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A 2020 Renal Cancer Update

Concise update of renal cancer including etiology pathophysiology and current treatment guidelines-also includes a description of the debate surrounding the debulking of renal cancers as well as results of adjuvant therapy trials in renal cancer

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A 2020 Renal Cancer Update

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  1. A 2020 Renal CancerUP DATE A Constantly EvolvingPallet of Therapeutic Opportunities Malcolm Brigden MDFRCP Associate Clinical Professor of Medical oncology University of Calgary

  2. A Holy Trinity of Canadian Renal Cancer Gurus

  3. Topics To Be Covered

  4. Topics To Be Covered

  5. Renal Cell Carcinoma (RCC) • Originates in the renal cortex • Most common solid lesion occurring in the kidney (80-85% of all primary renal neoplasms) Diseased Kidney

  6. Some RCC Statistics • An estimated 24,000 Canadians with a history of kidney and renal pelvis cancer were alive in 2004 • RCC incidence increasing • 5-year survival has improved • 50.9% 19751977 • 65.7% 19962003 • Most tumors are localized at initial diagnosis

  7. NA Yearly Kidney and Renal Pelvis Cancer Incidence and Mortality Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

  8. Extent of Disease at Diagnosis Most renal cancers are diagnosed when the disease is still localized to primary site National Cancer Institute. SEER cancer statistics fact sheet. Accessed 2008.

  9. Incidental vs Non-incidental Detection Today, >50% of RCCs are incidentally detected during noninvasive imaging used to evaluate nonspecific symptoms Incidentally detected tumors tend to be smaller and of lower stage than those detected in symptomatic patients Average size: 5 vs 8.5 cm Average pathologic stage T1/T2: 75% vs 43%

  10. Etiology of RCC Environmental and clinical risk factors Smoking Obesity Acquired cystic disease of the kidney (usually in association with dialysis) Analgesic abuse nephropathy Occupational exposure to toxic compounds Genetic predisposition Most important factors recognized

  11. Stages of RCC Stage I: Cancer is in the kidney only, size of tumor is ≤7.0 cm in diameter Stage II: Cancer is in the kidney only, but size of the tumor is >7.0 cm in diameter Stage IV: Tumor in the kidney extends beyond Gerota’s fascia and/or cancer has spread to one or more lymph nodes near kidney. Cancer may have spread to other organs such as lungs, liver, brain, or bones. Stage III: Tumor in the kidney may be any size, but extends beyond layer of tissue (Gerota’s fascia) that encapsulates kidney and adrenal gland. Cancer may have spread to blood vessels and one regional lymph node.

  12. Prognostic Factors and RCC-the Heng Criteria(Based on International mRCC Database Consortium) Clinical • Low Karnofsky performance (<80%) • Time from diagnosis to treatment <1 year Laboratory • Low haemoglobin (< LLN) • High “corrected” serum calcium (> ULN) • High neutrophils (> ULN) • High levels of platelets (> ULN)

  13. Scoring and Interpretation of The Heng(IMDC) Model for Risk Stratification in mRCC IMDC: International mRCC database consortium; LLN: lower limit of normal; mRCC: metastatic renal cell carcinoma; ULN: upper limit of normal Adapted from Heng DY, et al. J Clin Oncol 2009; 27:5794-9.

  14. Overall Survival by Risk Group: Heng (IMDC) Model Favorable:43 mos Median OS Intermediate:23 mos Poor:8 mos IMDC: International mRCC database consortium; OS: overall survival Heng DY, et al. Lancet Oncol 2013; 14:141-8.

  15. How Might We Use Prognostic Factors? Patient counselling • Clinical trial stratification and adjustment methods in retrospective studies Patient treatment • Can help choose first-line therapy (predictive markers) • Can help determine prognosis for deciding whether cytoreductive nephrectomy can be helpful

  16. Renal cancer is actually a variety of diseases Presented By W. Marston Linehan at 2015 Genitourinary Cancers Symposium

  17. Newer understanding of RCC pathophysiology-1 • renal cell cancer is actually a metabolic disease with abnormalities of a number of signalling pathways • The commonest genetic abnormality associated with renal cancer is mutation of the Von Hippel-Lindau(VHL) gene • VHL mutation→up-regulation of VEGF and platelet-derived growth factor • These mutations are powerful stimulants for angiogenesis and proliferation • In non-hereditary renal cancer→acquired VHL mutation results in dropping of the gene or its abnormal methylation • VHL mutation by itself does not produce renal cancer→ subsequent additional mutations are required

  18. VHL Von Hippel Lindau HIF1a Transcription of Genes Associated with Angiogenesis and Proliferation

  19. The Role of VEGF in RCC • VEGF binds to its receptors (VEGFRs) on endothelial cell surfaces • Promotes endothelial cell migration and proliferation for the development of new tumour-induced blood vessels • VEGF and VEGFR have proven to be attractive molecular targets for for RCC because they play key roles in tumour angiogenesis

  20. 1. Atkins MB, et al. Ann Oncol 2017;28:1484–94. The Immune System and RCC • Cancer cells express mutated proteins (neoantigens) recognised by the immune system with anti-tumour responses • T-cells play a key role but immune checkpoint pathways reduce inappropriate or sustained T-cell activation in healthy cells • Tumour cells can evade the immune system by exploiting immune checkpoint pathways IFNγ T-cellreceptor T-cellreceptor MHC MHC IFNγR PI3K Dendriticcell NFκB Other Tumour cell B7.1 CD28 PD-L1 T-cell PD-L1 PD-1 PD-1 Shp-2 Shp-2

  21. So what are targeted therapies in RCC ? • If we use the analogy of pesticides: empiric therapy would be “Raid” while targeted therapy is the “Roach Hotel.” Dr. David Gandara • A “smart” bomb versus a “cluster” bomb. Dr. Nevin Murray

  22. Treatments in Advanced RCC: Different Therapeutic Options

  23. Targeted Pathways in RCC treatment PD-1 and mTOR inhibitors VEGF and TKIs • From RJ. N Engl J Med 2017;376:354–66; . • mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor

  24. Targeted Therapies have Improved Overall Survival in Advanced RCC Compared to Chemotherapy/Cytokine Therapies 100 100 Proportion surviving Overall survival (probability) 80 80 20001 – Chemotherapy/Cytokine Era Median OS: 10 months 20092 – Targeted Therapies Era Median OS: 22 months 60 60 40 40 Favourable Intermediate Poor 0.75 20 20 0 0 0.53 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 0 12 24 36 48 60 Years following systemic therapy Time since therapy initiation (months) 0.07

  25. Historic Timeline for Licensing of Various RCC Treatments in Canada Sorafenib1 Nivolumab7 + Ipilimumab9 Temsirolimus3 Sunitinib2 Pazopanib5 First-line Second-line Nivolumab7 Cabozantinib10 Everolimus4 Axitinib6 Lenvatinib8 + Everolimus Checkpoint inhibitor Mode of action VEGFR TKI mTOR inhibitor VEGF-binding mAB

  26. Topics To Be Covered

  27. The way it was-First-line Treatment of Metastatic RCC:2017-18 Canadian Guidelines Treatment Status Therapy (Level 1evidence) OtherOptions (≥ Level2) PatientStatus Sunitinib Bevacizumab+ IFN Pazopanib High-doseIL-2 (Sorafenib) Observation ClinicalTrial Good or intermediaterisk FirstLine Sunitinib Clinicaltrial Poorrisk Temsirolimus*

  28. How have these evolved in 2019??With caveats: A VEGFR-directed TKI remains a standard of care for first-line treatment of mRCC in 2019 in Canada-so how might Pazopanib compare to Sunitinibin this regardthe Comparzand Pisces Trials

  29. Comparative Data:COMPARZ R A N D O M I S E n =557 Pazopanib • EligibilityCriteria • aRCC or mRCC with clear cellhistology • Measurabledisease • No prior systemictreatment • KPS ≥70 N =1110 Sunitinib 50mg/day n =553 Primary endpoint: PFS for non-inferiority (independentreview) Secondary endpoints: OS, ORR, PRO, safety, QoL, and medical resourceutilization KPS, Karnofsky performance status; QoL, quality oflife. Motzer RJ et al. N Engl J Med.2013;369:722-731.

  30. Comparative Data:COMPARZ PFSAssessment Independent Investigator 1.0 Pazopanib (n =557) Sunitinib (n =553) 8.4 months(8.3-10.9) 9.5 months(8.3-11.1) 10.5 months(8.3-11.1) 10.2 months(8.3-11.1) 0.8 HR,1.05 (95% CI,0.90-1.22) HR,1.00 (95% CI,0.86-1.15) 0.6 PFSprobability PFS non-inferiority demonstrated if upper bound of 95% CI for HR<1.25 0.4 0.2 0 0 4 8 12 16 20 24 28 32 Months *Per protocol population was consistent with the intent to treat (ITTpopulation) 36 40 Motzer RJ et al. N Engl J Med.2013;369:722-731.

  31. Comparative Data: PISCES 100 90 P <0.001 “Now that you have completedboth 80 treatments, which of the twodrugs 70 Patients,% 60 would you prefer to continue to takeas 50 treatment for your cancer,assuming 40 that both drugs work equallywell?” 30 20 8% 10 0 Preferredpazopanib Preferredsunitinib Nopreference Patients were still blind to the results of their disease assessment when they stated their preference Escudier B et al. J Clin Oncol.2014;32:1412-1418.

  32. But it is now 2019-The evolving First-line Landscape of RCC Treatment Nivolumab/Ipilimumab: randomized phase III CheckMate214trial Pembrolizumab/Axitinib randomized phase III Keynote 426trial Avelumab/Axitinib randomized phase III Javelin RCC 101trial NB: A Change in First-line Therapy Changesall SubsequentTherapies

  33. Nivolumab / Plus Ipilimumab vs Sunitinib for Treatment-NaïveAdvanced/ MetastaticRCC CheckMate 214: Study design Treatment Patients Randomize1:1 ArmA 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for four doses, then 3 mg/kg nivolumab IV Q2W • Stratifiedby • IMDC prognostic score (0 vs1– 2 vs3–6) • Region (US vs Canada/Euro pe vs Rest of World) Treatmentuntil progression or unacceptable toxicity • Treatment-naïve advanced or metastatic clear-cell RCC • Measurabledisease • KPS≥70% • Tumor tissueavailable • for PD-L1testing ArmB 50 mg sunitinib orally once daily for 4weeks (6-weekcycles) IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performancestatus; Q2W, every 2 weeks; Q3W, every 3weeks Co-primary endpoints: ORR (per IRRC), PFS (per IRRC),OS In IMDC intermediate- and poor-risk patients Motzer et al NEJM2018

  34. CheckMate 214: 30-month Updateon Progression-free Survival T. Presented at GU-ASCO 2019; Abstract #547.

  35. CheckMate 214: 30-month Update on Overall Survival T. Presented at GU-ASCO 2019; Abstract #547.

  36. Pembrolizumab/Axitinib vs Sunitinib for Treatment- NaïveAdvanced/ Metastatic RCC Keynote 426: Studydesign Treatment Patients Randomize1:1 ArmA Pembrolizumab 200mg IV q 3 weeks/ Axitinib 5 mg po BID daily for up to 24months • Stratifiedby • IMDC prognostic score (0 vs1– 2 vs3–6) • Region (US vs Canada/Euro pe vs Rest of World) Treatmentuntil progression or unacceptable toxicity • Treatment-naïve advanced or metastatic clear-cell RCC • Measurabledisease • KPS≥70% • Tumor tissueavailable • for PD-L1testing ArmB 50 mg sunitinib orally once daily for 4weeks (6-weekcycles) IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performancestatus; Q2W, every 2 weeks; Q3W, every 3weeks Co-primary endpoints: PFS,OS Rini et al NEJM2019

  37. Pembrolizumab/Axitinib as First-line Treatment for MetastaticRCC IMDC FavorableRisk Early analysis: no firm benefit (yet?) Rini et al ASCO2019

  38. Pembrolizumab/Axitinib as First-line Treatment for MetastaticRCC IMDC Intermediate / PoorRisk Significant benefit for Pembrolizumab /Axitinib Rini et al ASCO2019

  39. Javelin Renal101 StudyDesign Avelumab 10 mg/kg IVQ2W + Axitinib 5 mg PO BID (6-weekcycle) 6 R 1:1 Sunitinib 50 mg PO QD (4 weeks on, 2 weeksoff) Primaryendpoints PFS by RECIST v1.1 per independent review committee (IRC) in patients with PD-L1+ tumors (PD-L1+group)* OS in the PD-L1+group Motzer et al NEJM2019

  40. Javelin Renal101 PFS per IRC in OverallPopulation 100 Median PFS (95% CI), months Avelumab+Axitinib 13.8 (11.1,NE) Sunitinib 8.4 (6.9,11.1) Stratified HR, 0.69 (95% CI: 0.563,0.840) P = .0001 90 Progression-free survival,% 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 24 22 Months Is this enough? Motzer et al NEJM2019

  41. Javelin Renal101 Overall Survival (Immature at thisTime) 100 90 80 70 Overall survival,% Median OS (95% CI),months Avelumab +Axitinib Sunitinib Notreached Notreached 60 50 Stratified HR, 0.78 (95% CI: 0.554,1.084) P =.0679 40 30 20 10 0 • OS data areimmature • 14% of patients with event in the avelumab+ axitinibarm • 17% of patients with event in the sunitinibarm 2 4 6 8 10 12 14 16 18 20 22 24 26 Time since treatment initiation,months 0 Overall Survival needs to beawaited Motzer et al NEJM2019

  42. Summary- Immunotherapy Combinations in1st-Line-But a Caveat??What About Cabozantinib as a Single Agent-The CABOSUN Study The Caveat ,but wasSunitinib theright comparator in these studies in the first place?

  43. Increased Expression of MET and AXL in RCC is Associated with Poor Prognosis and Resistance to VEGFR Inhibitors 1. Choueiri TK, et al. N Engl J Med 2015;373:1814–23; 2. Gibney GT, et al. Ann Oncol; 2013;24:343–9; 3. Xie Z, et al. J Cancer 2016; 7:1205-1214. 4. Rankin EB, et al. PNAS 2014;111:13373–8. 5. Zhou L, et al. Oncogene 2016;35:2687–97.

  44. Mechanism of Action of Cabozantinib

  45. Cabozantinib as an Alternative to Sunitinib or Pazopanib: Phase 2 CABOSUN Study Design Tumor assessment by RECIST 1.1 Every other cycle* Treatment until disease progression or intolerable toxicity Cabozantinib60 mg qd orally • Advanced RCC (N=150) • Clear cell component • Measurable disease • No prior systemic therapy • ECOG PS 0-2 • IMDC intermediate or poor risk groups RANDOMIZATION 1:1 Sunitinib50 mg qd orally(4 weeks on/2 weeks off) • Stratification • IMDC risk group: intermediate, poor • Bone metastases: yes, no *One treatment cycle was defined as 6 weeks. ECOG: Eastern Cooperative Oncology Group; IMDC, International Metastatic RCC Database Consortium; RCC: renal cell carcinoma; RECIST: response evaluation criteria in solid tumors Choueiri TK, et J Clin Oncol 2017; 35(6):591-7.

  46. Phase 2 CABOSUN Study:Overall and Progression-free Survival Overall Survival: Trend in Favor of Cabozantinib PFS: Cabozantinib Significantly Longer than Sunitinib Probability of OS Probability of PFS Time Since Randomisation (Months) Time Since Randomisation (Months) No. at risk No. at risk • 2 Key caveats about CABOSUN: • Phase 2 trial: validation from a prospective phase 3 study required to be practice-changing • Limited sample size, relies on investigator reports for PFS CI: confidence interval; HR: hazard ratio; OS: overall survival; PFS: progression-free survival Choueiri TK, et al. Eur J Cancer 2018; 94:115-25.

  47. Randomized Phase II Assessment of Front-LineCabozantinibWhich prognostic groups benefitted the most? Choueiri TK et al:CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastaticrenalcellcarcinoma(mRCC) ofpoorandintermediateriskgroups (ESMO2016)

  48. Procopio G, (2018)- Safety and efficacy of cabozantinib in mRCC: Real-world data • At the time of analysis, median PFS was 8.0 months (range: 0.5–10.8 months) irrespective of the line of treatment • Median OS was not reached • 1-year OS was 65% • Incidence of Grade 3/4 AEs was 36% • Most common Grade 3/4 AEs were diarrhoea (7%), asthenia (7%) and hypertension (5%) • Dose was reduced due to AEs in 40 patients (42%) • 5 patients (5%) discontinued treatment because of AEs • AEs leading to a dose discontinuation were pulmonary embolism, severe gastrointestinal bleeding, diarrhoea and fatigue Conclusions: cabozantinib was effective in everyday clinical practice in large unselected population of mRCC patients who experienced disease progression after prior treatment. Cabozantinib treatment was well-tolerated with a manageable toxicity profile

  49. First Line Treatment in Metastatic RCC Some Conclusions • Our potential first line treatment options are constantlyevolving • Nivolumab/Ipilimumab may become a new standardin intermediate/poor riskpatients • Pembrolizumab/axitinibmay become a new standard inMetastatic • RCC across all riskgroups • Avelumab/axitinibmight also represent a new standard in Metastatic RCC across all risk groups although OS needs to beawaited • The Cabosun study suggests that Cabozanitib might be a superior • first line agent-It remains to be seen whether will be PCODR approved • for first-line indication(the Lenvatinib-Everolimus experience) • Long term remissions seempossible-but current sequencing strategies have to berefined

  50. Why might a VEGF TKI Work better in The favorable risk patients? Angiogenesis Gene Expression is Higher in Favorable MSKCC Risk Group T-effector GeneSignature P =0.1 PD-L1Expression P =0.35 Angiogenesis GeneSignature P =8.26e-05 100% 100% 100% 43% 26% AngioLow AngioHigh 75% 75% 75% 57% 57% 61% 64% Patients(%) Patients(%) Patients(%) 50% 50% 50% 74% 43% 43% 36% 39% 57% 25% 25% 25% 0% 0% 0% FavourableIntermediate/Poor n =156 n =667 FavourableIntermediate/Poor n =156 n =667 FavourableIntermediate/Poor n =156 n =667 Rini et al ESMO 2018 McDermott et al Nat Med2018

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