Metastatic Renal Cancer Medical Treatment Bohuslav Melichar, M.D., Ph.D. Professor and Head Department of Oncology Palacký University Medical School and Teaching Hospital Olomouc, Czech Republic
Peculiarities of RCC Resistance to cytotoxic agents High VEGF production (fosters the growth of metastases) Unusul sites of metastatic disease (e.g. breast, pancreas, thyroid) Unpredictable course of disease (spontaneous regression or rapidly fatal disease) Paraneoplastic syndromes
pontaneous complete regression of RCC lung metastases after nephrectomy Melichar et al. Acta Oncol 2009, 48, 925-927
RCC metastases to the pancreas Čečka et al. Hepatogastroenterology 2009, 56, 1213-1218
Randomized trial of IFN+ VBL vs. VBL Pyrhonen et al. J Clin Oncol 1999, 17, 2859
Molecular pathology of RCC Brugarolas. N Engl J Med 2007, 356, 185 187.
Expression of VEGF in different tumors Jubb et al. J Clin Pathol 2004, 57, 504-512
Actions of VEGF relevant for tumor growth Growth factor for endothelial cells (angiogenesis) Increased permeability (tumor hypertension, formation of malignant effusions) Inhibitory action on dendritic cells and lymphocytes (suppression of immune response) Growth factor of tumor cells
Patients progression-free (%) Time to progression in phase II trial of bevacizumab in RCC after cytokine failure 100 80 60 Bevacizumab 10mg/kg q2w; p<0.001 Bevacizumab 3mg/kg q2w Placebo 40 20 0 2.5 3.0 4.8 0 6 12 18 24 30 36 Months from date on-study Yang, et al. NEJM 2003;349:427 34
Probability of being progression-free Progression-free survival (investigator assessed) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 HR=0.63, p<0.0001 Median progression-free survival: Bevacizumab + IFN = 10.2 months IFN + placebo = 5.4 months 0.1 0 Number of patients at risk 5.4 10.2 0 6 12 18 24 Time (months) IFN + placebo 322 137 59 15 0 Bevacizumab + IFN 327 196 107 18 0 Escudier et al. Lancet 2007, 370, 2103-2111
CALGB 90206 Rini et al. J Clin Oncol 26, 2008, 5422
Too many drugs for mrcc???
TKIs in RCC, 2010
Selectivity of kinase inhibitors Karaman et al. Nature Biotech 2008, 26, 127-132
Sunitinib in the first-line therapy of mrcc Motzer et al. N Engl J Med 2007, 356, 115 124.
Overall survival after first-line sunitinib p = 0.051 unstratified; p = 0.049 stratified Motzer et al. J Clin Oncol 2009, 27, 3584
Pazopanib (GW786034) N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl- 3-sulphonamidophenyl)-2,4-pyrimidinediamine VEGFR-1 VEGFR-2 VEGFR-3 PDGF-aR PDGF-bR c-kit
Activity in mrcc in phase I trial Hurwitz HI et al. Clin Cancer Res 2009, 15, 4220
Randomized discontinuation trial of pazopanib Hutson TE et al. J Clin Oncol 2010, 28, 475-480
Response to pazopanib Hutson TE et al. J Clin Oncol 2010, 28, 475-480
VEG105192 Sternberg et al. J Clin Oncol 28, 2010, 1061
Pazopanib in the therapy of mrcc Sternberg et al. J Clin Oncol 28, 2010, 1061
Subgroup analyses in VEG105192 Sternberg et al. J Clin Oncol 28, 2010, 1061
Temsirolimus vs. interferon-alpha in patients with poor prognosis Hudes et al. N Engl J Med 2007, 356, 2271
Second-line therapy
PFS in patients treated with everolimus Motzer et al. Lancet 2008, 372, 449
Possible algorithm of targeted therapy of metastatic RCC Melichar B. Oncology (Basel) 2009, 77, 82-91.
New agents Axitinib Tivozanib Cabozantinib Dovitinib
Axitinib vs. sorafenib in second line therapy Rini BI et al. Lancet 2011, 378, 1931-1939
Abstract No. 4503 Axitinib for first-line metastatic RCC: Overall efficacy and pharmacokinetic analyses from a randomized phase II study BI Rini 1, V Grünwald 2, MN Fishman 3, B Melichar 4, T Ueda 5, PA Karlov 6, AH Bair 7, Y Chen 7, S Kim 7, E Jonasch 8 1 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 2 Hannover Medical School, Hannover, Germany; 3 H. Lee Moffitt Cancer Center, Tampa, FL, USA; 4 University Hospital, Olomouc, Czech Republic; 5 Chiba Cancer Center, Urology, Chiba, Japan; 6 City Clinical Oncology Dispensary, Saint-Petersburg, Russia; 7 Pfizer Oncology, San Diego, CA, USA; 8 The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Study Design Lead-in period (Cycle 1) Axitinib 5 mg BID (4 wks) During Cycle 1 (subset of patients) Randomization criteria a BP 150/90 mmhg and 2 concurrent anti-htn medications and No grade 3 or 4 axitinib-related toxicities and No dose reduction Yes No R A N D O M I Z E 1:1 Arm A Axitinib 5 mg BID + Axitinib dose titration b (blinded therapy) Arm B Axitinib 5 mg BID + Placebo dose titration b (blinded therapy) ABPM c 6-h PK sampling d a For at least 2 consecutive weeks b Titrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomization to dose titration were met Arm C Axitinib 5 mg BID (no dose titration) C Ambulatory blood pressure monitoring performed at baseline and on Cycle 1 Days 4 and 15 d 6-hr PK sampling performed on Cycle 1 Day 15 Rini et al. ASCO 2012
Clinical Efficacy of Axitinib for First-line Metastatic RCC Total a (N=213) Arm C Not eligible for dose titration (n=91) Arms A + B Eligible for dose titration (n=112) mpfs, mo (95% CI) b 14.5 (11.5, 17.4) 16.4 (11.0, 19.0) 14.5 (11.0, 19.3) ORR (95% CI) b 48% (41%, 55%) 59% (49%, 70%) 43% (34%, 53%) a Includes 10 patients who discontinued study treatment prior to decision for dose titration b As of April 30, 2012 CI = confidence interval; mpfs = median progression-free survival; ORR = objective response rate Rini et al. ASCO 2012
Clinical Outcome According to Diastolic Blood Pressure on Cycle 1 Day 15 Blood pressure parameter mpfs, mo ORR AUC 12, ng h/ml a DdBP DdBP dbp 10 mmhg, n=39 16.7 59% <10 mmhg, n=22 8.3 45% 15 mmhg, n=20 19.3 60% <15 mmhg, n=41 11.1 51% 90 mmhg, n=17 22.5 65% <90 mmhg, n=46 13.7 50% 176 63 235 93 195 110 a Geometric mean dbp = diastolic blood pressure (per ambulatory blood pressure monitoring); DdBP = change in dbp from baseline; 36 mpfs = median progression-free survival; ORR = objective response rate Rini et al. ASCO 2012
How we choose the agent? 1. Efficacy 2. Tolerance 3. Potential for second-line treatments 4. Patient preference
The concept of targeted therapy
Side effects of therapy in AVOREN Escudier et al. Lancet 2007, 370, 2103-2111
Progression-free survival Melichar et al. Ann Oncol 2008, 19, 1470 1476
Side-effects of sunitinib Motzer RJ et al. JCO 2009, 27, 3584-3590.
Side-effects of pazopanib Sternberg et al. J Clin Oncol 28, 2010, 1061
PISCES trial Escudier et al. ASCO 2012
Results of PISCES trial - efficacy Escudier et al. ASCO 2012
Results of PISCES trial patient preference Escudier et al. ASCO 2012
Case Study Male, born 1940 History of hypertension (since 1986) Nephrectomy for clear cell RCC in November 1997 Fall 2003 goiter detected Thyroidectomy performed in October 2003 Histology - clear cell RCC metastasis No evidence of other distant metastases
Case Study(continued) IFN-a (9 MU 3 times a week) administered between December 2003 and May 2005 Spring 2005 complained about diarrhea and obstipation, hiccups CT in May 2005 - pancreatic tumor (60 mm, located in the tail) and lung metastases detected Cytology of the pancreatic tumor clear cell RCC metastasis
Case Study (continued) Entered into the phase II discontinuation trial of pazopanib (800 mg daily) in March 2006 Good tolerance (diarrhea gr. 1, epistaxis gr. 1, dermatitis gr. 1, hair discoloration) Stable disease on repeated CT scans Last control March, 2012, still on medication (800 mg daily), performance status (WHO) 0
Conclusions Need to utilize the potential of all drugs active in metastatic RCC Optimal algorithm still a matter of debate Comparable efficacy data for many agents Tolerance (spectrum of toxicity) and patients preference are important considerations Difficulties with drug access in Central and Eastern states of the EU
Management of metastatic RCC is a team endeavor
Thank you for your attention Olomouc, Moravia, Czech Republic
Presentation was financialy supported by GSK