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Current Trends and Future Directions in Targeted Therapies for Advanced Renal Cell Carcinoma

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Current Trends and Future Directions in Targeted Therapies for Advanced Renal Cell Carcinoma

  1. 1. Current Trends and Future Directions in Targeted Therapies for Advanced Renal Cell Carcinoma Brian I. Rini, MD, FACP Professor of Medicine Cleveland Clinic Lerner College of Medicine
  2. 2. Disclosures Dr. Rini discloses the following commercial relationships: Consultant: Bristol-Myers Squibb, Merck, Pfizer, and Roche
  3. 3. Learning Objectives Describe factors that contribute to the development of RCC and the scientific foundation for targeted therapies Evaluate emerging data on the use of targeted therapies for advanced RCC Discuss relevant adverse events associated with targeted therapies for advanced RCC and evidence-based management strategies RCC = renal cell carcinoma.
  4. 4. Epidemiology of Kidney Cancer In 2018, 65,340 new diagnoses and 14,970 deaths attributed to RCC in the US 3.8% of adult malignancies Generally higher in North America and Europe, lower in Asia and South America Incidence in the US has risen over several decades Mortality has decreased Chow et al, 2010; NCCN, 2018; Siegel et al, 2018.
  5. 5. Different Types of Cancer Arise in the Kidney Shuch et al, 2015. 7% 16% 2% 75% Chromophobe Papillary Other Clear cell Medullary <0.5% Collecting duct <0.5% Translocation 1%
  6. 6. Risk Factors for RCC ~4% of cases are hereditary Some hereditary syndromes increase the risk for RCC 96% of cases are sporadic Overall, the pathogenesis of RCC is not well defined Known risk factors: ○ Smoking ○ Obesity ○ Hypertension Suspected risk factors: ○ Occupational exposures (eg, trichloroethylene) ○ Diabetes mellitus ccRCC = clear cell renal cell carcinoma. Banumathy et al, 2010; Chow et al, 2010; Protzel et al, 2012. Syndrome Gene/Chromosome Affected Von Hippel-Lindau (VHL) VHL Hereditary papillary RCC c-MET Hereditary leiomyomatosis and RCC Fumarate hydratase Birt-Hogg-Dubé (BHD) BHD folliculin Tuberous sclerosis TSC1,TSC2 Familial ccRCC 3p translocation
  7. 7. MSKCC Prognostic Risks: Integrated Factors MSKCC = Memorial Sloan Kettering Cancer Center; KPS = Karnofsky performance status; Hb = hemoglobin; cCa = corrected serum calcium; Dx = diagnosis; Tx = treatment; LDH = lactate dehydrogenase. Motzer et al, 2002. 5 factors: KPS, Hb, cCa, interval from Dx toTx, LDH
  8. 8. IMDC Model for VEGF-Targeted Therapy IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; VEGF = vascular endothelial growth factor. Heng et al, 2009. KPS <80 Dx toTherapy <1 year Anemia Hypercalcemia Neutrophilia Thrombocytosis Components of MSKCC Replace LDH
  9. 9. Prognostic Groups in mRCC with Frontline VEGF-Targeted Therapy mRCC = metastatic renal cell carcinoma; INTM = intermediate; OS = overall survival. Heng et al, 2009. Favorable: 0 adverse factors Intermediate: 1-2 adverse factors Poor: 3-6 adverse factors OS: 37 mo OS: 28.5 mo OS: 9.4 mo
  10. 10. Prognosis Post-Frontline VEGF-Targeted Therapy HR = hazard ratio. Ko et al, 2015.
  11. 11. Metastatic RCC Is a VEGF-Driven Disease mRNA = messenger ribonucleic acid; CNS = central nervous system; WBC = white blood cell. Jubb et al, 2004. VEGF-A expression in ~5,000 tissue specimens Adipose Adrenal Bloodvessel Bone Bonemarrow Breast Cervical CNS Colorectal Endometrium Esophagus Gallbladder Head&neck Heart Kidney Liver Lung Lymphoid Muscle Myometrium Neuroendocrine Ovary Pancreas Pituitary Placenta Prostate Skin Smallintestine Softtissue Stomach Testis Thymus Thyroid Urinary WBC HybridizationSignal IntensityforVEGF-AmRNA VEGF-A expression is 3.2-fold higher in kidney malignancies than in normal tissue 6000 5000 4000 3000 2000 1000 0
  12. 12. Biological Pathways and Therapeutic Targeted Agents for RCC Rini et al, 2009.
  13. 13. Median PFS With VEGF TKIs in Frontline Phase 3 Studies PFS = progression-free survival; TKI = tyrosine kinase inhibitor; BEV = bevacizumab; IFN = interferon. Escudier et al, 2007; Hutson et al, 2013; Motzer et al, 2013; Rini et al, 2014; Stenger, 2018; Motzer, Tannir et al, 2018. 11.0 10.2 8.4 9.5 9.1 12.7 10.1 6.5 12.3 0 5 10 15 20 MedianPFS(mo) 2007 2013 2017
  14. 14. Median OS With VEGF TKIs in Frontline Phase 3 Studies 2007 2013 2017 Escudier et al, 2010; Motzer et al, 2009; Motzer, Hutson et al, 2013; Motzer, Nosov et al, 2013; Stenger, 2018. 23.3 26.4 28.4 29.3 29.3 28.8 32.9 20 25 30 35 MedianOS(mo)
  15. 15. COMPARZ Established Sunitinib and Pazopanib as Frontline Options: PFS Motzer et al, 2016. Pazopanib Sunitinib
  16. 16. RECORD-3: Could an mTOR Inhibitor Be Suitable Frontline Therapy? aStratified by MSKCC prognostic factors. b4 weeks on and 2 weeks off. mTOR = mammalian target of rapamycin; PD = progressive disease; ORR = overall response rate. Motzer et al, 2014. Everolimus 10 mg/d Sunitinib 50 mg/db 2nd Line Primary:  PFS 1st line Secondary:  Combined PFS  ORR 1st line  OS  Safety Study end points Crossover upon PD 1:1 R A N D O M I Z Ea Everolimus 10 mg/d S C R E E N Sunitinib 50 mg/db 1st Line N=471
  17. 17. RECORD-3: Frontline PFS CI = confidence interval. Motzer et al, 2014. 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Time (mo) 238 233 164 181 118 145 88 108 68 84 44 55 31 42 23 28 12 15 5 9 0 3 0 0 Number of patients still at risk Everolimus Sunitinib Everolimus (events/n = 182/238) Sunitinib (events/n = 158/233) CumulativeEvent-FreeProbability(%) Median PFS (mo) Everolimus Sunitinib 7.85 10.71 HR 1.43 Two-sided 95% CI 1.15-1.77
  18. 18. Phase 3 Trial: Temsirolimus and IFN-α in Poor-Risk mRCC ULN = upper limit of normal; LLN = lower limit of normal; MU = million units; SC = subcutaneous; tiw = three times per week; IV = intravenous; CBR = clinical benefit rate. Hudes et al, 2007. Randomized, international, multicenter trial Primary end point: OS Secondary: PFS, ORR, CBR Treatment continued until PD, toxicity, or symptom deterioration Eligibility Criteria Previously untreated mRCC Poor prognosis (≥3 predictors of poor risk):  LDH >1.5 × ULN  Hemoglobin <LLN  Corrected calcium >10 mg/dL  Diagnosis to first treatment <1 yr  KPS 60-70  Multiple organ sites of metastasis IFN-α escalating to 18 MU SC tiw (n=207) Temsirolimus 25 mg IV weekly (n=209) Temsirolimus 15 mg IV weekly + IFN-α 6 MU SC tiw (n=210)
  19. 19. OS: ITT Population ITT = intention to treat; Tem = temsirolimus. Hudes et al, 2007. IFN Tem IFN +Tem Time to Death (mo from randomization) 1.00 0.75 0.50 0.25 0.00 SurvivalDistributionFunction 0 5 10 15 20 25 30 36 8.4 10.97.3 Median OS Tem 25 mg (n=209) IFN-α (n=207) P HR Months (95% CI) 10.9 (8.6-12.7) 7.3 (6.1-8.8) 0.008 0.73
  20. 20. Retrospective Studies of a 2/1 Sunitinib Schedule AE = adverse event. Atkinson et al, 2014; Bracarda et al, 2014; Kondo et al, 2014; Miyake et al, 2015; Najjar et al, 2014. Study N Results Bracarda et al, 2014 208  Maximum toxicity grade (≥3) was significantly reduced with 2/1 vs 4/2 (8% vs 46%; P<0.001) Atkinson et al, 2014 161  AE incidence decreased after switching to 2/1  Incidence of all AEs at next follow up was <30% after switching to 2/1 Najjar et al, 2014 30  The maximum toxicity with 4/2 was grade 3 in 87% of patients and grade 4 in 10%  In contrast, with 2/1 27% of patients experienced grade 3 toxicity and no grade 4 toxicities were observed Miyake et al, 2015 45  No significant difference in the overall incidence of AEs between 4/2 and 2/1  Proportion of patients with AEs grade ≥3 significantly lower in those on 2/1 compared with those on 4/2 (P=0.002) Kondo et al, 2014 48  Alternative schedule sunitinib showed a lower incidence of dose interruption and comparable outcomes with the traditional schedule group
  21. 21. TTP of Sunitinib 4/2 vs 2/1 TTP = time to progression. Lee et al, 2015.
  22. 22. Sunitinib 2/1: Duration of Toxicities HFS = hand-foot syndrome. Jonasch et al, 2018.
  23. 23. Sunitinib Intermittent Dosing: Prospective Phase 3 Study Ornstein et al, 2017. Clinical efficacy maintained, ORR 46% (after the first 4 cycles of therapy) Median PFS: 22.4 mo Median OS: 34.8 mo Median increase in tumor burden during sunitinib off-periods: 1.6 cm The goal of therapy is not to give pills everyday but to control disease
  24. 24. CABOSUN Trial Primary end point: PFS by investigator assessment Secondary end points: OS, ORR, safety Stratification: IMDC risk group: intermediate, poor Bone metastases: yes, no ECOG PS = Eastern Cooperative Oncology Group performance status; qd = once per day. Choueiri, Halabi et al, 2017; Ko et al, 2015; Heng et al, 2009. IMDC risk factors Time from diagnosis to therapy <1 yr Hb <LLN cCa >ULN KPS <80% Neutrophils >ULN Platelets >ULN Intermediate risk: 1-2 risk factors Poor risk: ≥3 risk factors Tumor assessment by RECIST 1.1 every other cycle Treatment until disease progression or intolerable toxicity Cabozantinib 60 mg qd orally (6-week cycles) R 1:1 Sunitinib 50 mg qd orally (4 weeks on/2 weeks off) Advanced RCC (N=157)  Clear cell component  Measurable disease  No prior systemic therapy  ECOG PS 0-2  IMDC intermediate- or poor-risk groups No crossover allowed
  25. 25. CABOSUN: Progression-Free Survival Choueiri, Halabi et al, 2017. n Median PFS (mo) Cabozantinib 79 8.2 (6.2-8.8) Sunitinib 78 5.6 (3.4-8.1) HR 0.66 (95% CI 0.46-0.95; one-sided P=0.012)
  26. 26. Ipilimumab + Nivolumab in IMDC Intermediate/Poor Risk RCC: OS NIVO = nivolumab; IPI = ipilimumab; NR = not reached; NE = not estimable; SUN = sunitinib. Motzer, Tannir et al, 2018. HR (99.8% CI), 0.63 (0.44-0.89) P=0.00003 Median OS, mo (95% CI) NIVO + IPI NR (28.2-NE) SUN 26.0 (22.1-NE) 425 399 372 348 332 318 300 241 119 44 2 0 422 387 352 315 288 253 225 179 89 34 3 0 # at Risk NIVO + IPI SUN
  27. 27. IMDC Favorable Risk Results PD-L1 = programmed death-ligand 1. Motzer, Tannir et al, 2018. Outcome NIVO + IPI n=125 SUN n=124 Confirmed ORR, % (95%CI) 29 (21-38) 52 (43-61) P<0.001 Median PFS, mo (95% CI) 15.3 (9.7-20.3) 25.1 (20.9-NE) HR (95% CI) 2.18 (1.29-3.68) P<0.001 Complete response, % 11 6 11% of patients in both arms had tumor PD-L1 expression ≥1%.
  28. 28. The Landscape of Sequential Therapy in 2015 Hirsch et al, 2016. Sunitinib or pazopanib Axitinib or everolimus Whatever is left The current paradigm of therapy in mRCC is an empiric sequence of monotherapies.
  29. 29. Axitinib vs Sorafenib: PFS mPFS = median progression-free survival. Rini, Escudier et al, 2011. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 P<0.0001 (log-rank) Stratified HR 0.665 (95% CI 0.544-0.812) Axitinib Sorafenib mPFS (mo) 95% CI 6.7 4.7 6.3-8.6 4.6-5.6 361 256 202 145 96 64 38 20 10 1 0 362 224 157 100 51 28 12 6 3 1 0 Subjects at risk (n) Axitinib Sorafenib
  30. 30. Everolimus Phase 3 Study: PFS Motzer et al, 2010.
  31. 31. Emerging Agents in Refractory RCC Tannir et al, 2018. Sunitinib or pazopanib Single-agent immunotherapy (nivolumab) VEGF + otherTKI targets (cabozantinib) VEGF + mTOR (lenvatinib + everolimus)
  32. 32. METEOR Study Design PD-1 = programmed death receptor 1; VEGFR = vascular endothelial growth factor receptor. Escudier et al, 2016. Advanced RCC (N=658)  Clear cell histology  Measurable disease  Progression on priorVEGFRTKI within 6 mo of enrollment  No limit to the number of prior therapies  Antibodies targeting PD-1/PD-L1 allowed  Brain metastases allowed if treated Cabozantinib 60 mg qd orally Everolimus 10 mg qd orally Randomization 1:1 No crossover allowed Tumor assessment by RECIST 1.1 every 8 weeks Treatment until loss of clinical benefit or intolerable toxicity Stratification: MSKCCrisk groups: favorable, intermediate, poor Number of priorVEGFR-TKIs: 1, 2, or more
  33. 33. METEOR: Progression-Free Survival and Response IRC = independent review committee. Choueiri et al, 2015; Choueiri et al, 2016. Median Cabozantinib (n=330) 7.4 mo Everolimus (n=328) 3.9 mo HR 0.51 (95% CI 0.41-0.62), P<0.0001 Cabozantinib (n=187) Everolimus (n=188) ORR per IRC (95% CI) 21% (16-28) 5% (2-9) Stable disease 62% 62% Progressive disease 14% 27% Unable to determine 3% 6%
  34. 34. Lenvatinib + Everolimus Randomized Phase 2 Study Design PO = by mouth. Motzer, Hutson et al, 2015; Motzer et al, 2016. Key eligibility criteria:  Advanced or metastatic RCC  Measurable disease  Progression on/after 1 prior VEGF-targeted therapy  Progression within 9 mos of stopping prior treatment  ECOG PS ≤1 Everolimus 10 mg PO qd Lenvatinib 18 mg PO qd + Everolimus 5 mg PO qd Lenvatinib 24 mg PO qd R A N D O M I Z E
  35. 35. Lenvatinib + Everolimus: Kaplan-Meier Estimate of PFS Motzer et al, 2016. PFS was significantly longer in patients in the lenvatinib plus everolimus group than in those in the everolimus alone group (HR 0.45; 95% CI 0.27-0.79); P=0.0029. Lenvatinib/ Everolimus Lenvatinib Everolimus ORR, % 35 39 0 95% CI 22-50 25-53 0-7
  36. 36. Biomarker Discovery Revealed Tantalizing Results, Yet None Have a Relevant Role in Treatment Selection dBP = diastolic blood pressure.; Hg = mercury. Rini, Schiller et al, 2011.
  37. 37. Transcriptome Map of Angiogenesis and Immune- Associated Genes in RCC Tumors IL = interleukin; IHC = immunohistochemistry. McDermott et al, 2017. Angiogenesis Immune, antigen presentation Myeloid inflammation (eg, CD34, KDR, VEGF-A) (eg, CD8A, IFNG, PSMB8) (eg, IL-6, PTGS2, IL-8) PD-L1 IHC IC0 IC1 IC2 IC3 3 -3 2 -2 -1 1 0
  38. 38. Sunitinib Demonstrated Improved PFS in AngiogenesisHigh Subset vs AngiogenesisLow Subset McDermott et al, 2017. High (n = 44) Low (n = 45) Sunitinib Sunitinib HR 95% CI Angiogenesis (high vs low) 0.31 0.18-0.55 High (n = 42) Low (n = 44) Atezolizumab HR 95% CI Angiogenesis (high vs low) 0.74 0.42-1.28 AtezolizumabAtezolizumab + Bevacizumab Atezolizumab + Bevacizumab HR 95% CI Angiogenesis (high vs low) 0.90 0.54-1.51 High (n = 45) Low (n = 43)
  39. 39. Non-Clear Cell mRCC: Phase 2 ASPEN Trial Armstrong et al, 2016. Metastatic RCC  Non-clear cell pathology: papillary, chromophobe, unclassified  No prior therapy  Measurable disease Stratified by papillary histology and MSKCC risk group Everolimus 10 mg orally once daily Days 1-42 Cycle = 6 weeks Sunitinib 50 mg orally Days 1-28 Cycle = 6 weeks N=108 R A N D O M I Z E Primary end point: Radiographic PFS
  40. 40. ASPEN: Progression-Free Survival of Sunitinib vs Everolimus Armstrong et al, 2015. Progression-Free SurvivalProbability Time Since Randomization (mo)
  41. 41. Side Effects of Targeted Therapy Predictable Directly related to the molecular target and mechanism of action in normal tissues Can affect multiple organ systems Early detection and early intervention can relieve or control most side effects Kirkali, 2011; Widakowich et al, 2007; ACS, 2016.
  42. 42. Adverse Event Sorafenib Sunitinib Pazopanib Axitinib Bevacizumab Everolimus Temsirolimus Fatigue + + + + + + + Hand-foot Syndrome + + + + – – – Hypertension + + + + + – – Diarrhea + + + + – + + Stomatitisa + + + + – + + Myelosuppression – + + – – + + Pneumonitis – – – – – + + Infections – – – – – + + Hypersensitivity reactionb – – – – + – + Proteinuria – – + – + – – Metabolic syndromec – – – – – + + Targeted Agents: Common Adverse Events aReactions occurred despite antihistamine pre-medication. bIncludes aphthous stomatitis, mucositis, mouth/tongue ulceration. cIncludes increased glucose, cholesterol, lipids, triglycerides. Nexavar® prescribing information, 2010; Sutent® prescribing information, 2011; Votrient® prescribing information, 2009; Inlyta® prescribing information, 2012; Avastin® prescribing information, 2009; Afinitor® prescribing information, 2010; Torisel™ prescribing information, 2007; Kirkali et al, 2011.
  43. 43. Adverse Event Sorafenib Sunitinib Pazopanib Axitinib Bevacizumab Everolimus Temsirolimus Fatigue + + + + + + + Hand-foot Syndrome + + + + – – – Hypertension + + + + + – – Diarrhea + + + + – + + Stomatitisa + + + + – + + Myelosuppression – + + – – + + Pneumonitis – – – – – + + Infections – – – – – + + Hypersensitivity reactionb – – – – + – + Proteinuria – – + – + – – Metabolic syndromec – – – – – + + Targeted Agents: Common Adverse Events aReactions occurred despite antihistamine pre-medication. bIncludes aphthous stomatitis, mucositis, mouth/tongue ulceration. cIncludes increased glucose, cholesterol, lipids, triglycerides. Nexavar® prescribing information, 2010; Sutent® prescribing information, 2011; Votrient® prescribing information, 2009; Inlyta® prescribing information, 2012; Avastin® prescribing information, 2009; Afinitor® prescribing information, 2010; Torisel™ prescribing information, 2007; Kirkali et al, 2011.
  44. 44. Fatigue Etiologies: Disease Treatment Normal activities Management Activity & exercise Disability placard Adjust dosing schedule: eg, sunitinib 2/1 schedule; breaks from therapy NCCN, 2018; Larkin et al, 2010; Bracarda et al, 2015.
  45. 45. Gastrointestinal Side Effects Diarrhea Mucositis Functional mucositis Clinical mucositis Nausea/vomiting Taste changes Anorexia Eisen et al, 2012; Lalla et al, 2008.
  46. 46. Management of Diarrhea Dietary recommendations Fluid intake 64 ounces per day Small, frequent meals Pharmacologic interventions Loperamide Diphenoxylate HCL/atropine sulfate Deodorized tincture of opium Psyllium fiber supplementation Metamucil Probiotics Eisen et al, 2012; NCI, 2017; Brose et al, 2014; McQuade et al, 2016.
  47. 47. Dermatologic Side Effects Dry skin Rash Pruritus Hand-foot syndrome (HFS) Palmar-plantar erythrodysesthesia syndrome (PPE) Hand-foot skin reaction (HFSR) ACS, 2016; Yang et al, 2010.
  48. 48. Dermatologic Side Effects (cont.) Photos courtesy of Laura Wood, RN.
  49. 49. Management of Dermatologic Side Effects Prevention/prophylaxis Early identification, notification, and intervention Concurrent approaches Gentle soaps and cleansers Topical emollients Anti-dandruff shampoos Steroids Topical or oral Treatment interruption or dose reduction ACS, 2016; Eisen et al, 2012.
  50. 50. The “3C” Approach to Manage MKI- HFSR Control calluses Prophylactic removal of hyperkeratotic areas before & during treatment Pumice stone, Ped Egg pedicure, podiatrist Comfort with cushions Protect pressure-sensitive areas of hands & feet ○ Well-padded, well-fitting, soft shoes ○ Insole cushions or inserts Cover with creams Frequent use of emollient creams Keratolytic agents on callused areas of palms & soles MKI-HFSR = multikinase inhibitor-associated hand-foot skin reaction. Wood et al, 2010.
  51. 51. Management of Hypertension HTN pretreatment criteria Maximize BP control prior to therapy initiation SBP ≤140 mm Hg and DBP ≤90 mm Hg HTN monitoring daily: Early detection and aggressive management to minimize complications of HTN Weekly: once HTN controlled & BP stable Dose modification guidelines Consider treatment interruption of severe HTN Consider cardiology consult BP goal: SBP <140 DBP <90 mm Hg HTN = hypertension; BP = blood pressure; SBP = systolic blood pressure. Maitland et al, 2010.
  52. 52. Management of Hypertension (cont.) Control HTN before starting therapy Blood pressure monitoring Take after blood pressure medication and before cancer therapy dose Daily: early detection and aggressive management to minimize complications of HTN Continue monitoring during treatment breaks Consider cardio-oncology consult Rini et al, 2015; Maitland et al, 2010.
  53. 53. Future Directions of Targeted Therapy in the Management of Advanced RCC
  54. 54. PFS in PD-L1+ Disease Atezo = atezolizumab. Motzer, Powles et al, 2018. Median PFS, mo (95% CI) Atezo + Bev 11.2 (8.9-15.0) Sunitinib 7.7 (6.8-9.7) HR 0.74 (95% CI 0.57-0.96) P=0.02 PFS assessed by investigators. Minimum follow-up, 12 mo. Median follow-up, 15 mo. The PFS analysis passed the pre-specified P value boundary of alpha = 0.04
  55. 55. Axitinib + Pembrolizumab Atkins et al, 2018.
  56. 56. Axitinib + Pembrolizumab (cont.) CR = complete response; PR = partial response; SD = stable disease; IQR = interquartile range; PR = partial response. Atkins et al, 2018. Best Objective Response CR 8% PR 65% SD 15% PD 6% In the 52 patients treated, 20 PFS events were reported. Median PFS was 20.9 mo (95% CI 15.4-not evaluable) Median OS was not reached at the median follow-up period of 20.4 mo (IQR 19.1-21.7); with deaths reported in 6 patients PD-L1+ vs -; ORR 89% vs 71%; PFS 20.7 vs 22.1 mo
  57. 57. Axitinib + Avelumab Choueiri et al, 2018.
  58. 58. Axitinib + Avelumab (cont.) Choueiri, Larkin et al, 2017. Confirmed Best Overall Response per RECIST v1.1, n (%) All Patients (N=55) Complete response 3 (6) Partial response 29 (53) Stable disease 11 (20) Progressive disease 10 (18) Nonevaluable 2 (4) Objective response rate, % (95% CI) 58% (44.1-71.3) Responses ongoing in 24 patients at data cutoff Tumor shrinkage in 84% of patients
  59. 59. Shifting the Balance Towards Antitumor Response With Combined VEGF/PD-1 Blockade Einstein & McDermott, 2017.
  60. 60. VEGF-TKI + I/O Combinations Have Shown Activity in mRCC I/O = immuno-oncology; Axi = axitinib; Pembro = pembrolizumab; Cabo = cabozantinib; f/u = follow up. Atkins et al, 2018; Choueiri, Larkin et al, 2017; Lee et al, 2017; Nadal et al, 2018; Escudier et al, 2018. Axi + Pembro (n=52) Axi + Avelumab (n=55) Lenvatinib + Pembro (n=30) Cabo + Nivo (n=13 RCC) Tivozanib + Nivo (n=14) ORR 73% 58% 63% 54% 64% CR 8% 6% – 0% 0% PFS 20.9 mo 29/55 pts (52.7%) remain on treatment NR 18.4 mo (longer than median f/u; censoring) 11/14 pts remain on treatment
  61. 61. VEGF-TKI + Anti–PD-L1 Phase 3 Study Designs Choueiri, Rini et al, 2017. Treatment-naive mRCC TKI + checkpoint inhibitor Sunitinib Randomization
  62. 62. Case Study 1 52-year-old man with left rib pain that began 3 weeks ago after playing touch football. Minimal pain relief with ibuprofen PMH: hypertension and hyperlipidemia controlled with meds Diagnostic workup: CXR revealed lytic lesion, left fourth, and numerous bilateral pulmonary nodules CT c/a/p showed 8-cm mass, upper pole left kidney, and multiple bilateral pulmonary nodules suspicious for metastatic disease; largest = 2.4 cm x 1.8 cm PMH = past medical history; CXR = chest X-ray; CT = computed tomography; c/a/p/ = chest/abdomen/pelvis.
  63. 63. Case Study 1 (cont.) Patient underwent laparoscopic nephrectomy Pathology: Tumor extension into renal vein with invasion of left adrenal gland (T3a) Lymph nodes negative (N0) Tumor stage: T3aN0M1 Histology: clear cell Fuhrman Grade 3 Started on sunitinib 50 mg/d x 28 days followed by 14- day rest period (schedule 4/2)
  64. 64. Case Study 1 (cont.) During 4-week follow-up visit: Complains of painful hands and feet and limited ambulation ○ Grade 3 hand-foot skin reaction Unable to eat for past 2 days ○ Grade 3 mucositis Reported home BP readings in 150/100 range Symptoms started mid-week 3 Expresses concern that sunitinib will be discontinued permanently
  65. 65. Case Study 1 (cont.) How would you treat this patient? a. Discontinue sunitinib and start another agent b. Hold sunitinib until resolution of toxicity, then resume at 2/1 schedule c. Hold sunitinib until resolution of toxicity, then resume at 37.5 mg 4/2 schedule
  66. 66. Case Study 1 (cont.) Amlodipine besylate 5 mg qd added for BP control Sunitinib held. After 1 week, side effects resolved to grade 1. Restarted at 50 mg schedule 2/1 No recurrence of grade 3 toxicities on subsequent cycles 42% reduction in tumor burden maintained for 2+ years
  67. 67. Case Study 2 64-year-old man with history of metastatic RCC 2/19/2005: S/P left nephrectomy and adrenalectomy; clear cell adrenal metastases 2009: Recurrence of lung nodules with biopsy consistent with clear cell RCC. In retrospect, had been present on scans for at least 2 years prior Patient is observed due to low-volume, indolent disease, and desire to avoid toxicity 6/2011: continued indolent growth on scans and increase in his total tumor burden as well as a new paratracheal LN. Patient was started on systemic therapy Sunitinib 50 mg 4/2 Tolerates reasonably well with fatigue and mild diarrhea 6/2012: RECIST PD with progressive lung nodules and mediastinal LN LN = lymph node; S/P = status post.
  68. 68. Best response on sunitinib PD on sunitinib Case Study 2 (cont.)
  69. 69. Case Study 2 (cont.) How would you treat this patient? a. Continue sunitinib as patient is tolerating well with “clinical benefit” with no symptoms from progressive disease b. Switch to axitinib at a starting dose of 5 mg BID c. Switch to nivolumab d. Switch to everolimus e. Switch to cabozantinib BID = twice a day.
  70. 70. Case Study 2 (cont.) Patient remains on sunitinib for another 6 months with continued slow but definitive progression New pancreatic metastases are seen on imaging at 6 months and patient has lost 10 lbs in last 4 months Patient starts axitinib 5 mg BID Tolerates well with grade 1 diarrhea, mild fatigue BP 130/70 mm Hg at baseline; over first 4 weeks of therapy no real change (120-135/70-75) Patient presents at 4 weeks asking about escalation of axitinib dose
  71. 71. Case Study 2 (cont.) Based on lack of BP elevation or other toxicity, dose of axitinib is empirically escalated to 7 mg BID The patient has a BP elevation of 10-15 mm Hg; mildly increased soreness of feet; but now has grade 3 fatigue CT scan at 8 weeks reveals regression of LN Patient goes back to axitinib 6 mg BID Tolerates well with grade 1 diarrhea, grade 1 fatigue Maintains PR for 12 months, then definitive progression PS 1, still reasonably active
  72. 72. Case Study 2 (cont.) Baseline s/p 2 cycles of axitinib 5->7 mg BID Grade 3 fatigue
  73. 73. s/p 4 cycles of axitinib (2 cycles at 5 mg BID) Grade 1 fatigue Case Study 2 (cont.) s/p 6 cycles of axitinib (2 cycles at 6 mg BID) Grade 1 fatigue
  74. 74. Case Study 2 (cont.) How would you treat this patient now? a. Switch to nivolumab b. Switch to cabozantinib
  75. 75. Key Takeaways RCC biology is characterized by reliance on the VEGF pathway Therapy targeted against VEGF is a cornerstone of treatment for advanced RCC and can control disease in a subset of patients but is generally not considered curative Moving forward, VEGF agents are likely to be a component of an immunotherapy-based combination with preliminary evidence of high clinical activity
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