The Ever-Changing Landscape Daniel Heng MD MPH FRCPC University of Calgary Outline Staging Genetics behind RCC Treatment of metastatic disease Case Prognostic Factors Mechanisms of Resistance Cytoreductive nephrectomy Staging Cohen et al NEJM 2004 Von Hippel Lindau VHL HIF1a Ub Ub Ub Ub Proteosome Degradation Of HIF1a Courtesy sppider.cchmc.org & www.bme.jhu.edu Von Hippel Lindau VHL HIF1a Transcription of Genes Associated with Angiogenesis and Proliferation Angiogenesis and Proliferation VEGF TGFa/B/ PDGF VEGFR EGFR PDGFR Angiogenesis Cell Proliferation Endothelial Stabilization Cohen et al NEJM 2005 Von Hippel Lindau 75-80% of sporadic clear cell RCCs have VHL defect: Frameshift / truncation mutation Deletion Promoter methylation CH3 Promoter Von Hippel Lindau Gene Transcription Cohen et al NEJM 2005 Targeted Therapies: The Revolution Courtesy AZ Targeted Therapy in mRCC VEGF inhibitors mTOR inhibitors Sunitinib Temsirolimus Sorafenib Everolimus Bevacizumab Pazopanib Axitinib Targets and Inhibitors Rini et al JCO 2005, 2009 Treatment of mRCC: 2011 Setting Patients Therapy Other Options (level 1 evidence) (>level 1 evidence) Untreated Good or Sunitinib HD IL-2 intermediate risk Bevacizumab+IFN Sorafenib Pazopanib Clinical Trial Observation Poor risk Temsirolimus Sunitinib Clinical Trial Second-line Cytokine Axitinib Sunitinib refractory Sorafenib Bevacizumab+IFN Prior VEGF Axitinib Targeted therapy Everolimus not previously used Clinical Trial Case I: JN • 60F otherwise healthy • Had abdominal discomfort so abdominal ultrasound was ordered • 7x5 cm central mass in right kidney incidentally detected • pT3a N0 M0 clear cell renal cell carcinoma resected by laparoscopic right radical nephrectomy • Staging CT scans revealed no other metastases Case I: JN Standard of care would be CT scans of the abdomen and pelvis with chest x-ray every 6 months for first 2 years yearly thereafter Because of 50% chance of recurrence, was offered adjuvant clinical trial REC2 clinical trial ○ One year of sunitinib, sorafenib, or placebo Case I: JN Consented to ASSURE clinical trial Had no side effects whatsoever … was she on placebo? 6 month CT scan clear 12 month CT scan ○ Multiple pulmonary metastases bilaterally max 2 cm ○ Liver metastases Case I: JN Case I: JN She now has metastatic disease Her calcium, LDH, neutrophils, platelets are within normal range, ECOG 0 Her hemoglobin is low at 100 What is her Prognostic Category? 1) Favorable risk – median OS 44 months 2) Intermediate risk – median OS 21 months 3) Poor risk – median OS 8 months Intl mRCC Database Consortium: Independent Predictors of Poor OS KPS < 80 Dx to Tx Interval <1yr Anemia Hypercalcemia Neutrophilia Thrombocytosis Heng et al JCO 2009 Prognostic Factors If patient has 0 factors: Favorable Prognosis If patient has 1-2 factors: Intermediate Prognosis If patient has 3-6 factors: Poor Prognosis Overall Survival in the New Era Favorable: 0 factors (mOS 44 mos) Intermediate: 1-2 factors (mOS 21 mos) Poor: 3-6 factors p<0.0001 (mOS 8 mos) Heng et al ASCO 2011 Case I: JN She has intermediate risk criteria due to anemia What first line targeted therapy would you choose? 1)Sunitinib 2)Temsirolimus 3)Everolimus 4)Interferon 5)High dose IL-2 Sunitinib PFS Motzer et al NEJM 2007 Pazopanib PFS Sternberg et al..J Clin Oncol 2010; 28: 1061-1068. Bevacizumab+IFN AVOREN Phase III Trial IFN-α2b SC Met clear cell RCC Treatment naive IFN-α2b SC + Bevacizumab IV Progression free survival benefit (10.2 vs. 5.4 months p<0.0001) No OS benefit due to crossover Temsirolimus Overall Survival Benefit TEMSR vs IFN log rank p=0.0069 PFS 3.7 vs. 1.9 months mOS 10.9 vs. 7.3 months Hudes et al NEJM 2007 Sorafenib PFS Progression-free Survival Improved with Sorafenib 1.00 Probability of Being Progression-free Sorafenib (n = 451) = 5.5 months 0.75 Placebo (n = 452) = 2.8 months Hazard ratio = 0.51; P < 0.001 0.50 0.25 0.00 0 2 4 6 8 10 12 14 16 18 20 Time from Randomization (Months) * Based on investigator assessment Escudier B, Eisen T, Stadler WM, et al. N Engl J Med. 2007;356:125-134. 47 Escudier et al NEJM 2007 Treatment of mRCC: 2011 Setting Patients Therapy Other Options (level 1 evidence) (>level 1 evidence) Untreated Good or Sunitinib HD IL-2 intermediate risk Bevacizumab+IFN Sorafenib Pazopanib Clinical Trial Observation Poor risk Temsirolimus Sunitinib Clinical Trial Second-line Cytokine Axitinib Sunitinib refractory Sorafenib Bevacizumab+IFN Prior VEGF Axitinib Targeted therapy Everolimus not previously used Clinical Trial Case I: JN • She chooses to be on sunitinib • She is dosed at the standard 50 mg 4 weeks on and 2 weeks off • Her baseline assessments included – CT scan of the chest, abdomen, pelvis – Bone scan (normal) – CBC, liver function tests, creatinine, baseline TSH – MUGA/echo only in patients with prior history of cardiac disease or significant risk factors Case I: JN • She is followed with CT scans every 3 months (every 2 cycles) – 3 month CT: 19% tumor reduction – 6 month CT: stable disease from previous – 9 month CT: stable disease from previous • At 11 months: – She develops significant anemia (Hb 88) – She is tired, symptomatic of anemia – Had syncopal episode – She requires a transfusion of 2 units PRBC Case I: JN • Sunitinib was held for 4 weeks but counts did not recover, required blood transfusions every 3 days • Became neutropenic despite not being on any drug • Considered bone marrow infiltration of RCC – Bone marrow biopsy could not confirm this (sampling error) – Decided that this was progressive disease and needed new line of therapy Mechanisms of Resistance Mechanisms of Resistance 1) Angiogenic redundancy – PDGF, FGF, PIGF 2) Intratumoral hypoxia induces redundancy factors Grepin R et al J Oncology 2010 Mechanisms of Resistance 3) Natural selection of more invasive tumor cells Grepin R et al J Oncology 2010 Mechanisms of Resistance 4) Recruitment of bone marrow derived proangiogenic and inflammatory cells – IL-6, GCSF recruitment 5) Targeted endothelial cells can recruit pericytes to protect them and release PDGF 6) Vessel cooption: smaller, new tumors develop around normal blood vessels Grepin R et al J Oncology 2010 Everolimus: Progression-Free Survival Central Radiology Review 100 80 Hazard ratio = 0.30 95% CI [0.22, 0.40] Median PFS 60 Everolimus: 4.0 mo Probability, % Placebo: 1.9 mo 40 Log rank P value <0.001 RAD001 (n=272) Placebo (n=138) 20 0 0 2 4 6 8 10 12 Months Patients at Risk Everolimus 272 132 47 8 2 0 0 Placebo 138 32 4 1 0 0 0 Motzer R, Escudier B, Oudard S et al. LBA 5026 ASCO 2008. Axitinib Progression-free Survival (IRC Assessment) Progression-Free Survival (probability) mPFS, mo 95% CI 1.0 Axitinib 6.7 6.3–8.6 0.9 Sorafenib 4.7 4.6–5.6 0.8 P<0.0001 (log-rank) 0.7 Stratified HR 0.665 0.6 (95% CI 0.544–0.812) 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Time (months) Subjects at risk, n Axitinib 361 256 202 145 96 64 38 20 10 1 0 Sorafenib 362 224 157 100 51 28 12 6 3 1 0 IRC = Independent Review Committee Rini et al ASCO 2011 Treatment of mRCC: 2011 Setting Patients Therapy Other Options (level 1 evidence) (>level 1 evidence) Untreated Good or Sunitinib HD IL-2 intermediate risk Bevacizumab+IFN Sorafenib Pazopanib Clinical Trial Observation Poor risk Temsirolimus Sunitinib Clinical Trial Second-line Cytokine Axitinib Sunitinib refractory Sorafenib Bevacizumab+IFN Prior VEGF Axitinib Targeted therapy Everolimus not previously used Clinical Trial Case I: JN • Began Everolimus 10mg/kg – No longer required transfusions – Feeling much better – Minimal side effects – Monitored with CT scans and Hb every 3 months • 3 month CT: stable disease, Hb 135 – 6 months: symptomatic anemia again, Hb 88 • Did not recover with everolimus cessation • Required transfusions every 3 days • Deemed to have progressive disease Case I: JN What third-line targeted therapy would you choose? 1)Sunitinib 2)Temsirolimus 3)Everolimus 4)Interferon 5)High dose IL-2 6)Pazopanib 7)Bevacizumab+IFN 8)Clinical Trial Case I: JN • Patient chooses pazopanib as she had third party insurance • Monitored patient with CT scans every 3 months – 3 months: 18% decrease – 6 months: slowly progressive liver disease, lungs stable (15% increase) – 9 months: progressive disease in liver (20% increase) Case I: JN Screening for clinical trial of BMS PD-1 inhibitor Still slightly anemic Lessons Learned Targeted therapy extended her life significantly “Thank you, this time last year I thought I wouldn’t be here anymore” Progression can come in different ways and not just on CT scans Third line therapy is therapy that you haven’t used before, if available Background Two prospective randomized trials1,2 with metastatic RCC showed that the addition of cytoreductive nephrectomy (CN) improves overall survival (OS) as compared to interferon-alpha (IFN-a) alone (13.6 months vs. 7.8 months; Hazard ratio=0.69, p=0.001) IFN-a is a historic standard of care. Patients were enrolled between 1991-1998. The role of debulking nephrectomy in the era of novel VEGF-targeted agents remains poorly defined. 1. Flanigan RC et al. N Eng J Med. 2001;345:1655. 2. Mickisch GH et al. Lancet. 2001;358:966 RCC Consortium Database Consecutive 645 patients with median follow up 25 months. Metastatic RCC, any histology. Treated with anti-VEGF agents: ○ Sunitinib ○ Sorafenib ○ Bevacizumab No prior VEGF-targeted agents. Data collected using uniform data collection software and standardized definitions. Excluded N=331 (s/p nephrectomy, but not cytoreductive). Overall Survival on Univariable Analysis mOS: 19.8 vs. 9.4 months Hazard Ratio:0.44 (95% CI: 0.32-0.59) p<0.001 Cytoreductive Nephrectomy Cytoreductive nephrectomy in era of targeted therapy may produce superior OS when adjusted for known prognostic factors Adjusted Hazard Ratio 0.68 (95% CI: 0.46, 0.99) Choueiri et al J Urol 2011 The impact of cytoreductive nephrectomy by risk groups1 Favorable risk group (N=23): 22/23 underwent CN Intermediate risk group (N=143): HR: 0.46 (95% CI: 0.27-0.78, p=0.004) Poor risk group (N=117): HR: 0.67 (95% CI: 0.44-1.01, p=0.056) 1. Heng et al. JCO 2009; 27: 5794-9 Cytoreductive Nephrectomy by KPS -KPS>80: 23.9 vs. 14.5 months, p=0.003 -KPS<80: 10.1 vs. 6 months, p=0.077 Cytoreductive Nephrectomy Cytoreductive Nephrectomy (CN) is independently associated with an improved overall survival in metastatic RCC patients treated with VEGF-targeted agents Cytoreductive nephrectomy in era of targeted therapy may produce superior OS when adjusted for known prognostic factors The benefit seems to be marginal in patients in the poor-risk group/poor KPS Prospective clinical trials in progress Choueiri et al J Urol 2011 Conclusions mRCC Treatment Revolution VEGF inhibitors mTOR inhibitors Clinical trials are important to find new drugs Cytoreductive nephrectomy may be helpful in certain patients Our patients are living much longer than they used to … progress!!
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