Aristotelis Bamias1, Vasilios Karavasilis2, Nikolaos Gavalas3, Kimon Tzannis4, Epaminontas Samantas5, Gerasimos Aravantinos6, Angelos Koutras7, Ioannis Gkerzelis8, Euthymios Kostouros4, Konstantinos Koutsoukos4, Flora Zagouri4, George Fountzilas9,10, Meletios-Athanasios Dimopoulos4. 1. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 80 Vas. Sofias Ave, 115 28, Athens, Greece. abamias@med.uoa.gr. 2. Department of Medical Oncology, Papageorgiou Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece. 3. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 80 Vas. Sofias Ave, 115 28, Athens, Greece. ngavalas@med.uoa.gr. 4. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 80 Vas. Sofias Ave, 115 28, Athens, Greece. 5. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece. 6. Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece. 7. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece. 8. Department of Urology, General Hospital Konstantopouleio Agia Olga, Athens, Greece. 9. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloníki, Greece. 10. Aristotle University of Thessaloniki, Thessaloníki, Greece.
Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. METHODS: A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. RESULTS: 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. CONCLUSIONS: In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01264341.
BACKGROUND:Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. METHODS: A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. RESULTS: 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. CONCLUSIONS: In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01264341.
Authors: Michael R Mancuso; Rachel Davis; Scott M Norberg; Shaun O'Brien; Barbara Sennino; Tsutomu Nakahara; Virginia J Yao; Tetsuichiro Inai; Peter Brooks; Bruce Freimark; David R Shalinsky; Dana D Hu-Lowe; Donald M McDonald Journal: J Clin Invest Date: 2006-10 Impact factor: 14.808
Authors: Robert J Motzer; Thomas E Hutson; Piotr Tomczak; M Dror Michaelson; Ronald M Bukowski; Olivier Rixe; Stéphane Oudard; Sylvie Negrier; Cezary Szczylik; Sindy T Kim; Isan Chen; Paul W Bycott; Charles M Baum; Robert A Figlin Journal: N Engl J Med Date: 2007-01-11 Impact factor: 91.245
Authors: P H Maxwell; M S Wiesener; G W Chang; S C Clifford; E C Vaux; M E Cockman; C C Wykoff; C W Pugh; E R Maher; P J Ratcliffe Journal: Nature Date: 1999-05-20 Impact factor: 49.962