Renal Cell Carcinoma Updated February 2016 by Dr. Safiya Karim (PGY 5 Medical Oncology Resident, University of Toronto)

Transcription

1 Renal Cell Carcinoma Updated February 2016 by Dr. Safiya Karim (PGY 5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Nimira Alimohamed (Staff Medical Oncologist, University of Calgary) and Dr.Bjarnason (Staff Medical Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY 5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY Incidence: 9 th most common cancer worldwide, 11 th most common in Canada, incidence 12.9/ 100,000 in Canada in 2015, highest incidence in developing countries, most common in 6 th 8 th decade of life, M > F Mortality : 5 year overall survival 71% (all stages) RISK FACTORS Environmental/Chemical/Infections: o Established: Smoking, phenacetin containing analgesics, hypertension, obesity o Possible: Diabetes Mellitus, trichloroethylene, renal cystic disease, renal transplant, end stage renal disease patients on dialysis, physical activity Genetic: o Clear cell Loss of mutation of Von Hippo Lindau gene (VHL ), mutations in PBRM1, BAP1, SETD2, as well as mutations in additional histone modifiers (KDM5a, ARID1a, and UTX) o Papillary cell mutations in MET pro oncogene, mutations in fumarase hydratase (FH)(causing syndrome of hereditary leiomyomatosis and renal cell carcinoma) o Chromophobe RCC loss of chromosomes 1,26,10,13, 17 and 21, mutations in PTEN, Birt Hogg Dube syndrome (caused by germline mutation in folliculin gene FLCN) o Renal medullary associated with hemoglobinopathies, most commonly sickle cell trait, loss of expression of the chromatin regulatory gene SNF5/INI 1. PREVENTION & SCREENING Prevention: Nil Screening: Only for high risk individuals i.e. VHL syndrome, tuberous sclerosis, strong family history, previous kidney irradiation, young patients with end stage renal disease on dialysis x >3 5 years. Screen with yearly U/S Abdo/ CT Abdo/ MRI B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS Common Symptoms: Flank pain, abdominal pain, hematuria, asymptomatic Common Signs: abdominal/ flank mass, paraneoplastic syndromes anemia, hypertension, hepatic dysfunction, feverand night sweats, hypercalcemia, cachexia, thrombocytosis Not so common: AA amyloidosis, polycythemia, polymyalgia rheumatica

2 INVESTIGATIONS Laboratory: (e.g. important bloodwork, tumour markers): CBC, lytes, urea, creatinine, calcium Diagnostic Imagingand staging: renal ultrasound, CT Abdo, MRI (if CT non diagnostic), CT Chest, CT Head, Bone scan (if bone pain or elevated ALP) Diagnostic Procedures: percutaneous biopsy, partial/ full nephrectomy PATHOLOGY & MOLECULAR BIOLOGY Common Histology: o Clear cell RCC o Papillary cell RCC o Chromophobe RCC o Rare: collecting duct, renal medullary, urothelial o Other types see 2013 Classification (Srigley, JR et al. Am J Surg Pathol 2013) Common Metastatic Sites: lung, bone, brain, liver, adrenals Relevant Molecular Biology: Lots of stuff here. Unclear what you are expected to know. Not generally agreed on biomarkers to guide the choice of therapy STAGING TNM: American Joint Committee on Cancer. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer;

3 5 yr overall survival by stage: I 80 95% II 80% III 60% IV 10 30% (improved with recent targeted therapies) Heng Prognostic factors (in metastatic disease): Poor prognostic factors: Karnovsky performance status (PS) <80% Hemoglobin less than lower limit of normal Time from diagnosis to treatment <1 year Corrected calcium above the upper limit of normal Platelets greater than the upper limit of normal Neutrophils greater than the upper limit of normal Favourable risk (0 factors) mos not reached, 2 yr OS =75% Intermediate risk (1 2 factors) mos 27 months, 2 yr OS = 53% Poor risk (3 6 factors) mos 8.8 months, 2 yr OS = 7% C) TREATMENT LOCALIZED / LOCALLY ADVANCED/ ADJUVANT Bottom Line General Approach : surgical resection via total or partial nephrectomy, if not a candidate for surgery and small renal mass (often just observed. This is a separate topic), radiofrequency ablation/ cryotherapy can be considered. Observation can also be considered. No role for adjuvant therapy post resection. Multiple negative IL2, interferon trials and now a negative Sutent vs Sorafenib vs observation trial. Surveillance : labs and imaging q 6months initially then less frequently for up to 6 years. Canadian and US guidelines available (see references) Prognosis: o Stage 1 5 yr OS 90% o Stage 2 5 yr OS 75 90% o Stage %

4 Important Phase III Clinical Trials: Adjuvant therapy trials: Adjuvant Phase III study of interferon alfa NL as adjuvant treatment for resectable renal cell carcino ma: an Eastern Cooperative Oncology Group/Intergroup trial. Messing et al. J Clin Oncol. 2003; 21(7): Regimen Interferon alfa NL x 12 cycles vs. observation Mechanism of Pleotrophic protein that has antiviral, immunomodulatory and antiproliferative activities Experimental Drug Primary Endpoint OS Secondary endpoint: recurrence free survival pt3 pt4a and/or node positive disease post nephectomy and lymphandectomy Size (N) 283 Results Median OS: 7.4 years vs years p=0.09 Median DFS: 2.2 years vs 3 years p=0.33 Toxicity Severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment Conclusion No benefit to adjuvant interferon on overall survival or on recurrence free survival Adjuvant ASSURE Trial Lancet oncology 2006 DOI: (16) Haas et al. Lancet Oncology March 9. Epub ahead of print. Regimen Sunitinib vs. Sorafenib vs Placebo Mechanism of Inhibition of vascular endothelial growth factor receptor, platelet derived growth factor, c kit and other kinases Experimental Drug Shown to be effective in metastatic disease Primary Endpoint DFS Completely resected high risk local/ locally advanced disease (pt1b high grade to pt4 any grade N any) Size (N) 1322 patients Results Median DFS: 5.6 vs. 5.6 vs. 5.7 Quality of Life: not reported Toxicity Higher rates of grade 3/4 hypertension, hand/foot, rash, fatigue with sunitinib and sorafenib Conclusion No benefit to adjuvant sunitinib or sorafenib in locally advanced high risk renal cell carcinoma Other Comments

5 METASTATIC Bottom Line General Approach: o First line: Sunitinib or Pazopanib for good/ intermediate risk patients. Temsirolimus is on option in poor risk patients o Second line: New evidence shows benefit of both Nivolumab (PD1 antibody) vs Everolimus in the second line setting, and Cabozantinib vs Everolimus. Funding decisions are pending. Current standard is everolimus or axitinib. o Third line and beyond: Everolimus if not previously used o Cytoreductive nephrectomy: Previous SWOG and EORTC studies showed improvements in overall survival in selected patients with cytoreductive nephrectomy. Current Phase III studies in the era of targeted therapy are ongoing. Need to carefully select patients. Prognosis: median OS months based on risk factors (see Heng criteria above) Important Phase III Clinical Trials: 1 st line trials: 1 st line Sunitinib vs Interferon Alpha in Metastatic Renal Cell Carcinoma Motzer et al. N Eng J Med. 2007; 356; Regimen Sunitinib 50mg daily x 4 weeks (then 2 weeks off) vs. interferon alpha 9MU SC 3x/week Mechanism of Tyrosine kinase inhibitor including VEGF receptor and platelet derived growth factor receptor Experimental Drug Primary Endpoint PFS Treatment naïve metastatic renal cell carcinoma No brain metastases No evidence of uncontrolled hypertension ECOG 0/1 Size (N) 750 patients Results PFS: 11 months (Sunitinib) vs. 5 months (Int.alpha) HR 0.42, p<0.001 Response Rate: 31% vs 6%, p>0.001 Overall Survival: Data not yet mature Quality of Life: Much better with sunitinib vs. interferon alpha based on FACT G and FKSI questionnaires. Toxicity Higher grade 3/4 fatigue in interferon group Higher rates of grade 3 diarrhea, vomiting, hypertension, and hand foot syndrome on sunitinib Higher rates of leucopenia, neutropenia, thrombocytopenia in sunitinib group Conclusion Significant improvement in PFS and QoL with Sunitinib vs. Interferon Alpha for treatment naïve metastatic renal celll carcinoma

6 Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB Rini et al. J Clin Oncol 2010; 28: Regimen Bevacizumab 10mg/kg q 2weeks and Interferon 2a 9MU SC 3x/ week vs.placebo plus Interferon 2a 9MU SC 3x/week Mechanism of Humanized monocolonal antibody towards VEGF Shown in phase 2 studies to be beneficial in metastatic RCC Experimental Drug Primary Endpoint OS Secondary endpoints: PFS, ORR and safety Metastatic renal cell ca with predominant clear cell component (>=50%) Undergone partial or full nephrectomy No prior systemic treatment No brain metastasis, adequate hepatic and renal function KPS >=70% Size (N) 649 Results OS: 23.3 months vs months, HR=0.91, p= PFS: 10.2 months vs. 5.4 months, HR 0.63, p=0.001 OS adjusted for independent factors predictive of survival HR 0.78, p=0.02 ORR : 70% vs. 39% Toxicity Higher rates of grade 3 + fatigue, asthenia, proteinuria, hypertension with bevacizumab + interferon 4 cases of GI perforation (1%) and 4 cases of arterial thrombotic events (1%) with bevacizumab + interferon Conclusion Bevacizumab + interferon did not show a statistically significant benefit in OS compared to placebo + interferon PFS was improved with bevicizumab + interferon compared to placebo + interferon Other Comments Several confounding factors may have led to no statistically significant OS benefit extensive use of TKI treatment post progression, cross over of 13 patients from placebo to bevacizumab arm upon progression Bevacizumab is not approved for the treatment of RCC in Canada

7 Bevacizumab plus interferon Alfa 2a for treatment of metastatic renal cell carcinoma: a randomized, double blind phase III trial Escudier et al. Lancet 2007; 370: Regimen Bevacizumab 10mg/kg q 2weeks and Interferon 2a 9MU SC 3x/ week vs. placebo and interferon 2a 9MU SC 3x/week Mechanism of Experimental Drug Humanized monocolonal antibody towards VEGF Shown in phase 2 studies to be beneficial in metastatic RCC Primary Endpoint OS Secondary endpoints: PFS, ORR and safety Metastatic renal cell ca with a clear cell component No prior systemic treatment No brain metastasis, adequate hepatic and renal function KPS >=70% BP <160/90 Size (N) 732 Results OS: 18.3 months vs months, HR=0.86, p=0.069 Median OS was better in patients who received subsequent TKI treatment Toxicity Higher rates of grade 3 + hypertension, anorexia, fatigue and proteinuria in bevacizumab arm Conclusion Bevacizumab + interferon did not show a statistically significant benefit in OS compared to Interferon alone Other Comments In a retrospective analysis, PFS, ORR and OS was statistically improved in patients who developed grade >=2 hypertension

8 Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial Rini et al. J Clin Oncol. 2014; 32: Regimen Temsirolimus 25mg IV weekly plus bevacizumab 10mg/kg IV q2weeks vs. Interferon 9MU SC 3x/week + bevacizumab 10mg/kg IV q2weeks Mechanism of Experimental Drug Temsirolimus is a highly specific inhibitor of mtor, the signaling pathway of which is altered in RCC with clear cell histology, of advanced stage, or with poor prognostic features. Has shown activity in phase 2 studies in pre treated patients with advanced RCC Bevacizumab is an inhibitor of VEGR, which is highly expressed The combination of temsirolimus and bevacizumab has the potential to further improve efficacy and possibly overcome or delay resistance to bevacizumab by concomitantly blocking alternative signaling pathways Primary Endpoint PFS Secondary endpoints: OS, ORR and safety Advanced renal cell ca with a clear cell component No prior systemic treatment No brain metastasis Adequate hepatic and renal function KPS >=70% No history of thrombotic events in past 6 weeks No inadequately controlled BP >=150/100 Size (N) 732 Results Median PFS: 9.1 months vs. 9.3 months, HR 1.1, p=0.8 ORR: 27.0% vs 27.4% Median OS: 25.8 vs. 25.5, HR =1.0, p=0.6 QOL No statistically significant difference Toxicity More grade >=3 hypercholesteremia, mucosal inflammation, stomatitis, hyperglycemia with temsiromlimus/ bevicizumab More grade >= 3 neutropenia and myalgia with interferon/ bevicizumab arm Conclusion No differences were observed for PFS, OS, or ORR between the combination regimens of temsirolimus/bevacizumab and IFN/bevacizumab when administered as first line treatment in patients with advanced RCC.

9 Axitinib versus sorafenib as first line therapy in patients with metastatic renal cell carcinoma: a randomised open label phase 3 trial Hutson et al. Lancet. 2014; 14, Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily Mechanism of Experimental Drug Axitinib is a potent and selective second generation VEGFR inhibitor Primary Endpoint PFS (non inferiority) Secondary endpoints: OS, ORR, response duration, patient reported outcomes, safety Metastatic RCC with a clear cell component ECOG 0 or 1 No previous systemic treatment No brain mets or CNS involvement Adequate organ function No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months Size (N) 288 Results Median PFS 10.1 months vs 6.5 months, HR=0.77, 95% CI p=0.038 Median PFS for ECOG 0 (prespecified analysis) 13.7 vs 6.6 months, HR=0.64, p=0.022 Median PFS for patients with previous nephrectomy (post hoc analysis) 10.3 vs. 6.4 months, HR=0.67, p=0.009 ORR: 32% vs 15%, p= Median duration of response: 14.7 vs months Patient reported outcomes: No significant difference between treatment arms Toxicity More diarrhoea, hypertension, weight decrease, decreased appetite, dysphonia, hypothyroidism and upper abdominal pain with axitinib More palmar plantar erythrodysaesthesia, rash, alopecia and erythema with sorafenib Conclusion Although median progression free survival was numerically longer with axitinib than with sorafenib, the difference was not significant Median PFS was statistically significant in ECOG 0 patients Other Comments Trial had an ambitious prediction of improved PFS of 4.3 months over sorafenib which is why it did not meet it s primary endpoint and did not get FDA approval in the first line even tough Axitinib was clearly better.

10 Pazopanib versus Sunitinib in Metastatic Renal Cell Carcinoma Motzer et al. N Eng J Med. 2014; 369: * Final overall survival data published as correspondance in N Eng J Med. 2014; 370: Regimen Pazopanib 800 mg once daily vs Sunitinib 50 mg daily x 4 weeks (then 2 weeks off) Mechanism of Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR) 1/ 2/ 3, plateletderived Experimental Drug growth factor receptors (PDGFR) a/ b and stem cell factor receptor c Kit Comparison of efficacy across trials suggested similar progression free survival benefits with pazopanib and sunitinib. 7 Comparison of safety suggested that pazopanib was associated with a lower incidence of fatigue, the hand foot syndrome, stomatitis, and myelosuppression and with a higher incidence of liver function abnormalities than was sunitinib Primary Endpoint PFS (non inferiority) Secondary endpoints: OS, ORR, QoL medical resource utilization Advanced and/or metastatic RCC with a clear cell component No previous systemic treatment KPS >=70% No brain mets, no poorly controlled hypertension Adequate organ function Size (N) 1110 Results Median PFS 8.4 vs 9.5 months, HR=1.05 (Similar amongst all subgroups) ORR: 31% vs 25%, p=0.03 Median OS: 28.3 months vs months, HR=0.92, p=0.24 Median duration of treatment: 8.0 months vs. 7.6 months QoL Fatigue and treatment related side effects were better with pazopanib compared to sunitinib Toxicity More hand foot syndrome, mucosal inflammation, stomatitis, hypothyroidism, dysgeusia, dyspepsia, epistaxis, and fatigue with sunitinib More changes in hair color, weight loss, and alopecia with pazopanib Conclusion This phase 3, randomized study showed noninferiority of progression free survival with pazopanib versus sunitinib. The similar rates of overall survival in the two groups and the higher objective response rates observed with pazopanib versus sunitinib are consistent with noninferiority in overall efficacy Other Comments These data may not apply in countries that do not use the Sutent 4/2 schedule as is true for most centers in Canada. Because of this the uptake of Pazopanib in Canada has been much lower than in most other countries.

11 2 nd line trials: Cabozitinib vs Everolimus in Advanced Renal Cell Carcinoma Choueiri et al. N Engl J Med 2015; 373: Regimen Cabozitinib 60mg OD vs Everolimus 10mg OD Mechanism of Cabozitinib is an oral small molecule tyrosine kinase inhibitor that targets VEGFR as well as MET and AXL, each of which has been Experimental Drug implicated in the pathogenesis of metastatic RCC or in the resistance to antiangiogenic drugs. Primary Endpoint PFS Secondary endpoints: OS, ORR 18 years plus Advanced or metastatic RCC with a clear cell component and measurable disease Previous treatment with at least 1 VEGFR targeting TKI with radiologic progression during treatment or within 6 months after the most recent dose KPS at least 70% No previous therapy with an mtor inhibitor or with cabozitinib Size (N) 658 Results PFS: 7.4 months with cabozitinib vs 3.8 months with everolimus, HR 0.58, p<0.001 ORR : 21% with cabozitinib vs 5% with everolimus, p<0.001 OS: trend towards better OS with cabozitinib at interim analysis with HR of 0.67, p=0.005 (p< required for significance at the interim analysis). OS analysis updated Feb 2016 in a press release state that OS data now show a statistically significant survival benefit for cabozitinib PFS and ORR were higher in patients on cabozitinib who only had sunitinib as previous therapy (post hoc analysis) Toxicity Grade 3/4 toxicity occurred in 68% of patients on cabozitinib vs. 58% of patients on everolimus Cabozitinib grade 3/4 toxicities included hypertension, diarrhea and fatigue Everolimus grade 3/4 toxicities included anemia, fatigue and hyperglycemia Conclusion Cabozitinib was associated with a higher PFS in patients with advanced RCC who had progressed on previous VEGF targeted therapy

12 Nivolumab vs. Everolimus in Advanced Renal Cell Carcinoma Motzer et al. N Engl J Med 2015;373: Regimen Nivolumab 3mg/kg IV q2weeks vs Everolimus 10mg OD Mechanism of Nivolumab is a fully human IgG4 PD 1 inhibitor that selectively blocks the interaction between PD 1 (expressed on activated t cells) and Experimental Drug PD L1 and 2 which are expressed on tumor cells. It has been hypothesized that blocking this interaction leads to restored antitumor immunity Primary Endpoint OS Secondary endpoints: ORR and safety Advanced or metastatic RCC with a clear cell component and measurable disease Received 1 or 2 previous regimens of antiangiogenic therapy No more than 3 previous total regimens of systemic therapy KPS of at least 70% Exclusion no CNS metastases, no previous treatment with an mtor inhibitor, no condition requiring glucocorticoids >10mg or prednisone per day Size (N) 821 Results OS: 25.0 months for nivolumab vs 19.6 months for everolimus, HR 0.73, p=0.002 OS benefit was seen regardless of PD L1 expression ORR: 25% with nivolumab vs 5% with everolimus, Odds ratio 5.98, p<0.001 PFS: nivolumab 4.6 months vs. everolimus 4.4 months, HR 0.88, p=0.11 Quality of Life: Improved in the nivolumab arm and significantly different from the everolimus arm Toxicity Grade 3/4 adverse events: 19% with nivolumab and 37% with everolimus Most common grade 3/4 toxicity with nivolumab was fatigue and with everolimus was anemia Conclusion Nivolumab was associated with longer overall survival and fewer grade 3/4 adverse events compared to everolims in patients with previously treated advanced renal cell carcinoma

13 2 nd line Sorafenib for Treatment of Renal Cell Carcinoma (TARGET): Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial Escudier et al. N Engl J Med 2007;356: and J Clin Oncol. 2009; 27: Regimen Sorafenib 400mg bid vs placebo Mechanism of Orally active multikinase inhibitor that blocks VEGFR 2, VEGFR 3, and PDGF receptor (PDGFR ), as well as RAF 1, Flt 3, and c KIT Experimental Drug Primary Endpoint OS Secondary endpoints: PFS, RR and patient reported outcomes Unresectable or metastatic RCC who had undergone 1 prior systemic treatment with IL 2 and/or interferon Size (N) 903 Results PFS: preplanned analysis in 2005 showed superior PFS for Sorafenib 5.5 months vs. 2,8 months, HR 0.44, p>0.001 Overall Survival: 17.8 months vs months, HR 0.88, p=0.146 (cross over was however allowed) OS (with crossover patients sensored) 17.8 months vs months, HR 0.78, p=0.287 Correlation with VEGF levels both high and low levels of VEGF responded to Sorafenib Toxicity Higher rates of grade 3 /4 hypertension, hand foot syndrome, rash/desquamation, diarrhea and fatigue in sorafenib groups Conclusion Sorafenib is effective as 2 nd line treatment for advanced/ metastatic renal cell carcinoma after 1 st line immunotherapy (INT or IL 2). Since these immunotherapies are never given 1 st line Sorafenib is not used 2 nd line in Canada.

14 2 nd line Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma Hutson et al. J Clin Oncol. 2014; 32: Regimen Temsirolimus 25mg IV weekly vs. Sorafenib 400 mg bid Mechanism of Temsirolimus is a highly specific inhibitor of mtor, the signaling pathway of which is altered in RCC with clear cell histology, of Experimental Drug advanced stage, or with poor prognostic features. Has shown activity in phase 2 studies in pre treated patients with advanced RCC Primary Endpoint PFS Secondary endpoints: OS, ORR and safety Any histology mrcc Progressive disease after sunitinib ECOG 0 or 1 No brain metastases Adequate hepatic, renal and cardiac function Size (N) 512 Results Median PFS: 4.3 vs. 3.9 months HR=0.87, p=0.89 ORR: 8% in both arms Median OS: 12.3 vs months, HR =1.31, p=0.01 Toxicity More grade >=3 anemia and hyperglycemia with temsirolimus More grade >=3 palmar plantar erythrodysesthesia with sorafenib Conclusion No differences were observed for PFS or ORR between temsirolimus vs. sorafenib in the 2 nd line setting OS was significantly improved with sorafenib compared to temsirolimus in the 2 nd line setting Other Comments A TKI to TKI sequence may be better than a TKI to mtor sequence?

15 Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial Rini et al. Lancet. 2011; 378, Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily Mechanism of Action Axitinib is a potent, selective, second generation inhibitor of VEGFR 1, 2, and of Experimental Drug 3 that blocks VEGFRs at sub nanomolar drug concentrations. Relative potency of axitinib is times greater than that of the first generation VEGFR inhibitors. Additionally, first generation inhibitors block other targets, such as platelet derived growth factor receptors (PDGFR), b RAF, KIT, and FLT 3, which are not substantially inhibited by axitinib.these off target activities might contribute to the adverse effects of the first generation inhibitors, suggesting that more specific inhibitors of VEGFR such as axitinib might have an enhanced therapeutic window. Primary Endpoint PFS (non inferiority) Secondary endpoints: OS, ORR, duration of response, time to deterioration Advanced/ metastatic RCC with a clear cell component ECOG 0 or 1 Progressive disease after 1 line of previous systemic treatment No brain mets or CNS involvement Adequate organ function No present use or anticipated need for cytochrome P450 (CYP)3A4 inhibiting, CYP3A4 inducing, or CYP1A2 inducing drugs; No known HIV or acquired immunodeficiency syndrome related disease No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months No DVE/ PE within the past 6 months Size (N) 723 Results Median PFS 6.7 months vs 4.7 months, HR=0.665, p<0.001 Median PFS for patients who had previously received cytokines 12.1 vs 6.5 months, HR=0.464, p<0.001 Median PFS for patients previously treated with sunitinib 4.8 vs 3.4 months, HR=0.741, p=0.01 ORR: 19% vs 9%, p= Median duration of response: 11 vs months Time to deterioration: 17% risk reduction with axitinib Toxicity Most common grade 3+ adverse events with axitinib: hypertension, diarrhea and fatigue Most common grade 3+ adverse events with sorafenib: palmar plantar erythrodysaesthesia, hypophosphataemia, lipase elevation, and hypertension Conclusion Axitinib led to a statistically significant and clinically meaningful increase in the primary efficacy endpoint of PFS compared with sorafenib Time to deterioration was also improved with axitinib The tolerability of axitinib was similar to that of sorafenib and other VEGFR inhibitors, with some exceptions Other Comments This study was not a blinded trial, although all efficacy endpoints were adjudicated by masked independent radiology review Patients on axitinib were able to increase their dosages while patients on sorafenib were not this may have led to increase efficacy of axitinib

16 2 nd line and beyond: Efficacy of everolimus in advanced renal cell carcinoma: a double blind, randomized, placebo controlled phase III trial Motzer et al. Lancet. 2008; 372: Regimen Everolimus 10 mg once daily vs placebo Mechanism of Everolimus is an inhibitor of the mammalian target of rapamycin (mtor), a component of an intracellular signalling pathway that Experimental Drug regulates cellular metabolism, growth, proliferation, and angiogenesis. Everolimus, a derivative of rapamycin, binds to an intracellular protein, FKBP 12, forming a complex that inhibits the mtor serine threonine kinase Primary Endpoint PFS Secondary endpoints: OS, ORR, safety, QoL, disease related symptoms mrcc with a clear cell component Progressed on or within 6 months of being on sunitinib or sorafenib No previous exposure to mtor inhibitor KPS >=70% No untreated brain metastases Adequate hepatic, renal and bone marrow function Size (N) 410 Results Median PFS: 4.0 vs. 1.9 months HR=0.30, p <0.001 ORR: 1% vs 0% Median OS: Not reached vs. 8.8 months, HR 0.83, p=0.23 QoL No significant difference between treatment arms Toxicity More grade 3/4 stomatitis, infections, non infectious pnuemonitis, lymphopenia, hyperglycemia, hypophosphotemia, hypercholesterolemia in everolimus group Conclusion Everolimus was associated with a reduction in the risk of progression or death compared with placebo in patients with metastatic renal cell carcinoma whose disease had progressed after treatment with VEGF targeted therapies Increased risk of toxicity with everolimus vs. placebo Other Comments OS likely not significant due to cross over In this study leading to the approval for Everolimus 2 nd line, 269 pts received Everolimus. However, most were heavily pretreated and received Everolimus 2nd line (89 pts), 3 rd line (141 pts), 4 th line (104 pts) and 5 th line (82 pts)

17 A randomized, double blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update Sternberg et al. European Journal of Cancer. 2013; 49: Regimen Pazopanib 800 mg once daily vs placebo Mechanism of Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR) 1/ 2/ 3, plateletderived Experimental Drug growth factor receptors (PDGFR) a/ b and stem cell factor receptor c Kit Primary Endpoint PFS Secondary endpoints: OS, ORR, QoL duration of response Advanced and/or metastatic RCC Clear cell or predominately clear cell Treatment naïve or patients who had progressed on 1 line of previous cytokine therapy ECOG 0 or 1 No brain metastases or leptomeningeal disease Adequate hepatic, renal and bone marrow function Size (N) 435 (233 treatment naïve, 202 pretreated) Results Median PFS entire population: 9.2 vs 4.2 months HR=0.46, p <0.001 Median PFS treatment naïve: 11.1 vs. 2.8 months, HR=0.4, p<0.001 Median PFS cytokine pretreated: 7.4 vs. 4.2 months, HR=0.54, p<0.001 ORR: 30% vs 3% Median OS: 22.9 months vs months, HR=0.91, p=0.224 QoL No significant difference between treatment arms Toxicity Higher rates of grade 3/4 adverse events with pazopanib 33% vs 7% Most common grade 3/4 adverse events with pazopanib were hypertension and diarrhea 3% arterial thrombotic events on pazopanib 13% all grades of hemorrhagic events on pazopanib Conclusion Pazopanib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with placebo in treatment naive and cytokine pretreated patients with advanced RCC. Pazopanib did not show a statistically significant effect on OS in the final ITT analysis Other Comments OS likely not significant due to cross over and post progression therapy (66% of patients in the placebo arm) Other Important Published Data: 1. Dabestani, S., Marconi, L., Hoffman, F. et al. Local treatments for metastases of renal cell carcinoma: a systematic review. Lancet Oncology 2014; 15: e Partial or complete removal of the metastatic lesions was associated with improved overall survival, especially in patients with adequate performance and functional statuses All included studies were retrospective analyses and there was a high degree of bias in this review

18 D) REFERENCES 1. Capitano, U. and Montosi, F. Renal Cancer. Lancet Epub ahead of print. 2. Renal Cell Cancer Treatment (PDQ ): Health Professional Version. PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); Dec Heng et al. Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor Targeted Agents: Results From a Large, Multicenter Study. J Clin Oncol. 2009; 27: Kassouf, W et al. Follow up guidelines after radical or partial nephrectomy for localized and locally advanced renal cell carcinoma. Can Urol Assoc J Feb; 3(1): Li, H., Samawi, H. and Heng, D. The use of prognostic factors in metastatic renal cell carcinoma. Urologic oncology: seminars and original investigations. 2015; 33: Srigley, JR et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013; 37(10): Follow up for clinically localized renal neoplasms: AUA guideline. Available at cancer follow up.cfm New data in the 2 nd line setting that will impact the Canadian landscape: Two new 2 nd line studies, published in the NEJM in September 2015 will impact the Canadian landscape for 2 nd line therapy. Both drugs are expected to obtain Health Canada approval and be funded in the 2 nd and perhaps also in the 3 rd line setting. Will displace Everolimus alone to 3 rd and 4 th line. In the first study, 658 patients were randomized to receive cabozantinib vs. Everolimus. Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval CI 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005) but did not cross the significance boundary for the interim analysis. These OS data have now been updated in a press release Feb , confirming that the OS data now show a significantly improved survival for cabozantinib. In the second study, 821 pts were randomized to Nivolumab vs. Everolimus. The median overall survival was 25.0 months (95% CI, 21.8 to not estimable) with Nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with Nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002), which met the pre specified criterion for superiority (P ). The objective response rate was greater with Nivolumab than with everolimus ( 25% vs. 5%; odds ratio, 5.98 (95% CI, 3.68 to 9.72); P<0.001). The main interest of immunotherapy is the potential for durable responses and even a cure in a subset of patients. The aggregate data on immunotherapy to date suggest that only 10 15% of RCC patients could be potentially cured. Therefore, targeted therapies will continue to be the most important therapy for the majority of RCC patient. In another phase II study that may have impact in the 2 nd line setting, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single agent lenvatinib (n=52), or single agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged PFS compared with everolimus alone (median 14.6 months (95% CI ) vs 5.5 months ( ); hazard ratio 0.40, 95% CI ; p=0.0005), but not compared with lenvatinib alone. Single agent lenvatinib significantly

19 prolonged progression free survival compared with everolimus alone (HR 0.61, 95% CI ; p=0.048). Combination lenvatinib/everolimus demonstrated an improved response rate compared with everolimus ( 43.1 % vs. 6.0%; P <0.0001). The difference in median overall survival between patients assigned lenvatinib plus everolimus and those allocated single agent everolimus was significantly increased ( 25.5 months (95% CI 16.4 NE) vs 15.4 months ( ); HR 0.51, 95% CI ; p=0.024).