer.
Caramel J et al.Cancer Cell Volume 24, Issue 4, 14 October 2013, Pages 466–480
Shading light on the EMT equivalent in melanoma Epithelial-mesenchymal transition is a phenomenon described for epithelial cancers, which allows tumor cells to achieve motility and invasiveness, typically associated with reduced proliferation and reduced differentiation. This process is a link between tumor cell proliferation and stemness and explains the transcriptional plasticity of tumor cells. Caramel et al. have now illustrated the impact of the MAP kinase pathway in this context. The data show that the activated MAP kinase pathways governs EMT transcription factors in melanoma.
Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells
Stefani Spranger, Robbert M. Spaapen, Yuanyuan Zha, Jason Williams, Yuru Meng, Thanh T. Ha and Thomas F. GajewskiSci Transl Med 28 August 2013: Vol. 5, Issue 200, p. 200ra116
The ping-pong effect between melanomas cells and reactive T-lymphocytes
There is the concept, that melanoma can be distinguished in subgroups that are recognized by immune reactions and subgroups that are invisible for immune cells. The elegant paper of Spranger et al. now demonstrates that PD-ligand 1, an immunosuppressive molecule expressed by melanoma cells and other immunosuppressive molecules is up-regulated by interferon gamma, secreted by CDA positive T-cells. These data are especially interesting in the context of successful use of anti-PD1 targeted antibodies in advanced melanoma and other cancer types.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, IliNature 500, 415–421 (22 August 2013)
This very impressive article gives for the first time detailed insight in the catalogue of somatic mutations from different cancer types. Interestingly melanoma is the cancer with the highest prevalence of somatic mutations across all human cancer types investigated. In this paper the signatures of mutational processes were categorized. Melanoma is characterized by signatures associated with advanced age, genotoxic effects of UV-light and interestingly by a signature of temozolomide, which is probably acquired during treatment of metastatic disease.
Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells
Alexander Roeschsend, Adina Vultur, Ivan Bogeski, Huan Wang, Katharina M. Zimmermann, David Speicher, Christina Körbel, Matthias W. Laschke, Phyllis A. Gimotty, Stephan E. Philipp, Elmar Krause, Sylvie Pätzold, Jessie Villanueva, Clemens Krepler, Mizuho FCancer Cell Volume 23, Issue 6, 10 June 2013, Pages 811–825
Today we understand cancer metastases as a complex heterogeneous organized cell accumulation that includes proliferative components and slow growing components that present stem cell like features. Roesch et al. have now investigated a new treatment approach that might preferentially target slow cycling cells in melanoma metastases that present stemness features.
Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA.Science. 2013 Feb 22;339(6122):957-9.
The groups of the German Cancer Center in Heidelberg Germany and of the Dana Faber Cancer Center Boston, USA have described mutations in the promoter region of the temolerase reverse transcriptase (TERT gene). These mutations are functional, because they cause an up regulation of the TERT and nicely illustrate the relevance of mutations outside of the coding regions of the genome.
Jedd D. Wolchok, Harriet Kluger, Margaret K. Callahan, Michael A. Postow, Naiyer A. Rizvi, Alexander M. Lesokhin, Neil H. Segal, M.D., Ph.D., Charlotte E. Ariyan, M.D., Ph.D., Ruth-Ann Gordon, Kathleen Reed, Matthew M. Burke, Anne Caldwell, Stephanie A. KN Engl J Med 2013; 369:122-133 July 11, 2013
The use of the antibody Ipilimumab, which interferes with one important checkpoint during immune activation can induce some clinical responses and has an impact on longterm survival of patients with metastatic melanoma. Now antibodies interfering with another immune checkpoint, the PD1-molecule present on activated T-cells, are documented to result in a significant number of rapid and stable remissions. These two papers announce a new era in immunotherapy that will have an impact on the management of advanced cancer patients of several types, including lung cancer and renal cell carcinoma.
Meghna Das Thakur, Fernando Salangsang, Allison S. Landman, William R. Sellers, Nancy K. Pryer, Mitchell P. Levesque, Reinhard Dummer, Martin McMahon & Darrin D. StuartNature 494,251–255 (14 February 2013)
In an elegant mouse model Das Thakur M et al. have shown that human melanomas upregulate BRAF in order to cope with BRAF inhibitors. After this reactive upregulation, the withdrawal of vemurafenib results in a growth arrest. This paper suggests that intermittent dosing of a BRAF kinase inhibitor might results in delayed resistance.