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Optimal Use of mTOR Inhibitors
Clinical Science Symposium
Wednesday, 19 March 2014
Wednesday, 19 March 2014
13:30–15:15
OPENING SYMPOSIUM
6 Proffered paper oral Safety of everolimus and exemestane in advanced breast cancer: Preliminary results from the phase IIIb EVEREXES study Invited
Abstract not received Invited
2 Endocrine therapy Abstract not received
Wednesday, 19 March 2014
inhibitors. The results from early phase clinical studies of PI3 kinase and AKT inhibitors will be reviewed. Conflict of interest: Advisory board: Novartis, Roche, AstraZeneca. Other substantive relationships: Research funding AstraZeneca
9th European Breast Cancer Conference − Opening Symposium 1 Immunogenic cell death
S39
15:45–17:25
Y.H. Im1 , J.H. Sohn2 , Y.C. Chang3 , S.A. Im4 , K.S. Lee5 , W.C. Noh6 , S. Chua7 , H.L. Xue8 , S.B. Kim9 . 1 Samsung Medical Centre, Haematology-oncology, Seoul, South Korea; 2 Severance Hospital Yonsei University Health System, Oncology, Seoul, South Korea; 3 Mackay Memorial Hospital, General Surgery, Taipei, Taiwan; 4 Seoul National University Hospital, Haemato-oncology, Seoul, South Korea; 5 National Cancer Centre, Center for Breast Cancer, Gyeonggi-do, South Korea; 6 Korea Cancer Center Hospital, General Surgery (Breast Cancer Centre), Seoul, South Korea; 7 Maroondah Hospital, Breast Oncology, Ringwood East, Australia; 8 Novartis Asia Pacific Pharmaceuticals Pte. Ltd., Development and Medical Affairs, Singapore, Singapore; 9 Asan Medical Centre, Oncology, Seoul, South Korea
CLINICAL SCIENCE SYMPOSIUM
Optimal Use of mTOR Inhibitors 3 Predictive biomarkers
Invited
F. Andre1 . 1 Institut Gustave Roussy, Department of Medical Oncology, Paris, France mTOR inhibitors have been shown to improve efficacy endpoints in patients with ER-positive metastatic breast cancer who are resistant to endocrine therapy. Current research aims at identifying predictive biomarkers for treatment efficacy in order to better stratify the population eligible to such approach. There are four different classes of predictive biomarkers for the efficacy of mTOR inhibitors. The first aim is to identify the population who present a high sensitivity to the drug. The mTOR activation, evaluated through the quantification of phosphor-4EBP1 or S6K has been associated with high treatment efficacy in TAMRAD and BOLERO 3 trials. This tool, although challenging, could be interesting to identify a population where everolimus could be prescribed. Gene expression assessed by DNA-arrays or RT-PCR could be an alternative biomarker of mTOR activation. The second aim of biomarkers is to identify “outlier” responders to mTOR inhibitors, ie the patients who present an oncogene-addiction to mTOR. Several studies have suggested that mutations located on TSC1 could define a population of patients with extreme sensitivity to mTOR inhibitors. The identification of such patients could be of interest to develop highly bioactive mTOR inhibitors. The third aim of predictive biomarkers will be to identify a population who present a primary resistance to the drugs. Using samples from BOLERO2 trials, investigators have suggested that FGFR1 amplification and a high number of genomic alterations could be predictive for primary resistance to everolimus. Finally, some biomarker work aim at differentiating drug classes. As illustration, several teams have evaluated whether PIK3CA mutations could predict sensitivity to mTOR inhibitors. Compelling data indicate that such genomic alterations do not predict sensitivity to mTOR inhibitors, suggesting a different positioning between PI3K and mTOR inhibitors. Conflict of interest: Advisory board: novartis. Corporate-sponsored research: novartis 4 How to manage the safety issues of mTOR inhibitors
Invited
Abstract not Received 5 After mTOR inhibitors: What is next?
Invited
N. Turner1 . 1 The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom Substantial evidence supports activation of the PI3K-AKT-mTOR pathway in all subtypes of breast cancer. This talk will review the evidence for activation of the pathway in breast cancer, the diversity of the mechanisms through which the pathway can be activated, and the evidence that the different mechanisms of activation may predict for sensitivity to specific pathway
Background: BOLERO-2 demonstrated the efficacy of everolimus (EVE) plus exemestane (EXE) for the treatment of postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. In this study fewer than 10% of enrolled patients were from the Asia Pacific, Northern/Southern African and Middle Eastern regions. Taking into account the potential effects of ethnic and cultural differences on treatment effectiveness, it is important to confirm the safety and efficacy profile of EVE+EXE in these populations. Materials and Methods: EVEREXES is an open-label phase IIIb, single arm, multi-center, international trial. Up to 400 post-menopausal, HR-positive and HER2-negative, advanced breast cancer patients will be enrolled in 15 countries from the above regions, and treated with EVE+EXE as per the BOLERO-2 protocol. The primary objective is to establish the safety and tolerability profile of EVE+EXE (assessed according to CTCAE criteria). Secondary objectives are evaluation of efficacy (assessed by PFS, ORR, and CBR) and change in ECOG performance status, and to provide early access to EVE+EXE for participants. Here we present preliminary safety data. Results: To date (30/Oct/2013), 107 patients have been enrolled from South Korea (57), Taiwan (20), Australia (15), Thailand (8), Malaysia (3), Turkey (3) and Jordan (1). At a median follow up of 13.2 weeks, we observed early onset of predominantly grade 1/2 adverse events (AEs), with a small proportion (<10%) of grade 3 AE. 55% of patients developed stomatitis (4% grade 3), 36% skin toxicity (1% grade 3), 23% elevated liver enzymes (7% grade 3), 10% hyperglycaemia (2% grade 3), 10% hyperlipidaemia (no grade 3) and 7% infections (no grade 3). Two cases each of grade 1/2 non-infectious pneumonitis were reported. One grade 4 AE was observed (rectal bleeding). Overall, 22 patients underwent dose adjustments/temporary interruptions and 9 discontinued treatment (5 due to AEs). For the conference venue updated results with a projected total enrollment of 180 patients will be presented. Conclusions: This preliminary analysis confirms that the early pattern of AEs observed in EVEREXES is similar to that seen in BOLERO-2. With only 5/107 patients permanently discontinuing treatment due to AEs, we conclude that the EVE safety profile in BC patients considered in this study is both predictable and manageable, so long as close monitoring, dose adjustment and management guidelines are implemented early during treatment. Conflict of interest: Corporate-sponsored research: EVEREXES is sponsored by Novartis Pharmaceuticals Ltd. Other substantive relationships: Hong Ling Xue is an employee of Novartis Asia Pacific Pharmaceuticals Pte. Ltd.
Wednesday, 19 March 2014
Wednesday, 19 March 2014
13:30–15:15
OPENING SYMPOSIUM
6 Proffered paper oral Safety of everolimus and exemestane in advanced breast cancer: Preliminary results from the phase IIIb EVEREXES study Invited
Abstract not received Invited
2 Endocrine therapy Abstract not received
Wednesday, 19 March 2014
inhibitors. The results from early phase clinical studies of PI3 kinase and AKT inhibitors will be reviewed. Conflict of interest: Advisory board: Novartis, Roche, AstraZeneca. Other substantive relationships: Research funding AstraZeneca
9th European Breast Cancer Conference − Opening Symposium 1 Immunogenic cell death
S39
15:45–17:25
Y.H. Im1 , J.H. Sohn2 , Y.C. Chang3 , S.A. Im4 , K.S. Lee5 , W.C. Noh6 , S. Chua7 , H.L. Xue8 , S.B. Kim9 . 1 Samsung Medical Centre, Haematology-oncology, Seoul, South Korea; 2 Severance Hospital Yonsei University Health System, Oncology, Seoul, South Korea; 3 Mackay Memorial Hospital, General Surgery, Taipei, Taiwan; 4 Seoul National University Hospital, Haemato-oncology, Seoul, South Korea; 5 National Cancer Centre, Center for Breast Cancer, Gyeonggi-do, South Korea; 6 Korea Cancer Center Hospital, General Surgery (Breast Cancer Centre), Seoul, South Korea; 7 Maroondah Hospital, Breast Oncology, Ringwood East, Australia; 8 Novartis Asia Pacific Pharmaceuticals Pte. Ltd., Development and Medical Affairs, Singapore, Singapore; 9 Asan Medical Centre, Oncology, Seoul, South Korea
CLINICAL SCIENCE SYMPOSIUM
Optimal Use of mTOR Inhibitors 3 Predictive biomarkers
Invited
F. Andre1 . 1 Institut Gustave Roussy, Department of Medical Oncology, Paris, France mTOR inhibitors have been shown to improve efficacy endpoints in patients with ER-positive metastatic breast cancer who are resistant to endocrine therapy. Current research aims at identifying predictive biomarkers for treatment efficacy in order to better stratify the population eligible to such approach. There are four different classes of predictive biomarkers for the efficacy of mTOR inhibitors. The first aim is to identify the population who present a high sensitivity to the drug. The mTOR activation, evaluated through the quantification of phosphor-4EBP1 or S6K has been associated with high treatment efficacy in TAMRAD and BOLERO 3 trials. This tool, although challenging, could be interesting to identify a population where everolimus could be prescribed. Gene expression assessed by DNA-arrays or RT-PCR could be an alternative biomarker of mTOR activation. The second aim of biomarkers is to identify “outlier” responders to mTOR inhibitors, ie the patients who present an oncogene-addiction to mTOR. Several studies have suggested that mutations located on TSC1 could define a population of patients with extreme sensitivity to mTOR inhibitors. The identification of such patients could be of interest to develop highly bioactive mTOR inhibitors. The third aim of predictive biomarkers will be to identify a population who present a primary resistance to the drugs. Using samples from BOLERO2 trials, investigators have suggested that FGFR1 amplification and a high number of genomic alterations could be predictive for primary resistance to everolimus. Finally, some biomarker work aim at differentiating drug classes. As illustration, several teams have evaluated whether PIK3CA mutations could predict sensitivity to mTOR inhibitors. Compelling data indicate that such genomic alterations do not predict sensitivity to mTOR inhibitors, suggesting a different positioning between PI3K and mTOR inhibitors. Conflict of interest: Advisory board: novartis. Corporate-sponsored research: novartis 4 How to manage the safety issues of mTOR inhibitors
Invited
Abstract not Received 5 After mTOR inhibitors: What is next?
Invited
N. Turner1 . 1 The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom Substantial evidence supports activation of the PI3K-AKT-mTOR pathway in all subtypes of breast cancer. This talk will review the evidence for activation of the pathway in breast cancer, the diversity of the mechanisms through which the pathway can be activated, and the evidence that the different mechanisms of activation may predict for sensitivity to specific pathway
Background: BOLERO-2 demonstrated the efficacy of everolimus (EVE) plus exemestane (EXE) for the treatment of postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. In this study fewer than 10% of enrolled patients were from the Asia Pacific, Northern/Southern African and Middle Eastern regions. Taking into account the potential effects of ethnic and cultural differences on treatment effectiveness, it is important to confirm the safety and efficacy profile of EVE+EXE in these populations. Materials and Methods: EVEREXES is an open-label phase IIIb, single arm, multi-center, international trial. Up to 400 post-menopausal, HR-positive and HER2-negative, advanced breast cancer patients will be enrolled in 15 countries from the above regions, and treated with EVE+EXE as per the BOLERO-2 protocol. The primary objective is to establish the safety and tolerability profile of EVE+EXE (assessed according to CTCAE criteria). Secondary objectives are evaluation of efficacy (assessed by PFS, ORR, and CBR) and change in ECOG performance status, and to provide early access to EVE+EXE for participants. Here we present preliminary safety data. Results: To date (30/Oct/2013), 107 patients have been enrolled from South Korea (57), Taiwan (20), Australia (15), Thailand (8), Malaysia (3), Turkey (3) and Jordan (1). At a median follow up of 13.2 weeks, we observed early onset of predominantly grade 1/2 adverse events (AEs), with a small proportion (<10%) of grade 3 AE. 55% of patients developed stomatitis (4% grade 3), 36% skin toxicity (1% grade 3), 23% elevated liver enzymes (7% grade 3), 10% hyperglycaemia (2% grade 3), 10% hyperlipidaemia (no grade 3) and 7% infections (no grade 3). Two cases each of grade 1/2 non-infectious pneumonitis were reported. One grade 4 AE was observed (rectal bleeding). Overall, 22 patients underwent dose adjustments/temporary interruptions and 9 discontinued treatment (5 due to AEs). For the conference venue updated results with a projected total enrollment of 180 patients will be presented. Conclusions: This preliminary analysis confirms that the early pattern of AEs observed in EVEREXES is similar to that seen in BOLERO-2. With only 5/107 patients permanently discontinuing treatment due to AEs, we conclude that the EVE safety profile in BC patients considered in this study is both predictable and manageable, so long as close monitoring, dose adjustment and management guidelines are implemented early during treatment. Conflict of interest: Corporate-sponsored research: EVEREXES is sponsored by Novartis Pharmaceuticals Ltd. Other substantive relationships: Hong Ling Xue is an employee of Novartis Asia Pacific Pharmaceuticals Pte. Ltd.