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SUNITINIB MALATE (SU11248) – EFFICACY IN RENAL CELL CARCINOMA (RCC)
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1058
SUNITINIB MALATE (SU11248) – EFFICACY IN RENAL CELL CARCINOMA (RCC)
RANDOMISED PHASE III TRIAL OF THE MULTIKINASE INHIBITOR SORAFENIB (BAY 43-9006) IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA (RCC)
Motzer R.1, Rini B.2, Michaelson D.3, Redman B.4, Hudes G.5, Wilding G.6, Bukowski R.7, George D.8, Kim S.9, Baum C.9 1
Memorial Sloan-kettering Cancer Center, Genitourinary Oncology Service, New York, United States, U.C.S.F., Comprehensive Cancer Center, San Francisco, United States, 3Dana Farber, Harvard Cancer Center, Boston, United States, 4University of Michigan, Comprehensive Cancer Center, Ann Arbor, United States, 5Fox Chase Cancer Center, Genitourinary Malignancies Program, Philadelphia, United States, 6University of Wisconsin, Medical Oncology Section, Madison, United States, 7Cleveland Clinic Foundation, Experimental Therapeutics, Cleveland, United States, 8Duke University, Durham, United States, 9Pfizer Inc., Pfizer Global R & D, San Diego, United States 2
INTRODUCTION & OBJECTIVES: Metastatic RCC (mRCC) is associated with a 5-year survival rate of ≤10%, is highly resistant to chemotherapy, and only a limited subset of patients benefit from cytokine therapy (high-dose IL-2 and/or IFN-α).1 Historical data from 251 patients receiving conventional second-line therapies have reported a response rate of 4% and progression-free survival (PFS) of 2.4 months.2 Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor of VEGFR, PDGFR and other tyrosine protein kinases. We performed two multicentre single arm phase II studies to demonstrate and confirm the overall response rate (ORR), PFS, overall survival (OS) and tolerability with sunitinib in patients with cytokine-refractory mRCC. MATERIAL & METHODS: Eligibility for both trials included measurable disease, failure of one prior cytokine therapy, ECOG PS of 0/1, and adequate organ function. Patients received sunitinib 50 mg q.d. orally for 4 weeks, followed by 2 weeks off treatment to comprise a cyclical 6-week regimen. Best response was assessed using RECIST. RESULTS: Results from the two phase II studies (total N=168) demonstrated an ORR of 42%. PFS correlated with tumour response: median PFS was 14.8 months in responders (n=71), 7.9 months in those with stable disease ≥3 months (n=41), and 2.1 months in patients with stable disease <3 months or progressive disease (n=56). In the first study, median OS was 16.4 months;3 median OS in the second study has not yet been reached. Overall, the majority of treatment-related adverse events and haematological abnormalities were grade 1 and 2. These included the following treatment-related adverse events and laboratory abnormalities (grade 3/4) reported in trial 1 and trial 2, respectively: fatigue (11%, 11%), diarrhoea (3%, 3%), stomatitis (2%, 5%), neutropenia (13%, 16%), anemia (10%, 6%), and thrombocytopenia (0%, 6%). Other targeted therapies as single agents for secondline treatment of mRCC have been associated with response rates of 2–10% and PFS/TTP of 5– 6 months.4–6 CONCLUSIONS: Sunitinib has demonstrated substantial single-agent antitumour activity in mRCC, with both durable ORR and prolonged median PFS comparing positively with those observed for other second-line therapies. Sunitinib is currently under investigation in a randomised phase III study as a first-line therapy versus interferon-α. References 1. Motzer RJ, Bander NH, Nanus DM. N Engl J Med 1996;335:865–75. 2. Motzer RJ, Bacik J, Schwartz LH, et al. J Clin Oncol 2004;22:454–63. 3. Motzer RJ, Michaelson MD, Redman BG, et al. J Clin Oncol 2005; in press. 4. Escudier B, Szczylik C, Eisen T, et al. 41st Annual Meeting of the American Society of Clinical Oncology, 13–17 May 2005, Orlando, Florida; oral presentation. 5. Yang JC, Haworth L, Sherry RM, et al. N Engl J Med 2003;349:427–34. 6. Atkins MB, Hidalgo M, Stadler WM, et al. J Clin Oncol 2004;22:909–18.
1059 BEVACIZUMAB TREATMENT FOR MULTI-METASTATIC RENAL CANCER: RESULTS AFTER 6 MONTHS Larré S., Schoepen Y., De La Taille A., Paule B., Salomon L., Vordos D., Hoznek A., Abbou C.C. Hopital Henri Mondor (APHP), Dept. of Urology (pr. Abbou), Paris, France INTRODUCTION & OBJECTIVES: Bevacizumab is a promising strategy for metastatic renal cell carcinoma patients. It may inhibit metastasis progression by neutralizing antibody against vascular endothelial factor. The objective of this work was to assess efficacy of Bevacizumab in multi-metastatic patient, after failure of immunotherapy. MATERIAL & METHODS: 6 patients, 44 to 71 years old, who primarily underwent nephrectomy for renal cancer, had a multi-metastatic progression despite interferon immunotherapy. Each patient received 3 months Bevacizumab at doses of 10mg/kg (IV) given every two weeks. Efficacy of treatment was assessed on CT-Scan measurement of metastasis prior and after therapy. RESULTS: Results were assessed after 6 months. The delay between nephrectomy and beginning of Bevacizumab therapy was between 20 and 115 months. Patients received 5 to 9 cycles of Bevacizumab that was well tolerated. No hypertension or proteinuria were observed. One patient died from his renal cancer. CT-Scan controls showed metastasis burden reduction in 2 cases, stabilisation in 1 case, and progression in the 2 last cases (new metastasis with stabilisation of previous metastasis). The mean time before progression was 5.5 months. CONCLUSIONS: Bevacizumab therapy in metastatic renal cancer, after failure of immunotherapy, seemed to be an interesting approach for metastatic renal cancer patients with low toxicity.
Escudier B.1, Szczylik C.2, Eisen T.3, Oudard S.4, Stadler W.M.5, Schwartz B.6, Shan M.6, Bukowski R.M.7 1 Gustave Roussey Institute, Medical Oncology, Paris, France, 2Central Clinic Hospital, Clinical Oncology, Warsaw, Poland, 3Royal Marsden Hospital, Medical Oncology, London, United Kingdom, 4Georges Pompidou European Hospital, Medical Oncology, Paris, France, 5Chicago Cancer Research Center, Medical Oncology, Chicago, United States, 6Bayer Pharmaceuticals, Medical Oncology, Connecticut, United States, 7Cleveland Clinic Taussig Cancer Center, Oncology, Cleveland, United States
INTRODUCTION & OBJECTIVES: Sorafenib (BAY 43-9006), an oral multi-kinase inhibitor with effects on the tumour and vasculature, was shown in a Phase II trial to have anti-tumour activity in patients (pts) with metastatic RCC. The primary aim of this Phase III, double-blind, placebo-controlled trial was to assess the effects of sorafenib added to best supportive care (BSC) on overall survival (OS) in pts with confirmed, advanced clear-cell RCC. MATERIAL & METHODS: Pts (ECOG PS 0–1) who had failed one prior systemic therapy for advanced RCC were stratified according to low or intermediate Motzer prognostic factor, and randomised to receive continuous oral sorafenib 400 mg bid or placebo with BSC. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS) (single, planned analysis after 363 progressions), best response (RECIST), health-related quality of life (HRQOL) and symptom response. Adverse events (AEs) were recorded by CTCAE v3.0. RESULTS: 905 patients have been randomised. First interim analysis on 769 pts has been recently reported. Baseline characteristics for all 769 pts were: mean age, 58 yrs; ECOG 0:1, 47%:51%; Motzer prognostic factor low: intermediate, 51%:49%; prior cytokine therapy, 82%; prior nephrectomy, 93%. These were similar between treatment groups. Median PFS (independent review) was 24 weeks for sorafenib and 12 weeks for placebo (hazard ratio sorafenib/placebo, 0.44; p<0.000001). At 3 months post-randomization, 75% of pts on sorafenib were progression free versus 43% of those on placebo. Changes in tumour vascularisation, as assessed by Color Doppler ultrasonography, were highly predictive of PFS. A statistical significant difference of observed mean changes between treatment arms in the PWB of the FACT-G and FACT-KSI-10 scores over time was seen. Drug-related AEs (sorafenib:placebo) included rash/desquamation (31%:11%), diarrhea (30%:7%), hand–foot skin reaction (26%:5%), and hypertension (8%:<1%). Fatigue (18%:14%) was not significantly different between sorafenib and placebo. No significant biochemical toxicity was observed. CONCLUSIONS: Sorafenib significantly prolongs PFS compared with placebo in pts with previously treated advanced RCC, and is well tolerated with manageable side-effects.
O15 PROSTATE CANCER: INTERMITTENT HORMONAL TREATMENT Friday, 7 April, 15.45-17.15, Room Bordeaux / Level 3 1060 ANALYSIS OF BODY TEMPERATURE CHANGES DURING HOT FLUSHES IN MEN AFTER BILATERAL ORCHIDECTOMY FOR PROSTATE CANCER Heyns C., Aziz N. University of Stellenbosch and Tygerberg Hospital, Urology, Tygerberg, South Africa INTRODUCTION & OBJECTIVES: Very little has been published on the nature and severity of changes in body temperature during hot flushes experienced by men after bilateral orchidectomy for prostate cancer. This is in contrast to hot flushes in post-menopausal women, where several studies have reported on changes in the core and surface body temperature changes during episodes where patients experience hot flushes. MATERIAL & METHODS: The study included men attending the Urological Oncology clinic at our institution for follow-up after bilateral orchidectomy (BO) for locally advanced or metastatic prostate cancer. A questionnaire was used to record the patient’s experience with regard to the prevalence, severity, onset and duration of hot flushes. In a subgroup of men the core (oral) and surface (forehead) temperatures were recorded simultaneously during hot flushes, and at 6-hourly intervals between hot flushes, for a period of 2-4 weeks. RESULTS: In the period from February 2004 to February 2005, 97 patients were evaluated. Hot flushes had been experienced by 83 (86%) of these men, spontaneous remission occurred in only 9%, and 90% of the men stated that they were unaware that the hot flushes were related to their bilateral orchidectomy. The average time between bilateral orchidectomy and the onset of hot flushes was 60 days (range 2-540 days). The average number of hot flushes was 3.4 per day (range 1-10 per day). The average duration of hot flushes was 243 seconds (range 5-1800 seconds). Detailed analysis of temperature recordings in 16 patients showed that during hot flushes the mean surface (forehead) temperature was 0.22C higher than the mean core (oral) temperature, the mean core temperature was 0.22C higher during hot flushes compared to the periods between hot flushes, and the mean surface temperature was 0.48C higher during hot flushes compared with the periods between hot flushes (all differences p <0.001). CONCLUSIONS: This study showed that the great majority of men experience hot flushes after bilateral orchidectomy for prostate cancer, while the spontaneous remission rate is quite low. There is considerable variation in the time of onset, number, severity and duration of hot flushes. Mean core and surface body temperatures during hot flushes are higher compared with mean core and surface temperatures, respectively, in the normal periods between hot flushes. The mean surface temperature is higher than the mean core body temperature during the period when the patient experiences a hot flush.
Eur Urol Suppl 2006;5(2):287
1058
SUNITINIB MALATE (SU11248) – EFFICACY IN RENAL CELL CARCINOMA (RCC)
RANDOMISED PHASE III TRIAL OF THE MULTIKINASE INHIBITOR SORAFENIB (BAY 43-9006) IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA (RCC)
Motzer R.1, Rini B.2, Michaelson D.3, Redman B.4, Hudes G.5, Wilding G.6, Bukowski R.7, George D.8, Kim S.9, Baum C.9 1
Memorial Sloan-kettering Cancer Center, Genitourinary Oncology Service, New York, United States, U.C.S.F., Comprehensive Cancer Center, San Francisco, United States, 3Dana Farber, Harvard Cancer Center, Boston, United States, 4University of Michigan, Comprehensive Cancer Center, Ann Arbor, United States, 5Fox Chase Cancer Center, Genitourinary Malignancies Program, Philadelphia, United States, 6University of Wisconsin, Medical Oncology Section, Madison, United States, 7Cleveland Clinic Foundation, Experimental Therapeutics, Cleveland, United States, 8Duke University, Durham, United States, 9Pfizer Inc., Pfizer Global R & D, San Diego, United States 2
INTRODUCTION & OBJECTIVES: Metastatic RCC (mRCC) is associated with a 5-year survival rate of ≤10%, is highly resistant to chemotherapy, and only a limited subset of patients benefit from cytokine therapy (high-dose IL-2 and/or IFN-α).1 Historical data from 251 patients receiving conventional second-line therapies have reported a response rate of 4% and progression-free survival (PFS) of 2.4 months.2 Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor of VEGFR, PDGFR and other tyrosine protein kinases. We performed two multicentre single arm phase II studies to demonstrate and confirm the overall response rate (ORR), PFS, overall survival (OS) and tolerability with sunitinib in patients with cytokine-refractory mRCC. MATERIAL & METHODS: Eligibility for both trials included measurable disease, failure of one prior cytokine therapy, ECOG PS of 0/1, and adequate organ function. Patients received sunitinib 50 mg q.d. orally for 4 weeks, followed by 2 weeks off treatment to comprise a cyclical 6-week regimen. Best response was assessed using RECIST. RESULTS: Results from the two phase II studies (total N=168) demonstrated an ORR of 42%. PFS correlated with tumour response: median PFS was 14.8 months in responders (n=71), 7.9 months in those with stable disease ≥3 months (n=41), and 2.1 months in patients with stable disease <3 months or progressive disease (n=56). In the first study, median OS was 16.4 months;3 median OS in the second study has not yet been reached. Overall, the majority of treatment-related adverse events and haematological abnormalities were grade 1 and 2. These included the following treatment-related adverse events and laboratory abnormalities (grade 3/4) reported in trial 1 and trial 2, respectively: fatigue (11%, 11%), diarrhoea (3%, 3%), stomatitis (2%, 5%), neutropenia (13%, 16%), anemia (10%, 6%), and thrombocytopenia (0%, 6%). Other targeted therapies as single agents for secondline treatment of mRCC have been associated with response rates of 2–10% and PFS/TTP of 5– 6 months.4–6 CONCLUSIONS: Sunitinib has demonstrated substantial single-agent antitumour activity in mRCC, with both durable ORR and prolonged median PFS comparing positively with those observed for other second-line therapies. Sunitinib is currently under investigation in a randomised phase III study as a first-line therapy versus interferon-α. References 1. Motzer RJ, Bander NH, Nanus DM. N Engl J Med 1996;335:865–75. 2. Motzer RJ, Bacik J, Schwartz LH, et al. J Clin Oncol 2004;22:454–63. 3. Motzer RJ, Michaelson MD, Redman BG, et al. J Clin Oncol 2005; in press. 4. Escudier B, Szczylik C, Eisen T, et al. 41st Annual Meeting of the American Society of Clinical Oncology, 13–17 May 2005, Orlando, Florida; oral presentation. 5. Yang JC, Haworth L, Sherry RM, et al. N Engl J Med 2003;349:427–34. 6. Atkins MB, Hidalgo M, Stadler WM, et al. J Clin Oncol 2004;22:909–18.
1059 BEVACIZUMAB TREATMENT FOR MULTI-METASTATIC RENAL CANCER: RESULTS AFTER 6 MONTHS Larré S., Schoepen Y., De La Taille A., Paule B., Salomon L., Vordos D., Hoznek A., Abbou C.C. Hopital Henri Mondor (APHP), Dept. of Urology (pr. Abbou), Paris, France INTRODUCTION & OBJECTIVES: Bevacizumab is a promising strategy for metastatic renal cell carcinoma patients. It may inhibit metastasis progression by neutralizing antibody against vascular endothelial factor. The objective of this work was to assess efficacy of Bevacizumab in multi-metastatic patient, after failure of immunotherapy. MATERIAL & METHODS: 6 patients, 44 to 71 years old, who primarily underwent nephrectomy for renal cancer, had a multi-metastatic progression despite interferon immunotherapy. Each patient received 3 months Bevacizumab at doses of 10mg/kg (IV) given every two weeks. Efficacy of treatment was assessed on CT-Scan measurement of metastasis prior and after therapy. RESULTS: Results were assessed after 6 months. The delay between nephrectomy and beginning of Bevacizumab therapy was between 20 and 115 months. Patients received 5 to 9 cycles of Bevacizumab that was well tolerated. No hypertension or proteinuria were observed. One patient died from his renal cancer. CT-Scan controls showed metastasis burden reduction in 2 cases, stabilisation in 1 case, and progression in the 2 last cases (new metastasis with stabilisation of previous metastasis). The mean time before progression was 5.5 months. CONCLUSIONS: Bevacizumab therapy in metastatic renal cancer, after failure of immunotherapy, seemed to be an interesting approach for metastatic renal cancer patients with low toxicity.
Escudier B.1, Szczylik C.2, Eisen T.3, Oudard S.4, Stadler W.M.5, Schwartz B.6, Shan M.6, Bukowski R.M.7 1 Gustave Roussey Institute, Medical Oncology, Paris, France, 2Central Clinic Hospital, Clinical Oncology, Warsaw, Poland, 3Royal Marsden Hospital, Medical Oncology, London, United Kingdom, 4Georges Pompidou European Hospital, Medical Oncology, Paris, France, 5Chicago Cancer Research Center, Medical Oncology, Chicago, United States, 6Bayer Pharmaceuticals, Medical Oncology, Connecticut, United States, 7Cleveland Clinic Taussig Cancer Center, Oncology, Cleveland, United States
INTRODUCTION & OBJECTIVES: Sorafenib (BAY 43-9006), an oral multi-kinase inhibitor with effects on the tumour and vasculature, was shown in a Phase II trial to have anti-tumour activity in patients (pts) with metastatic RCC. The primary aim of this Phase III, double-blind, placebo-controlled trial was to assess the effects of sorafenib added to best supportive care (BSC) on overall survival (OS) in pts with confirmed, advanced clear-cell RCC. MATERIAL & METHODS: Pts (ECOG PS 0–1) who had failed one prior systemic therapy for advanced RCC were stratified according to low or intermediate Motzer prognostic factor, and randomised to receive continuous oral sorafenib 400 mg bid or placebo with BSC. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS) (single, planned analysis after 363 progressions), best response (RECIST), health-related quality of life (HRQOL) and symptom response. Adverse events (AEs) were recorded by CTCAE v3.0. RESULTS: 905 patients have been randomised. First interim analysis on 769 pts has been recently reported. Baseline characteristics for all 769 pts were: mean age, 58 yrs; ECOG 0:1, 47%:51%; Motzer prognostic factor low: intermediate, 51%:49%; prior cytokine therapy, 82%; prior nephrectomy, 93%. These were similar between treatment groups. Median PFS (independent review) was 24 weeks for sorafenib and 12 weeks for placebo (hazard ratio sorafenib/placebo, 0.44; p<0.000001). At 3 months post-randomization, 75% of pts on sorafenib were progression free versus 43% of those on placebo. Changes in tumour vascularisation, as assessed by Color Doppler ultrasonography, were highly predictive of PFS. A statistical significant difference of observed mean changes between treatment arms in the PWB of the FACT-G and FACT-KSI-10 scores over time was seen. Drug-related AEs (sorafenib:placebo) included rash/desquamation (31%:11%), diarrhea (30%:7%), hand–foot skin reaction (26%:5%), and hypertension (8%:<1%). Fatigue (18%:14%) was not significantly different between sorafenib and placebo. No significant biochemical toxicity was observed. CONCLUSIONS: Sorafenib significantly prolongs PFS compared with placebo in pts with previously treated advanced RCC, and is well tolerated with manageable side-effects.
O15 PROSTATE CANCER: INTERMITTENT HORMONAL TREATMENT Friday, 7 April, 15.45-17.15, Room Bordeaux / Level 3 1060 ANALYSIS OF BODY TEMPERATURE CHANGES DURING HOT FLUSHES IN MEN AFTER BILATERAL ORCHIDECTOMY FOR PROSTATE CANCER Heyns C., Aziz N. University of Stellenbosch and Tygerberg Hospital, Urology, Tygerberg, South Africa INTRODUCTION & OBJECTIVES: Very little has been published on the nature and severity of changes in body temperature during hot flushes experienced by men after bilateral orchidectomy for prostate cancer. This is in contrast to hot flushes in post-menopausal women, where several studies have reported on changes in the core and surface body temperature changes during episodes where patients experience hot flushes. MATERIAL & METHODS: The study included men attending the Urological Oncology clinic at our institution for follow-up after bilateral orchidectomy (BO) for locally advanced or metastatic prostate cancer. A questionnaire was used to record the patient’s experience with regard to the prevalence, severity, onset and duration of hot flushes. In a subgroup of men the core (oral) and surface (forehead) temperatures were recorded simultaneously during hot flushes, and at 6-hourly intervals between hot flushes, for a period of 2-4 weeks. RESULTS: In the period from February 2004 to February 2005, 97 patients were evaluated. Hot flushes had been experienced by 83 (86%) of these men, spontaneous remission occurred in only 9%, and 90% of the men stated that they were unaware that the hot flushes were related to their bilateral orchidectomy. The average time between bilateral orchidectomy and the onset of hot flushes was 60 days (range 2-540 days). The average number of hot flushes was 3.4 per day (range 1-10 per day). The average duration of hot flushes was 243 seconds (range 5-1800 seconds). Detailed analysis of temperature recordings in 16 patients showed that during hot flushes the mean surface (forehead) temperature was 0.22C higher than the mean core (oral) temperature, the mean core temperature was 0.22C higher during hot flushes compared to the periods between hot flushes, and the mean surface temperature was 0.48C higher during hot flushes compared with the periods between hot flushes (all differences p <0.001). CONCLUSIONS: This study showed that the great majority of men experience hot flushes after bilateral orchidectomy for prostate cancer, while the spontaneous remission rate is quite low. There is considerable variation in the time of onset, number, severity and duration of hot flushes. Mean core and surface body temperatures during hot flushes are higher compared with mean core and surface temperatures, respectively, in the normal periods between hot flushes. The mean surface temperature is higher than the mean core body temperature during the period when the patient experiences a hot flush.
Eur Urol Suppl 2006;5(2):287