- Email: [email protected]
New Molecular Targets in Melanoma
Annals of Oncology 23 (Supplement 9): ix46, 2012 doi:10.1093/annonc/mds383
melanoma therapy: from frustration to enthusiasm 69IN
NEW MOLECULAR TARGETS IN MELANOMA
R. Marais Chester Beatty Laboratories, The Institute of Cancer Research, London, UNITED KINGDOM
abstracts
70IN
HOW TO OVERCOME RESISTANCE IN MUTATION DRIVEN THERAPIES COMBINATION TARGETED THERAPY REGIMENS
K.T. Flaherty Developmental Therapeutics, Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA The identification of BRAF mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. Seven years passed between the identification of BRAF mutations and the validation of this target in melanoma patients with a potent and specific BRAF inhibitor, PLX4032. As phase II and phase III single-agent trials have established BRAF inhibition as a new standard of care for the BRAF mutated subpopulation, attention now turns to understanding mechanisms of resistance and rational combination approaches. The available evidence regarding acquired resistance mechanisms does not point to an obvious approach for developing second line or salvage therapy for these patients. Current efforts are focused on combining other targeted therapies with BRAF inhibitors in the subgroup of patient who have BRAF mutations to overcome de novo resistance. The spectrum of potential combination therapy regimens is broad. It has been known for several years that BRAF mutations are accompanied by genetic alterations that activate the PI3K pathway and CDK4. Characterizing more than one genetic alteration before selecting such combinations is feasible and an appropriate way to stratify patients for next-generation combination therapy clinical trials. Recent evidence suggests that stromal secreted by the tumor microenvironment confers resistance to BRAF
71IN
ANTI CTLA4 AND PREDICTIVE BIOMARKERS
J.S. Weber Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, UNITED STATES OF AMERICA The recent US FDA and EU EMA regulatory approval of ipilimumab, a CTLA-4 antibody, has highlighted the need for pharmacodynamic and predictive markers of its clinical benefit. Ipilimumab’s RECIST response rate is in the realm of 10%, with another 10-20% of patients having clinical benefit with stable disease past 6 months. Response and overall survival are related pharmacokinetically to its Cminns levels, although the rate of immune related adverse events also rises with increased dose. Several studies in the metastatic and adjuvant settings have defined pharmacodynamics and predictive markers for ipilimumab and determine if they are associated with clinical benefit. HLA-DR, as well as the activation marker ICOS are increased on CD4 and CD8 T cells after ipilimumab treatment. An increase in the early total lymphocyte count may be associated with outcome. Microarray analyses suggest that expression of a large number of genes are altered in CD4 T cells by ipilimumab, but fewer genes are impacted in CD8 T cells. Central memory cells are increased, with a corresponding decrease in naïve T cells. Gata3, a Th2 polarizing molecule was increased, yet TH17 cell induction and IL-17 levels were increased. Examination of tumors in patients treated with ipilimumab revealed a significant influx of CD8 T cells, which may be primarily PD-1 positive. In an adjuvant trial, pre-treatment CD8/EOMES/Ki67 positive T cells were significantly associated with relapse-free survival, and CD4/EOMES/Ki67 T cells were associated with low levels of irAEs, the mechanism-based side effects of ipilimumab. Analysis of tumor gene expression by microarrays suggest that an immune signature may also be predictive of benefit. The newly developed checkpoint inhibitor antibodies against PD-1 have been associated with excellent responses of long duration in melanoma, renal cell cancer and non-small cell lung cancer. Increases in circulating T regulatory cells and CD4/CTLA-4 expressing T cells was associated with response in one study. In tumors, PD-1 expression assessed by immunohistochemical staining was associated with outcome, and no patient with absent PD-L1 expression responded. These data provide a rationale for further marker testing and novel trials of sequenced antibodies. Disclosure: J.S. Weber: I have received honraria of less than 10,000 USD from BMS, have sat on advisory boards for BMS, and my institution has received research money from BMS
72IN
THE COMBINATION OF CHEMO AND IMMUNOTHERAPY: HOW FOES BECOME FRIENDS
No abstract submitted at time of going to press.
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on April 10, 2016
Recent years have seen dramatic advances in the development of targeted and immunological therapeutics for melanoma. In the area of targeted therapy, the development of BRAF inhibitors has led to new paradigms of melanoma treatment, because BRAF drugs such as vemurafenib and dabrafinib can achieve objective responses in BRAF mutant melanoma patients. However, these responses are generally short-lived, and relapse may be inevitable. Notably, BRAF inhibitors drive an unexpected paradox: while they inhibit RAF signalling in cells expressing mutant BRAF, they activate RAF signalling in cells expressing oncogenic or activated RAS. This is because these inhibitors drive the formation of homo and hetero-dimers between BRAF and the closely related protein CRAF. The activation of this paradox appear, at least in some instances to underlie the mechanisms of resistance, and they also drive one of the curious side-effects of these drugs, the induction of non-melanoma neoplasms in the skin. Critically, it appears that upon activation of the paradox, the tumour cells can switch from being sensitive to the drug to being addicted to it. This creates an unexpected complication when managing these patients, but shows how improving our knowledge of the processes that drive tumourigenesis is critical to developing novel therapeutic strategies for cancer patients. Disclosure: I have received an honourarium from Roche. I have consulted (unpaid) for novartis; I have consulted (unpaid) for Genentec.
inhibitor therapy and HGF antibodies o small molecule c-met inhibitors represent available investigational agents to combined. Additionally, emerging evidence suggests that BRAF inhibitors induce a secondary immune response and combinations with various active immunotherapies is being pursued. However, the current inability to predict which patients are most likely to benefit from immunotherapy represents a persistent challenge in arriving at a personalized approach with such combinations. Similarly, combination therapy with BRAF inhibitors and anti-apoptotic drugs and agents that target developmental pathways in melanoma show promise but do not have an associated predictive biomarker. Disclosure: K.T. Flaherty: Consultant - Roche/Genentech, GlaxoSmithKline
melanoma therapy: from frustration to enthusiasm 69IN
NEW MOLECULAR TARGETS IN MELANOMA
R. Marais Chester Beatty Laboratories, The Institute of Cancer Research, London, UNITED KINGDOM
abstracts
70IN
HOW TO OVERCOME RESISTANCE IN MUTATION DRIVEN THERAPIES COMBINATION TARGETED THERAPY REGIMENS
K.T. Flaherty Developmental Therapeutics, Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA The identification of BRAF mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. Seven years passed between the identification of BRAF mutations and the validation of this target in melanoma patients with a potent and specific BRAF inhibitor, PLX4032. As phase II and phase III single-agent trials have established BRAF inhibition as a new standard of care for the BRAF mutated subpopulation, attention now turns to understanding mechanisms of resistance and rational combination approaches. The available evidence regarding acquired resistance mechanisms does not point to an obvious approach for developing second line or salvage therapy for these patients. Current efforts are focused on combining other targeted therapies with BRAF inhibitors in the subgroup of patient who have BRAF mutations to overcome de novo resistance. The spectrum of potential combination therapy regimens is broad. It has been known for several years that BRAF mutations are accompanied by genetic alterations that activate the PI3K pathway and CDK4. Characterizing more than one genetic alteration before selecting such combinations is feasible and an appropriate way to stratify patients for next-generation combination therapy clinical trials. Recent evidence suggests that stromal secreted by the tumor microenvironment confers resistance to BRAF
71IN
ANTI CTLA4 AND PREDICTIVE BIOMARKERS
J.S. Weber Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, UNITED STATES OF AMERICA The recent US FDA and EU EMA regulatory approval of ipilimumab, a CTLA-4 antibody, has highlighted the need for pharmacodynamic and predictive markers of its clinical benefit. Ipilimumab’s RECIST response rate is in the realm of 10%, with another 10-20% of patients having clinical benefit with stable disease past 6 months. Response and overall survival are related pharmacokinetically to its Cminns levels, although the rate of immune related adverse events also rises with increased dose. Several studies in the metastatic and adjuvant settings have defined pharmacodynamics and predictive markers for ipilimumab and determine if they are associated with clinical benefit. HLA-DR, as well as the activation marker ICOS are increased on CD4 and CD8 T cells after ipilimumab treatment. An increase in the early total lymphocyte count may be associated with outcome. Microarray analyses suggest that expression of a large number of genes are altered in CD4 T cells by ipilimumab, but fewer genes are impacted in CD8 T cells. Central memory cells are increased, with a corresponding decrease in naïve T cells. Gata3, a Th2 polarizing molecule was increased, yet TH17 cell induction and IL-17 levels were increased. Examination of tumors in patients treated with ipilimumab revealed a significant influx of CD8 T cells, which may be primarily PD-1 positive. In an adjuvant trial, pre-treatment CD8/EOMES/Ki67 positive T cells were significantly associated with relapse-free survival, and CD4/EOMES/Ki67 T cells were associated with low levels of irAEs, the mechanism-based side effects of ipilimumab. Analysis of tumor gene expression by microarrays suggest that an immune signature may also be predictive of benefit. The newly developed checkpoint inhibitor antibodies against PD-1 have been associated with excellent responses of long duration in melanoma, renal cell cancer and non-small cell lung cancer. Increases in circulating T regulatory cells and CD4/CTLA-4 expressing T cells was associated with response in one study. In tumors, PD-1 expression assessed by immunohistochemical staining was associated with outcome, and no patient with absent PD-L1 expression responded. These data provide a rationale for further marker testing and novel trials of sequenced antibodies. Disclosure: J.S. Weber: I have received honraria of less than 10,000 USD from BMS, have sat on advisory boards for BMS, and my institution has received research money from BMS
72IN
THE COMBINATION OF CHEMO AND IMMUNOTHERAPY: HOW FOES BECOME FRIENDS
No abstract submitted at time of going to press.
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on April 10, 2016
Recent years have seen dramatic advances in the development of targeted and immunological therapeutics for melanoma. In the area of targeted therapy, the development of BRAF inhibitors has led to new paradigms of melanoma treatment, because BRAF drugs such as vemurafenib and dabrafinib can achieve objective responses in BRAF mutant melanoma patients. However, these responses are generally short-lived, and relapse may be inevitable. Notably, BRAF inhibitors drive an unexpected paradox: while they inhibit RAF signalling in cells expressing mutant BRAF, they activate RAF signalling in cells expressing oncogenic or activated RAS. This is because these inhibitors drive the formation of homo and hetero-dimers between BRAF and the closely related protein CRAF. The activation of this paradox appear, at least in some instances to underlie the mechanisms of resistance, and they also drive one of the curious side-effects of these drugs, the induction of non-melanoma neoplasms in the skin. Critically, it appears that upon activation of the paradox, the tumour cells can switch from being sensitive to the drug to being addicted to it. This creates an unexpected complication when managing these patients, but shows how improving our knowledge of the processes that drive tumourigenesis is critical to developing novel therapeutic strategies for cancer patients. Disclosure: I have received an honourarium from Roche. I have consulted (unpaid) for novartis; I have consulted (unpaid) for Genentec.
inhibitor therapy and HGF antibodies o small molecule c-met inhibitors represent available investigational agents to combined. Additionally, emerging evidence suggests that BRAF inhibitors induce a secondary immune response and combinations with various active immunotherapies is being pursued. However, the current inability to predict which patients are most likely to benefit from immunotherapy represents a persistent challenge in arriving at a personalized approach with such combinations. Similarly, combination therapy with BRAF inhibitors and anti-apoptotic drugs and agents that target developmental pathways in melanoma show promise but do not have an associated predictive biomarker. Disclosure: K.T. Flaherty: Consultant - Roche/Genentech, GlaxoSmithKline