VIEWS: 5 PAGES: 31 POSTED ON: 5/8/2014
Targeted Therapy for Renal Cell Cancer Dr.Mahmoodzadeh Oncologist-Hematologist Kidney Neoplasms n Primary or Secondary (metastatic) n Renal cell carcinoma (RCC) represents 80-85% of primary renal neoplasms n Transitional cell carcinoma 8% n Rare tumors include: - Oncocytomas - Collecting duct tumors - Renal sarcomas - Nephroblastoma (Wilms’ tumor in children) - Renal medullar carcinoma (Sickle cell disease) Pathogenesis of VHL n Von Hippel-Lindau protein, product of VHL gene, is a tumor suppressor n VHL inhibits hypoxia-inducible genes involved in angiogenesis such as VEGF, TGF-a, GLUT-1 n VHL destabilizes and promotes ubiquination of HIF-a (hypoxia-inducible factor) n Loss of VHL results in tumor angiogenesis, tumor-cell proliferation epithelial cell proliferation Advanced RCC Treatment n Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy n Surgery is palliative therapy - Solitary metastatic site - Solitary recurrence following nephrectomy - Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction Why using TKIs for Kidney cancer treatment ? n Many kidney cancers are associated with a kinase mutation responsible for angiogenesis factors overexpression n TKIs are targeted therapies: increasing response and reducing side effects. 5 Targeted Therapy n Based on advances in the understanding of the molecular biology of RCC - Highly vascularlized tumor with increased VEGF and EGFR expression - Tumor growth mediated via VEGF pathway and mammalian target of rapamycin (mTOR) pathway What is a tyrosine kinase receptor ? 7 VEGF Pathway Inhibition n Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF receptor - Sunitinib (Sutent) - Sorafenib (Nexavar) n Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor - Bevacizumab (Avastin) Sunitinib n Two phase II trials evaluating activity and safety in previously treated advanced RCC - 25-36% of patients had an objective response - Progression free survival (PFS) 8.3-8.7 months - Median survival 16.4 months n Side effects include fatigue, HTN, nausea, diarrhea, mucositis, and hypothyroidism Sunitinib n Phase III trial 750 pts with untreated stage IV RCC Sunitinib vs. INFa n Sunitinib showed prolonged median PFS 11 vs. 5m and higher response rate of 31% vs. 6% Motzer RJ, et al. NEJM. 2007;356:115-124 SUTENT Efficacy and Safety Were Demonstrated Using a 50-mg Starting Dose SUTENT dose may be easily adjusted in 12.5-mg increments n No dose adjustment is recommended based on age, race, gender, body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B) 13 Sorafenib n Phase II and phase III trials in advanced RCC n Phase III TARGET study of 903 previously tx pts w/ stage IV RCC randomized to Sorafenib vs. placebo - Sorafenib improved median PFS 5.5 vs. 2.8m - No statistically significant survival benefit, median survival of 17.8 vs. 15.2 m n Side effects include HTN, fatigue, rash, hand- foot syndrome, diarrhea, nausea 15 Marco Antonio Arap, New directions in the management of renal cell carcinoma 2007 16 Kinase profile of Pazopanib Kinase affinity profile Ki app (nM) VEGFR-1 10 VEGFR-2 4 VEGFR-3 6 PDGFR-a 2 PDGFR-b 5 C-Kit 15 Sora Suniti Pazop feni nib anib b 17 VEGF-A/B PDGF-a/b PDGF-a/b VEGFR- VEGF-C 1/2 PDGFR VEGFR-3 Pz Pz Pz Pz Pz Pz Pz 18 Clinical trial of Pazopanib n Patient with metastasic RCC n 800mg once a day n No treatment holiday n versus placebo n Half patient naïve and half with prior cytokine treatment Primary endpoints: ◦ PFS: Progression free survival 19 Overview of clinical trial results Treatment naïve Cytokine Refractory OS PFS PFS 5,8 mos. Sorafenib 5,9 mos. 10,7 mos*. (Phase II results only) Sunitinib 11 mos. 8,7 mos. 26,4 mos. Pazopanib 11,1 mos. 7,4 mos. 21.1 mos. * : Cross-over 20 Bevacizumab n Phase II trial of 116 pts, Bevacizumab increased TTP 4.8 vs. 2.5m for placebo group. -No difference in median survival n Phase III AVOREN trial of 648 untreated pts - INFa plus Avastin or placebo - Avastin group resulted in PFS of 10.2 vs. 5.4 m. - Unclear activity as single agent however n Not FDA approved, but can be used as second-line therapy mTOR Pathway Inhibition n Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase n Phase III trial 626 untreated poor-prognosis pts with stage IV RCC tx w/ TMSR, TMSR +INFa, or INFa. - TMSR prolonged survival compared to INFa (10.9 vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m) - Benefit greater in non-clear cell RCC RECENTIN : Cediranib n AstraZeneca n Oral inhibitor of the : n VEGF-R 1/2/3 n C-kit n PDGF-R n Efficacy Racenta vs Placebo 23 Axitinib (Bayer, AG013736) Inhibs specifically: VEGFR 1-2-3 and PDGFR b Low effects on C-kit or flt-3 No cross resistance with sorafenib 24 The ideal kinase inhibiting profile in RCC The perfect tyrosine kinase inhibitor treating RCC § should inhib: o VEGFR 1-2-3 o PDGFR a-b o Raf § Without inhibiting ◦ FLT-3 ◦ C-kit 25 Immunotherapy n Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-91 months n Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction n Treatment requires ICU monitoring n Used for patients that can tolerate side effects Chemotherapy n RCC is only minimally responsive to chemotherapy n 83 clinic trials involving over 4000 pts, overall response rate is only 6% n On-going clinical trials of combination chemotherapy including Gemcitabine and 5-FU n Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine Radiation Therapy n RCC relatively radioresistant n XRT has limited use in metastatic disease - Painful bone or recurrent abdominal metastases - Brain metastases Summary n RCC is relatively rare but increasing incidence n Associated with tobacco and inherited disorders n Surgery is the only curative modality for Stage I, II, and III n Stage IV disease holds poor prognosis despite advancements in molecular understanding n IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA approved treatments for advanced RCC Thanks for your attention 31
"Renal Cell Carcinoma"