A) PUBLIC HEALTH EPIDEMIOLOGY

Transcription

1 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: Established: Smoking, phenacetin containing analgesics, hypertension, obesity Possible: Diabetes Mellitus, trichloroethylene, renal cystic disease, renal transplant, end-stage renal disease patients on dialysis, physical activity Genetic: Clear cell (ccrcc) o Loss of mutation of Von Hippo Lindau gene (VHL) 58% of ccrcc VHL gene on chromosome 3p regulates hypoxia induced pathway (HIF) and targets it for degradation. In ccrcc, its dysfunctional and HIF accumulates leading to activate of survival genes that mediate glucose transport, proliferation and angiogenesis (VEGF). o mutations in PBRM1 (40%), BAP1 (15%), SETD2 (15%) which part of the chromatin remodeling-histone methylation pathway. Like VHL also located on the chromosome 3p. BAP1 associated with shorter survival. o Succinate Dehydrogenase Familial Renal Ca (clear cell and chromophobe) with mutated succinate dehydrogenase D o Tuberous Sclerosis Complex with mutated TSC1/2 Papillary cell o Type 1 - MET gain on pro-oncogene o Type 2 - Hereditary Leiomyomatosis RCC. Associated with CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2 antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) assoc. with poor survival and mutation of the gene encoding fumarate hydratase (FH) (NEJM 2016) Chromophobe RCC o 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) Renal medullary o associated with hemoglobinopathies, most commonly sickle cell trait, loss of expression of the chromatin regulatory gene SNF5/INI-1. Most RCC of both types express PD-L1 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, fever and 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 Imaging and 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 Management of Solitary Renal Mass (Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline Feb 2017) o Renal tumor biopsy should be obtained if it would change managment o Standard partial nephrectomy for all patients whom intervention is indicated. Radical if partial not possible o Percutaneous thermal ablation can be considered if can achieve complete ablation and biopsy should be obtained Patients with radiographic T3+ or node involvement should have lymph node staging done PATHOLOGY & MOLECULAR BIOLOGY Common Histology: Clear cell RCC aka ccrcc (75%) VHL Non Clear Cell RCC (nccrcc) o Papillary cell RCC Type I (5%) cmet, Type 2 (10%) FH, cmyc o Chromophobe RCC (5%) and Oncocytoma (5%) - both BHD 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 o All patients with non-clear cell, except chromophobe do poorly once they develop mets 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 Kidney cancer TNM staging AJCC UICC 2017 Primary tumor (T) T category T1 T1a T1b T2 T2a T2b T3 T3a T3b T3c T4 T criteria Tumor 7 cm in greatest dimension, limited to the kidney Tumor 4 cm in greatest dimension, limited to the kidney Tumor >4 cm but 7 cm in greatest dimension, limited to the kidney Tumor >7 cm in greatest dimension, limited to the kidney Tumor >7 cm but 10 cm in greatest dimension, limited to the kidney Tumor >10 cm, limited to the kidney Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota's fascia Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota's fascia Tumor extends into the vena cava below the diaphragm Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava Tumor invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland) Regional lymph nodes (N) N1 Metastasis in regional lymph node(s) Distant metastasis (M) M1 Distant metastasis

3 STAGE 5 yr overall survival Stage I T1N % Stage II T2N0 80% Stage III T3N0 or N+ 60% Stage IV T4 or M % (improved with recent targeted therapies) Prognostic Factors in Stage IV: MSKCC RF older, published in Most trials stratified based on these factors. Uses LDH, HgB, serum Ca, time <1 year of disease free, KPS <=80%. Validated from a time of treated with only interferon and immunotherapy as treatments. A more recent paper (with Canadian investigators) looked at prognostic factors in the modern era of patients treated with VEGF inhibitors (JCO 2009). It validated some factors of MSKCC (HgB, Ca2+, time to targeted treatment, KPS <80), but added thrombocytosis, neutrophila and lost LDH. The result was: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Prognostic Factors 1. Anaemia 2. Thrombocytosis 3. Neutrophilia 4. Hypercalcemia 5. Karnofsky performance status <80, 6. < 1 year from diagnosis to first-line targeted therapy favorable risk (no risk factors, median OS 43 months) intermediate risk (one to two risk factors, median OS of 22 months) poor risk (three or more risk factors, median 8 months) Has been externally validated in patient treated with VEGF inhibitors - median OSs at 44 months, 21 months, and 8 months for the favorable, intermediate, and poor risk C) TREATMENT LOCALIZED / LOCALLY ADVANCED/ ADJUVANT - Bottom Line General Approach: Surgery - surgical resection) via total or partial nephrectomy for Stage I-III o 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. o No role for adjuvant therapy post resection. Multiple negative trials, see below. - Surveillance: labs and imaging q 6months initially then less frequently for up to 6 years. Canadian and US guidelines available (see references

4 Adjuvant therapy trials: Adjuvant Immunotherapy Although immunotherapy has had a response in advanced RCC, IFN-alpha and IL-2 have not had a survival benefit in adjuvant setting. Awaiting data on checkpoint inhibitors Adjuvant Phase III study of interferon alfa-nl as adjuvant treatment for resectable renal cell carcinoma: 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 Action of antiproliferative activities Experimental Drug Primary Endpoint OS Secondary endpoint: recurrence free survival Inclusion/Exclusion pt3-pt4a and/or node positive disease post nephrectomy 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 Anti-angiogenic or targeted therapy Three trials thus far. Two negative, one marginally positive. o ASSURE - 1 year of Sunitinib or Sorafenib vs placebo (no difference in DFS or OS) o S-TRAC 1 year of sunitinib or placebo (improvement in DFS) o PROTECT 1 year of pazopanib (pending, likely negative) ASSURE Trial Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial Lancet 2016 Regimen Sunitinib vs. Sorafenib vs Placebo Mechanism of Action Inhibition of vascular endothelial growth factor receptor, platelet of Experimental derived growth factor, c-kit and other kinases Drug Shown to be effective in metastatic disease Primary Endpoint DFS Inclusion/Exclusion Clear or non-clear RCC, Int Risk (pt1b-t3an0) High risk (pt3a-pt4n or ptany N+) Size (N) 1322 patients Results Median DFS: 5.8, 6.1, 6.6 (placebo) year. No difference in DFS 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

5 S-TRAC Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy Ravaud et al NEJM Dec 2016 Regimen Sunitinib 50mg/d 4 on/2off vs. placebo Mechanism of Action Inhibition of vascular endothelial growth factor receptor, platelet of Experimental derived growth factor, c-kit and other kinases Drug Shown to be effective in metastatic disease Primary Endpoint DFS (independent and investigator review) Inclusion/Exclusion predominant clear cell RCC, high risk by UCLA Integrated Staging System (based on T stage, Fuhrman nuclear grade and ECOG) Size (N) 615 patients Results Median DFS: 6.8 years vs 5.6 years (HR 0.76, p=0.03) (only for independent review; investigator review was not significant) * OS pending Toxicity Higher rates of grade 3/4 hypertension, hand/foot, rash, fatigue with sunitinib and sorafenib Conclusion Patients with high risk for recurrence, DFS was improved with Sunitinib for independent review, not investigator). Why? It s likely the DFS is on the cusp of significance and few changes pushes it the other way. Other Comments Bottom Line 1 year of sunitinib is high risk = 1 year of DFS for high risk patients. Why difference between ASSURE and S-TRAC regarding sunitinib in adjuvant setting? Patient characteristics o Stage - ASSURE allowed pt1b, S-TRAC only allowed pt1b if node +. 33% of ASSURE patients had Stage I or II disease, 0% in S-TRAC. S-TRAC stratified to look at high risk patients (pt3/4 or node+) o Pathology - S-TRAC required clear pathology, ASSURE did not (20% were not clear cell). o Dose all S-TRAC started at 50mg dose, 70% at 50mg dose in ASSURE. Also S-TRAC had 88% relative dose intensity throughout trial, only 40% in ASSURE PROTECT Trial Ongoing trial of pazopanib vs placebo post nephrectomy (ASCO 2017) But media has stated this likely be negative. Neoadjuvant Therapy Is it safe? Yes, TKI? Bev Does it downsize RCC reliably? Not to the extent of changing operability No role in general care of good PS patients. Can be used on poor performance pts or pts with extensive mets to do upfront systemic treatment. Then avoid Sx if not responding.

6 METASTATIC DISEASE Bottom Line General Approach: o Cytoreductive nephrectomy +/- metastasectomy (if solitary): o Retrospective analysis of large database of patients who received VEGF or mtor inhibitor drugs suggest a longer surgical with cytoreductive nephrectomy vs no sugery (17.1 vs 7.7 mo) (JCO Sept 2016) o Current Phase III studies in the era of targeted therapy are ongoing (SURTIME and CARMENA pending). Need to carefully select patients. Typically if good PS, good-int risk and ccrcc typically undergo upfront nephrectomy o Role of metastasectomy Retrospective data has found survival benefit. Ideal candidates are single site of disease >1 year after initial nephrectomy o If resect all disease (primary and met), can observe until relapse. If Stage IV or relapsed: o First line: Sunitinib or Pazopanib for good/ intermediate risk patients. (preferred tx) Bevacizumab +IFN (Bev not approved in Canada) Temsirolimus (for poor prognosis patients) Axitinib o Second line: Nivolumab (PD1 antibody) (>Everolimus) (preferred tx) Cabozantinib (> Everolimus). (preferred tx) Axitinib Everolimus o Third line and beyond: Everolimus if not previously used - Prognosis: median OS months based on risk factors (see Heng criteria above Historical Treatment High dose IL-2 reported to have achieved a complete response in 5% of met RCC patients. However, associated with severe cardiotoxicity and only used in specialized hospital with an ICU to manage the serious side effects Patient Status Therapy (Level 1 evidence) Other Options (>= Level 2) 1st line Good or intermediate risk Sunitinib Bevacizumab/IFN Pazopanib High dose IL-2 Sorafenib Observation or CT Poor risk Temsirolimus Sunitinib or CT 2nd line Post-TKI Nivolumab Cabozantinib Axitinib Sunitinib Bevacizumab Axitinib CT 3rd line Post-2 TKIs Post TKI and mtor Nivolumab Cabozantinib Everolimus Sorafenib Post TKI and Nivolumab Axitinib? Everolimus? If patient is poor prognosis, consider temsirolimus over sunitinib Poor prognosis defined if at least 3 out of 6 risk factors are present (minimum of 3 poor-risk features required):

7 From NEJM Review Jan 2017 Systemic Therapy for Metastatic Renal-Cell Carcinoma Increased expression of MET and AXL has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of renal-cell carcinoma. Hence the development of cabazantinib. First Line Trials RR PFS (mo) mos (mo) Sunitinib IFN (Motzer NEJM 31% 6% 11 5 HR=0.42 p< HR =082, p=0.05 Sunitinib Pazopanib (Motzer NEJM Bev+IFN IFN AVOREN Trial Bev+IFN IFN CALGB90206 Temsirolimus Temsirolimus+IFN IFN 25% 31% 26% 13% 31% 13% NS HR=0.71, p< HR=0.62, p< NS NS NS

8 Important Phase III Clinical Trials: 1 st line trials: (1) Sunitinib (Sutent) Dose 50mg daily for 4 weeks with 2 weeks rest, or 37.5mg daily continuously. Reduce to 37.5 or 25 mg A/E- low antiemetic protocol Hepatically cleared, cytochrome p450 3A4 S/E myelosuppression, cardiac toxicity, hepatic and renal dysfunction, sunitib-induce hypothyroidism, HTN, hand and foot syndrome, Monitor With b/w, also TSH every cycle. ECHO at start. 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 Multikinase inhibitor targeting several tyrosine kinases (PDGFR, Action VEGFR, c-kit, FLT-3, RET) Primary Endpoint PFS Inclusion/Exclusion Treatment naïve metastatic renal cell carcinoma (90% had nephrectomy) No brain metastases No evidence of uncontrolled hypertension ECOG 0/1 Size (N) 750 patients Results PFS: 11 months (Sunitinib) vs. 5 months (IFN) HR 0.42, p<0.001 Response Rate: 31% vs 6%, p<0.001 OS: updated trend towards months vs months, P =.051 However, there was cross over. When subgroup reviewed who did not cross over difference on mos was 28 mo vs 14 mo. Quality of Life: Much better with sunitinib vs. interferon alpha based on Toxicity Higher FACT-G grade and 3/4 FKSI fatigue questionnaires. 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 cell carcinoma Notes on Sutent: Probability of tumor response increases with daily sunitinib exposure (also associated with longer median TTP and OS) = one size dose not fit all. 4w on 2 off may not be suitable for all. It s too toxic for many patients, steady state and max AUC is by day Therefore, can consider shorter duration (max activity by day 7-14) and shorter break (rebound after 2 weeks off) Bjarnason et al Urol Oncology 2014 Individualized treatment Treat to G2 Toxicity o Single center retrospective review across 5 years o Start 50mg/2 4wON/2wOFF, o DL-1: Patients than cannot take 50 mg for 28 days: 50 mg/d individualized # of days / 7 days off o DL-2: Patients than cannot take 50 mg for at least 7 days: 37.5 mg/d individualized # of days / 7 days off o DL-3: Patients than cannot take 37,5 mg for at least 7 days: 25 mg/d individualized # of days / 7 days off o The dose schedule modified groups had mpfs mo and OS mo that was significantly better than the PFS 5.3 mo; P<0.001 and OS 14.4 mo; P = 0.03)

9 (2) Pazopanib (Votrient) Dose 800mg daily (empty stomach) continuous q4w. Reduce to 400/200mg. A/E- low antiemetic protocol Hepatically cleared, cytochrome p450 3A4 S/E myelosuppression, cardiac toxicity, hepatic and renal dysfunction, pazopanib-induce hypothyroidism, HTN, hair color changes, fatigue Monitor With b/w, also TSH every cycle. ECHO at start. Comparison of TKI Sutent inhibits broader TKI and strong against c-kit and Flt-3. Soreafenib had modest activity against both. Pazopanib less activity against Flt-3, thus less myelosuppression. (Recall FLT3 gene is frequently mutated in AML). Pazo has lower IC50 for VEGFR when compared to sorafenib and sunitinib. COMPARZ Trial (non-inferiority trial) 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 Action of growth factor receptors (VEGFR)-1/-2/-3, plateletderived growth factor Experimental Drug 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) Inclusion/Exclusion 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 mos: 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 First line pazopanib and sunitinib are non-inferior similar PFS, OS, but better ORR Less fatigue, H&F syndrome and thrombocytopenia with Pazo, but more transaminitis. 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.

10 Results of the COMPARZ trial, are supported by a smaller Phase II trial (PISCES JCO May 2014) PISCES trial randomized patients to Pazopanib 800mg daily for 10 weeks on, then two week break (placebo) then Sunitinib 50mg for 10 weeks (4 ON/2 OFF) or vise versa. Primary endpoint was patient preference at 22 weeks. Results 70% patients preferred pazopanib due to improvements in QOL, 22% preferred sunitib, 8% had no preference. Also reported less fatigue and dysguesia with pazopanib. (3) Bevacizumab + IFN a. AVOREN Trial improves mpfs 5.4 to 10.2 mo b. CALGB improves mpfs 5.2 to 8.5 months Note: OS was numerically superior but was not significant for both trials. Bev+IFN was approved for advanced RCC in 2009 AVOREN Trial 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: 2137 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 Action Shown in phase 2 studies to be beneficial in metastatic RCC Primary Endpoint OS Secondary endpoints: PFS, ORR and safety Inclusion/Exclusion 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

11 The US did a similar trial, the CALGB 90206: 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 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 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 PFS: 8.5 vs 5.2 mo mos was better in patients who received subsequent TKI 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 (4) Temsirolimus Dose: 25mg IV over 30 min qweekly. Dose reduce to 20, 15mg. Premeds diphenhydramine 25-50mg IV prior A/E- low antiemetic protocol Hepatically cleared, cytochrome p450 3A4 S/E myelosuppression, cardiac toxicity, hepatic and renal dysfunction, lung dysfunction (pneumonitis). CXR prior to start. Why use with poor performance patients? Because well tolerated and side-effects are mainly metabolic with minimal impact on QOL (compared with oral TKIs). Main effects are hyperglycemia (26%), hypercholesterolemia (24%) and hyperlipidemia (27%) NEJM Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma 626 pts randomized in first line with untreated poor prognosis met RCC to 25mg IV temsirolimus q3w, 3M units of IFN-alpha SQ q3w or combination of 15mg of temsirolimus and 6M U q3w. Results o Temsirolimus alone had improved OS and PFS. Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months

12 Resistance to VEGF and and mtor treatments will occur in nearly all patients. On strateguy has been to combine treatments. This has shown no change in PFS or OS but simply more toxicity. INTORACT Trial Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: 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 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. mtor regulates micronutrients, cell growth, apoptosis, and angiogenesis by its downstream effects on a variety of proteins 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 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. (4) Axitinib (Inlyta) Dose 5mg PO daily and may escalate to 10mg PO BID or reduce to 2/4mg daily. Cycle 4 weeks. A/E low emetogenic protocol S/E - diarrhea, hepatic dysfunction, drug interactions (cyto 3a4), HTN, dyspepsia, dyspnea Mechanism inhibits VEGFR 1-3, c-kit, PDGFR, thus angiogenis. But also might induce autophagy (like sorafenib) and also binds to BCR-ABL fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform in CML.

13 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 Action 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 Inclusion/Exclusion 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 mpfs 10.1 months vs 6.5 months, HR=0.77, 95% CI p=0.038 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. Cabozantinib CABOSUN Trial (Chouleri JCO 2017) o Phase pts with mrcc clear cell component, first line treatment randomized to cabozantinib 60mg daily vs sunitinib 50mg daily 4/2. Patient were intermediate or poor risk by IMRCC criterion. Primary endpoint was PFS. OS secondary. o Results PFS 8.2 vs 5.6 months (HR 0.69 p=0.012) ORR 46% vs 18% OS 30.3 vs 21.8 months (HR= 0.8 (not significant) o Conclusions Cabo is active, but we need Phase 3 trial No dose/schedule individualization for sunitinib Unlikely to be approved.

14 2nd line trials: Typical sequencing can be VEGF-VEGF-mTOR or the sandwich VEGF-mTOR-VEGF. At this time would do pazopanib, then axitnib then everolimus. Patient Status Therapy (Level 1 evidence) Other Options (>= Level 2) 1st line Good or intermediate risk Sunitinib Bevacizumab/IFN Pazopanib High dose IL-2 Sorafenib Observation or CT Poor risk Temsirolimus Sunitinib or CT 2nd line Post-TKI Nivolumab Cabozantinib Axitinib Sunitinib Bevacizumab Axitinib CT 3rd line Post-2 TKIs Post TKI and mtor Nivolumab cabozantinib Everolimus Sorafenib Post TKI and Nivolumab Axitinib? Everolimus? MET and AXL seem to be associated with tumor progression, also causes resistance to VEGFR inhibitors like sunitinib. Therefore, cabazantinib may be more effective. What makes you decide? o Toxicity Against EVE poor pulmonary function or diabetes Against Axitinib refractory HTN o Efficacy Against EVE Axitinib more likely to elicit a response in symptomatic pts. Also two trials (INTROSEC and METEOR) have shown TKI to TKI better than TKI to mtor. o Local factors funding (1) Nivolumab Indicated after failure of first line TKI or second line after failure of 2 TKI Dose: 3mg/kg (max 240mg total) over 1 hr in 100cc NS q2w. Continue until progression, but note should continue if suspect pseudoprogression. If so continue for another 6 weeks and if scans show an additional 10% increase in volume or new lesions, then progression CheckMate 025 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 Action of the interaction between PD-1 (expressed on activated t-cells) and PD-L1 Experimental Drug 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

15 Inclusion/Exclusion 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= 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 Treat beyond progression? - nivolumab treatment beyond first progression was associated with reduced tumor burden in approximately 50% of patients with advanced RCC and 14% achieved greater than or equal to 30% reduction in tumor burden (2) Cabozantinib (Cabometyx) METEOR trial showed improved OS and PFS vs everolimus in second line. Similar OS benefit as Nivolumab approximately 5 months. Not yet available in Canada METEOR Trial 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 Action of 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 Inclusion/Exclusion Secondary endpoints: OS, ORR 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

16 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: (final analysis) mos 21.4 vs 16.5 mo (HR 0.66, P= ) 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 (3) Sorafenib A oral bioavailable small molecule inhibitor of VEGFR, PDGFR and Raf TARGET trial shows improvement in PFS 5.5 vs 2.8 months who failed prior thearpy TARGET Sorafenib for Treatment of Renal Cell Carcinoma: 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, Action of 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 Inclusion/Exclusion Unresectable or metastatic RCC who had undergone 1 prior systemic treatment with IL-2 and/or interferon Size (N) 903 Results PFS 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 censored) 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.

17 INTORSECT Trial 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 Action of pathway of which is altered in RCC with clear cell histology, of advanced Experimental Drug 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 Inclusion/Exclusion 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 P (oddly sorafenib arm had better OS) 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 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?

18 (4) Axitinib Dose 5mg PO BID and may escalate to 10mg PO BID. Low emetogenic. S/E diarrhea, hepatic dysfunction, HTN AXIS Trial 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 Axitinib is a potent, selective, second-generation inhibitor of VEGFR 1, 2, and Action of 3 that blocks VEGFRs at sub-nanomolar drug concentrations. Relative potency of Experimental Drug 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 Inclusion/Exclusion 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 mos 20.1 vs 19.2 mo HR 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 could increase their dosages while patients on sorafenib were not this may have led to increase efficacy of axitinib Patients who developed dhtn (>90 mmhg) on trial had improvement in both arms than those who remained normotensive.

19 2 nd line and beyond: EVEROLIMUS RECORD1 Trial 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), Action of a component of an intracellular signalling pathway that regulates cellular Experimental Drug 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 Inclusion/Exclusion 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)

20 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 Action of growth factor receptors (VEGFR)-1/-2/-3, plateletderived growth factor Experimental Drug receptors (PDGFR)-a/-b and stem cell factor receptor c-kit Primary Endpoint PFS Inclusion/Exclusion 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 Pathology Types: (1) Non-Clear Cell RCC Limited data, but can use Sunitinib. In ASPEN trial showed improved PFS and OS vs everolimus Sarcomatoid (5% of RCC) features indicates poor prognosis. mpfs 5.3 mo and mos 11.7 mos with VEGF inhibitors

21 Blockage of VEGFR or delpletion will cause HTN, fatigue, proteinuria and increased risk of bleeding and thrombotic events. All of the anti-vegf will cause these side effects to varying degrees Soreafenib, sutininib and pazopanib also inhibit PDGF, Flt3 and other TKI thus cause H&F syndrome, diarrhea, and dysgusia. Sutent is particular prone at inducing hypothyroidism and CHF (~2-3%) mtor inhibitors uniquely cuase hypertriglyceridemia, hyperglycemia and non-infectious pneumonitis.

22