Renal Cell Carcinoma Updated February 2016 by Dr. Safiya Karim (PGY­5 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 PGY­5 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: 9th most common cancer worldwide, 11th most common in Canada, incidence 12.9/

100,000 in Canada in 2015, highest incidence in developing countries, most common in 6th­ 8th 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,

end­stage 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 pro­oncogene, 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, Birt­Hogg­Dube 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/INI­1.

­ PREVENTION & SCREENING ­ Prevention: Nil ­ Screening: Only for high­risk individuals – i.e. VHL syndrome, tuberous sclerosis, strong family

history, previous kidney irradiation, young patients with end­stage renal disease on dialysis x >3­5 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

INVESTIGATIONS ­ Laboratory: (e.g. important bloodwork, tumour markers): CBC, lytes, urea, creatinine, calcium ­ Diagnostic Imagingand staging: renal ultrasound, CT Abdo, MRI (if CT non­diagnostic), CT

Chest, CT­Head, 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; 2010479­89

5 yr overall survival by stage: I – 80­95% II – 80% III – 60% IV – 10­30% (improved with recent targeted therapies) Heng Criteria ­ 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 (1­2 factors) – mOS 27 months, 2 yr OS = 53% Poor risk (3­6 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 75­90% o Stage 3 – 59­70%

­ Important Phase III Clinical Trials:

Adjuvant therapy trials:

Adjuvant Phase III study of interferon alfa­NL 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): 1214­22

Regimen Interferon­alfa­NL x 12 cycles vs. observation Mechanism of Action of Experimental Drug

Pleotrophic protein that has antiviral, immunomodulatory and antiproliferative activities

Primary Endpoint OS Secondary endpoint: recurrence free survival

Inclusion/Exclusion Criteria

pT3­pT4a and/or node positive disease post nephectomy and lymphandectomy

Size (N) 283 Results Median OS: 7.4 years vs. 10.4 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: http://dx.doi.org/10.1016/S0140­6736(16)00559­6 Haas et al. Lancet Oncology. 2016 March 9. Epub ahead of print.

Regimen Sunitinib vs. Sorafenib vs Placebo Mechanism of Action of Experimental Drug

Inhibition of vascular endothelial growth factor receptor, platelet derived growth factor, c­kit and other kinases

Shown to be effective in metastatic disease Primary Endpoint DFS Inclusion/Exclusion Criteria

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

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 second­line 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 8­24+ months based on risk factors (see Heng criteria above) ­ Important Phase III Clinical Trials:

1st line trials:

1st line Sunitinib vs Interferon Alpha in Metastatic Renal Cell Carcinoma

Motzer et al. N Eng J Med. 2007; 356; 2. 115­24

Regimen Sunitinib 50mg daily x 4 weeks (then 2 weeks off) vs. interferon alpha 9MU SC 3x/week

Mechanism of Action of Experimental Drug

Tyrosine kinase inhibitor – including VEGF receptor and platelet derived growth factor receptor

Primary Endpoint PFS Inclusion/Exclusion Criteria

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 FACT­G and FKSI questionnaires.

Toxicity Higher grade 3/4 fatigue in interferon group Higher rates of grade 3 diarrhea, vomiting, hypertension, and

hand­foot syndrome on sunitinib Higher rates of leucopenia, neutropenia, thrombocytopenia in sunitinib

group Conclusion Significant improvement in PFS and QoL with Sunitinib vs.

Interferon­Alpha for treatment naïve metastatic renal celll carcinoma

Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in

Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206 Rini et al. J Clin Oncol 2010; 28: 2137­43

Regimen Bevacizumab 10mg/kg q 2weeks and Interferon­2a 9MU SC 3x/ week

vs.placebo plus Interferon­2a 9MU SC 3x/week Mechanism of Action 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

Inclusion/Exclusion Criteria

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. 21.3 months, HR=0.91, p=0.3360

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

Bevacizumab plus interferon Alfa­2a for treatment of metastatic renal cell carcinoma: a randomized, double­blind phase III trial Escudier et al. Lancet 2007; 370: 2103­11

Regimen Bevacizumab 10mg/kg q 2weeks and Interferon­2a 9MU SC 3x/ week vs. placebo and interferon­2a 9MU SC 3x/week

Mechanism of Action 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

Inclusion/Exclusion Criteria 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. 17.4 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

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: 752­59

Regimen Temsirolimus 25mg IV weekly plus bevacizumab 10mg/kg IV q2weeks vs. Interferon 9MU SC 3x/week + bevacizumab 10mg/kg IV q2weeks

Mechanism of Action 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 pre­treated 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

Inclusion/Exclusion Criteria

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 first­line treatment in patients with advanced RCC.

Axitinib versus sorafenib as first­line therapy in patients with metastatic renal­cell carcinoma: a randomised open­label phase 3 trial

Hutson et al. Lancet. 2014; 14, 1287­94

Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily

Mechanism of Action of Experimental Drug

Axitinib is a potent and selective second­generation VEGFR inhibitor

Primary Endpoint PFS (non­inferiority) Secondary endpoints: OS, ORR, response duration, patient reported

outcomes, safety

Inclusion/Exclusion Criteria

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 0.56­1.05 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 (post­hoc analysis) –10.3 vs. 6.4 months, HR=0.67, p=0.009

ORR: 32% vs 15%, p=0.0006 Median duration of response: 14.7 vs. 14.3 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 palmar­plantar erythrodysaesthesia, rash, alopecia and erythema with sorafenib

Conclusion Although median progression­free 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.

Pazopanib versus Sunitinib in Metastatic Renal­Cell Carcinoma

Motzer et al. N Eng J Med. 2014; 369: 722­731 * Final overall survival data published as correspondance in N Eng J Med. 2014; 370: 1769­1770

Regimen Pazopanib 800 mg once daily vs Sunitinib 50 mg daily x 4 weeks (then 2 weeks off)

Mechanism of Action of Experimental Drug

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)­1/­2/­3, plateletderived growth factor receptors (PDGFR)­a/­b and stem cell factor receptor c­Kit

Comparison of efficacy across trials suggested similar progression­free 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 liver­function abnormalities than was sunitinib

Primary Endpoint PFS (non­inferiority) Secondary endpoints: OS, ORR, QoL medical resource utilization

Inclusion/Exclusion Criteria

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. 29.1 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

progression­free 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.

2nd line trials:

Cabozitinib vs Everolimus in Advanced Renal Cell Carcinoma Choueiri et al. N Engl J Med 2015; 373:1814­23

Regimen Cabozitinib 60mg OD vs Everolimus 10mg OD Mechanism of Action of Experimental Drug

Cabozitinib is an oral small­molecule tyrosine kinase inhibitor that targets VEGFR as well as MET and AXL, each of which has been implicated in the pathogenesis of metastatic RCC or in the resistance to antiangiogenic drugs.

Primary Endpoint PFS Secondary endpoints: OS, ORR

Inclusion/Exclusion Criteria

18 years plus Advanced or metastatic RCC with a clear cell component and

measurable disease Previous treatment with at least 1 VEGFR­targeting 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<0.0019 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 (post­hoc 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

Nivolumab vs. Everolimus in Advanced Renal­Cell Carcinoma

Motzer et al. N Engl J Med 2015;373:1803­13

Regimen Nivolumab 3mg/kg IV q2weeks vs Everolimus 10mg OD Mechanism of Action of Experimental Drug

Nivolumab is a fully human IgG4 PD­1 inhibitor that selectively blocks the interaction between PD­1 (expressed on activated t­cells) and PD­L1 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

Inclusion/Exclusion Criteria

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 PD­L1 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

2nd 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;356:125­34. and J Clin Oncol. 2009; 27:3312­3318.

Regimen Sorafenib 400mg bid vs placebo Mechanism of Action of Experimental Drug

Orally active multikinase inhibitor that blocks VEGFR­2, VEGFR­3, and PDGF receptor (PDGFR­), as well as RAF­1, Flt­3, and c­KIT

Primary Endpoint OS Secondary endpoints: PFS, RR and patient reported outcomes

Inclusion/Exclusion Criteria

Unresectable or metastatic RCC who had undergone 1 prior systemic treatment with IL­2 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. 15.2 months, HR 0.88, p=0.146

(cross­over was however allowed) OS (with crossover patients sensored) – 17.8 months vs. 14.3

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, hand­foot syndrome,

rash/desquamation, diarrhea and fatigue in sorafenib groups Conclusion Sorafenib is effective as 2nd line treatment for advanced/ metastatic

renal cell carcinoma after 1st line immunotherapy (INT or IL­2). Since these immunotherapies are never given 1st line Sorafenib is not used 2nd line in Canada.

2nd line

Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second­Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Hutson et al. J Clin Oncol. 2014; 32: 760­767

Regimen Temsirolimus 25mg IV weekly vs. Sorafenib 400 mg bid Mechanism of Action 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 pre­treated patients with advanced RCC

Primary Endpoint PFS Secondary endpoints: OS, ORR and safety

Inclusion/Exclusion Criteria

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. 16.6 months, HR =1.31, p=0.01

Toxicity More grade >=3 anemia and hyperglycemia with temsirolimus More grade >=3 palmar­plantar erythrodysesthesia with sorafenib

Conclusion No differences were observed for PFS or ORR between temsirolimus vs. sorafenib in the 2nd line setting

OS was significantly improved with sorafenib compared to temsirolimus in the 2nd line setting

Other Comments A TKI to TKI sequence may be better than a TKI to mTOR sequence?

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a

randomised phase 3 trial Rini et al. Lancet. 2011; 378, 1931­39

Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily Mechanism of Action of Experimental Drug

Axitinib is a potent, selective, second­generation inhibitor of VEGFR 1, 2, and 3 that blocks VEGFRs at sub­nanomolar drug concentrations. Relative potency of axitinib is 50–450 times greater than that of the first­generation VEGFR inhibitors. Additionally, first­generation inhibitors block other targets, such as platelet­derived growth factor receptors (PDGFR), b­RAF, KIT, and FLT­3, which are not substantially inhibited by axitinib.These off­target activities might contribute to the adverse effects of the first­generation inhibitors, suggesting that more specific inhibitors of VEGFR such as axitinib might have an enhanced therapeutic window.

Primary Endpoint PFS (non­inferiority) Secondary endpoints: OS, ORR, duration of response, time to deterioration

Inclusion/Exclusion Criteria

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)3A4­inhibiting,

CYP3A4­inducing, or CYP1A2­inducing drugs; No known HIV or acquired immunodeficiency syndrome­related 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=0.0001 Median duration of response: 11 vs. 10.6 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: palmar­plantar 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

2nd line and beyond:

Efficacy of everolimus in advanced renal cell carcinoma: a double­blind, randomized, placebo­controlled phase III trial

Motzer et al. Lancet. 2008; 372: 449­56

Regimen Everolimus 10 mg once daily vs placebo Mechanism of Action of Experimental Drug

Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a component of an intracellular signalling pathway that regulates cellular metabolism, growth, proliferation, and angiogenesis. Everolimus, a derivative of rapamycin, binds to an intracellular protein, FKBP­12, forming a complex that inhibits the mTOR serine­threonine kinase

Primary Endpoint PFS Secondary endpoints: OS, ORR, safety, QoL, disease related symptoms

Inclusion/Exclusion Criteria

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, non­infectious 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 VEGF­targeted 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 2nd line, 269 pts received Everolimus. However, most were heavily pretreated and received Everolimus 2nd line (89 pts), 3rd line (141 pts), 4th line (104 pts) and 5th line (82 pts)

A randomized, double­blind 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: 1287­1296

Regimen Pazopanib 800 mg once daily vs placebo Mechanism of Action of Experimental Drug

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)­1/­2/­3, plateletderived growth factor receptors (PDGFR)­a/­b and stem cell factor receptor c­Kit

Primary Endpoint PFS Secondary endpoints: OS, ORR, QoL duration of response

Inclusion/Exclusion Criteria

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. 20.5 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 treatment­naive and cytokine­pretreated 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: e549­61. 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

D) REFERENCES 1. Capitano, U. and Montosi, F. Renal Cancer. Lancet. 2015. Epub ahead of print. 2. Renal Cell Cancer Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); 2002­2015 Dec 3. 3. 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: 5794­99. 4. Kassouf, W et al. Follow­up guidelines after radical or partial nephrectomy for localized and locally advanced renal cell carcinoma. Can Urol Assoc J. 2009 Feb; 3(1): 73–76. 5. 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: 509­516 6. Srigley, JR et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013; 37(10): 1469­89. 7. Follow­up for clinically localized renal neoplasms: AUA guideline. Available at https://www.auanet.org/education/guidelines/renal­cancer­follow­up.cfm New data in the 2nd line setting that will impact the Canadian landscape: Two new 2nd line studies, published in the NEJM in September 2015 will impact the Canadian landscape for 2nd line therapy. Both drugs are expected to obtain Health Canada approval and be funded in the 2nd and perhaps also in the 3rd line setting. Will displace Everolimus alone to 3rd and 4th 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 1 2016, 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 pre­specified criterion for superiority (P≤0.0148). 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 10­15% 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 phase­II study that may have impact in the 2nd line setting, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single­agent lenvatinib (n=52), or single­agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged PFS compared with everolimus alone (median 14.6 months (95% CI 5.9–20.1) vs 5.5 months (3.5–7.1); hazard ratio 0.40, 95% CI 0.24–0.68; p=0.0005), but not compared with lenvatinib alone. Single­agent lenvatinib significantly

prolonged progression­free survival compared with everolimus alone (HR 0.61, 95% CI 0.38–0.98; 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 single­agent everolimus was significantly increased (25.5 months (95% CI 16.4–NE) vs 15.4 months (11.8–19.6); HR 0.51, 95% CI 0.30–0.88; p=0.024).