Daniel Heng, MD, MPH, FRCPC @DrDanielHeng Chair GU Tumour Group, Tom Baker Cancer Centre Clinical Professor, University of Calgary CLINICAL CHALLENGES IN METASTATIC RENAL CELL CARCINOMA: THE RIGHT THERAPY FOR THE RIGHT PATIENT
Disclosures Consultancies and/or research funding from BMS Eisai Ipsen Novartis Pfizer
Prognostic Factors Outline First Line Therapy Advances Cytoreductive Nephrectomy Second line therapy Evolving Algorithm The Future
mrcc treatment Treating Metastatic RCC Start drug therapy More common Cytoreductive nephrectomy then targeted therapy Active surveillance (small, slow growth) Metastasectomy (solitary, resectable, disease-free interval) Better prognosis 4
International mrcc Database Consortium PROGNOSTIC FACTORS
International mrcc Database Consortium Currently includes 9,500 patients from 38 international institutions Poland Italy 6
Risk Stratification International mrcc Database Consortium (IMDC) Prognostic Factors Clinical Low Karnofsky performance (<80%) Time from diagnosis to treatment <1 year Laboratory Low hemoglobin (< LLN) High corrected serum calcium (> ULN) High neutrophils (> ULN) High levels of platelets (> ULN) Categorized into 3 risk groups with decreasing associated survival time Favorable (0 factors) Intermediate (1 2 factors) Poor (3+ factors) Heng DY, et al. J Clin Oncol. 2009;27:5794-5799. 7
IMDC Prognostic Factors Favorable 43 months 43 mo Intermediate 23 months 23 mo Poor 8 mo Heng DY, et al. Lancet Oncol. 2013;14:141-148. 8
IMDC in Second-Line Targeted Therapy Poor 5.4 mo Int 16.6 mo Favorable 35.3 mo Ko JJ, et al. GU Cancers Symposium 2014. Abstract 398. 9
IMDC in Third-Line Targeted Therapy Wells JC, et al. Eur Urol. 2016;71:204-209. 10
IMDC in Non-clear Cell RCC Kroeger N, et al. Cancer. 2013;119:2999-3006. IMDC in Papillary RCC TKI First Line Wells JC, et al. Cancer Med. 2017;6:902-909. IMDC in Nivolumab Second Line Yip S, et al. ASCO 2018 Abstract 492 11
How Do We Use Prognostic Factors? Patient counseling Clinical trial stratification and adjustment methods in retrospective studies Patient treatment Temsirolimus can be used in poor-risk individuals Can help determine prognosis for deciding whether cytoreductive nephrectomy can be helpful Can help choose first-line therapy 12
FIRST-LINE THERAPY
PFS probability IMDC: Comparative Effectiveness of First-Line Pazopanib and Sunitinib OS probability Progression-free survival Overall survival 1.0 0.8 Median PFS, months (95% CI) Pazopanib (n = 914): 8.3 (7.2 8.9) Sunitinib (n = 6,493): 8.4 (8.2 8.7) P =.17 1.0 Median OS, months (95% CI) Pazopanib (n = 915): 22.6 (21.1 24.7) Sunitinib (n = 6,490): 22.3 (21.4 23.2) 0.8 P =.65 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 25 50 75 100 125 Time, months 0 25 50 75 100 125 Time, months ORR between sunitinib and pazopanib (1687/5561 [30%] vs 196/707 [28%], respectively; Fisher s exact test = 0.16) Ruiz-Morales JM, et al. Eur J Cancer. 2016;65:102-108. 14
CheckMate 214: Study Design Patients Treatment Treatment-naive advanced or metastatic clear cell RCC Measurable disease KPS 70% Tumor tissue available for PD-L1 testing Randomize 1:1 Stratified by IMDC prognostic score (0 vs 1 2 vs 3 6) Region (US vs Canada/Europe vs rest of world) Arm A 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for 4 doses, then 3 mg/kg nivolumab IV Q2W Arm B 50 mg sunitinib orally once daily for 4 weeks (6-week cycles) Treatment until progression or unacceptable toxicity IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks. Escudier B, et al. Ann Oncol. 2017;28(suppl 5):v605-v649. 15
Co-primary endpoint Overall survival (probability) OS: IMDC Intermediate/Poor Risk 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. at risk NIVO + IPI SUN 0 3 6 9 12 15 Months Median OS, months (95% CI) NIVO + IPI SUN NR (28.2 NE) 26.0 (22.1 NE) Hazard ratio (99.8% CI) = 0.63 (0.44 0.89) P <.0001 18 21 24 27 30 33 425 399 372 348 332 318 300 241 119 44 2 0 422 387 352 315 288 253 225 179 89 34 3 0 Escudier B, et al. Ann Oncol. 2017;28(suppl 5):v605-v649. 16
Exploratory endpoint ORR and PFS: IMDC Favorable Risk Outcome Confirmed ORR, % (95% CI) PFS, median (95% CI), months NIVO + IPI N = 125 N = 249* SUN N = 124 29 (21 38) 52 (43 61) P =.0002 15.3 (9.7 20.3) 25.1 (20.9 NE) HR (99.1% CI) = 2.18 (1.29 3.68) P <.0001 *Eleven percent of patients in both arms had tumor PD-L1 expression 1%. IRRC assessed by RECIST v1.1. IRRC assessed. Escudier B, et al. Ann Oncol. 2017;28(suppl 5):v605-v649. 17
First-Line Therapy: Practice-Changing Ipi/Nivo for first line in IMDC intermediate/poor-risk patients These patients may have higher inflammatory and tumor burden to give IO agents something to potentiate PD-L1 is not predictive for OS don t order it But it is for PFS PD-L1 enriches patient population for responders but does not determine which patient should receive frontline IO; poor negative predictive value Important to remember RCC is still addicted to angiogenesis 18
Phase III First-Line IO Combinations CheckMate 214* Ipilimumab/Nivolumab VS Sunitinib CheckMate 9ER Cabozantinib/Nivo VS Sunitinib JAVELIN Renal 101 Axitinib/Avelumab VS Sunitinib *Results available. IMmotion151* Bevacizumab/ Atezolizumab VS Sunitinib EISAI 307 Lenvatinib/Everolimus VS Lenvatinib/Pembro VS Sunitinib KEYNOTE-426 Axitinib/Pembrolizumab VS Sunitinib 19
To Cut or Not to Cut? CYTOREDUCTIVE NEPHRECTOMY
Value of Cytoreductive Nephrectomy OS benefit of nephrectomy compared with no nephrectomy in mrcc patients treated with targeted therapies*, retrospective analysis 3,245 mrcc patients 2,569 (79%) patients with nephrectomy Excluded: 1,587 (49%) patients with nephrectomy before metastases 676/1,658 (41%) No cytoreductive nephrectomy 982/1,658 (59%) Cytoreductive nephrectomy* *Sunitinib (67%); sorafenib (20%); bevacizumab (4%); temsirolimus (3.6%); pazopanib (2.8%); other (2.6%). Sunitinib (79%); sorafenib (8.6%); bevacizumab (1.5%); temsirolimus (6.4%); pazopanib (2.8%); other (1.7%). Heng DY, et al. Eur Urol. 2014;66:704-710. 21
OS probability Cytoreductive Nephrectomy Has a Favorable Effect on OS 1.00 Median OS + CN (n = 982) 20.6 months CN (n = 676) 9.5 months 0.8 HR* = 0.60 (95% CI: 0.52 0.69) P <.0001 0.6 0.4 0.2 0 0 20 40 60 80 100 Time, months *Adjusted for IMDC criteria. HR, hazard ratio. Heng DY, et al. Eur Urol. 2014;66:704-710. 22
IMDC Prognostic Factors Predict Benefit From Cytoreductive Nephrectomy Number of IMDC factors No nephrectomy OS, months (n) Nephrectomy OS, months (n) P value 0 92% of patients with nephrectomy; insufficient number to compare 1 22.5 (72) 30.4 (178).002 2 10.2 (143) 20.2 (253) <.001 3 10.0 (113) 15.9 (106) <.001 4 5.4 (103) 6.0 (67).166 5 3.6 (36) 2.8 (14).504 6 75% of patients without nephrectomy; insufficient number to compare Heng DY, et al. Eur Urol. 2014;66:704-710. 23
CARMENA: Cytoreductive Nephrectomy Mejean A, et al. ASCO 2018. Abstract LBA3. 24
Patient Characteristics Mejean A, et al. ASCO 2018. Abstract LBA3. 25
Overall Survival by Patient Population Mejean A, et al. ASCO 2018. Abstract LBA3. 26
Cytoreductive Nephrectomy With CARMENA, cytoreductive nephrectomy threshold is higher: caveats due to trial issues More intermediate/poor-risk patients should receive systemic therapy first; also consider deferred nephrectomy per SURTIME It is still about patient selection Poor-risk patients do not benefit from CN and should be started on targeted therapy I would still do CN in Favorable risk: Large kidney mass if removed can do surveillance Int risk: Large kidney mass with a few small pulmonary nodules Bleeding or painful kidney mass in low-bulk metastatic disease Heng DY, et al. Eur Urol. 2014;66:704-710. 27
SECOND LINE AND BEYOND
Overall survival Presented by Robert Motzer at Genitourinary Cancers Symposium 2016.
Immune-mediated Adverse Reactions Result from increased I MMUNE-MEDI or excessive immune ATED activity ADVERSE REACTI ONS Can be severe or Follow life-threatening, color code affecting to appropriate various management organs guide section. GASTROINTESTINAL GOTOPAGE6 Signs and symptoms such as Diarrhea Abdominal pain Blood or mucus in stool Bowel perforation Peritoneal signs Ileus LIVER GOTOPAGE8 Signs such as Abnormal liver function tests (eg, AST, ALT) or total bilirubin SKIN GOTOPAGE10 Symptoms such as Pruritus Rash NEUROLOGIC GOTOPAGE12 Symptoms such as Unilateral or bilateral weakness Sensory alterations Paresthesia ENDOCRINE GOTOPAGE14 Signs and symptoms such as Fatigue Headache Mental status changes Abdominal pain Unusual bowel habits Hypotension Abnormal thyroid function tests and/or serum chemistries OTHER ADVERSE REACTIONS, including ocular manifestations GOTOPAGE16 ference ID: 3088772 Approved 930050989 1.0 Please see each organ system section for related guidance. See checklist on the next page. 3
Cabozantinib Phase III Study (METEOR): Design Phase III randomised, multicentre, open-label study to evaluate the efficacy and safety of cabozantinib vs everolimus in patients with RCC who had progressed on prior VEGFR therapy Patients 18 years of age Advanced/Metastatic clear cell RCC Measurable disease Received 1 prior VEGFR therapy and progressed 6 months after most recent dose Karnofsky PS 70 Adequate organ and bone marrow function Stratification factors Number of previous VEGFR therapies MSKCC criteria Cabozantinib 60 mg oral OD Randomisation 1:1 No crossover allowed Tumour assessment every 8 weeks (RECIST v1.1) Treatment until loss of clinical benefit or intolerable toxicity Everolimus 10 mg oral OD Endpoints Primary PFS* (independent review) Secondary OS ORR Safety MSKCC, Memorial Sloan Kettering Cancer Center; OD, daily; PS, performance status. *PFS defined as the interval between the dates of randomisation and first documentation of disease progression or death from any cause. 1. Choueiri TK, et al. N Engl J Med. 2015;373:1814-1823. 32
Roles of MET and AXL in RCC MET and AXL in RCC Receptor Activation and tumourigenic activities MET 2 Loss of VHL expression/vhl mutation and hypoxia lead to upregulation of MET in ccrcc Activation of MET through gene mutations identified in hereditary/sporadic papillary RCC Dysregulation of MET implicated in tumour development, invasion, and angiogenesis AXL expression directly activated by HIF-1 and HIF-2 AXL 3 In metastatic ccrcc, inactivation of AXL reverses invasive and metastatic phenotype AXL expression in primary ccrcc tumours correlates with aggressive tumour behaviour and increased risk of patient mortality Increased expression of MET and AXL in RCC is associated with poor prognosis and resistance to VEGFR inhibitors 1,3 ccrcc, clear-cell RCC; MET, hepatocyte growth factor receptor 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. Rankin EB, et al. PNAS 2014;111:13373 8. 33
METEOR Study: OS Second Interim Analysis (ITT population) Overall survival, % 100 80 No. of patients Median overall survival (95% CI), mo No. of deaths Cabozantinib 330 21.4 (18.7 NE) 140 Everolimus 328 16.5 (14.7 18.8) 180 60 HR = 0.66 (95% Cl: 0.53 0.83; P =.0003) 40 20 No. at Risk Cabozantinib Everolimus 0 Cabozantinib Everolimus 0 3 6 9 12 15 18 21 24 27 330 318 296 328 307 262 264 229 Months 239 178 202 141 30 105 41 6 3 0 82 32 8 1 0 Data cutoff: 31 Dec 2015. 1. Choueiri TK, et al. Lancet Oncol. 2016;17:917-927. 34
Cabozantinib Phase 1 Study: Activity Against Bone Metastases Clinical activity against metastatic lesions in bone was observed in some patients This scan shows partial bone resolution in a symptomatic RCC patient with predominantly osteolytic bone metastases who was previously treated with sorafenib, everolimus, and sunitinib This patient reduced the number of narcotics (3 opioid medications to 2) and their frequency (6-7 doses of narcotics per day to 2-3 doses per day or less), continuing on reduced narcotics until Week 25 when pain began to increase in intensity 1. Choueiri TK, et al. Ann Oncol 2014;25:1603-8 (supplementary data)
IMDC Real World Evidence: 2 nd line Cabozantinib vs Nivolumab Cabozantinib N= 53 Nivolumab N=225 IMDC Risk Category (p=0.8766) Favorable Risk 6/39 (15%) 21/157 (13%) Intermediate Risk 27/39 (69%) 107/157 (68%) Poor Risk 6/39 (15%) 29/157 (19%) Best Response: CR 1/40 (3%) 2/140 (1%) PR 7/40 (18%) 28/140 (20%) SD 23/40 (58%) 48/140 (34%) PD 9/40 (23%) 62/140 (44%) ORR 8/40 (20%) 30/140 (21%) Stukalin et al GU ASCO 2018
IMDC Real World Evidence: 2 nd line Cabozantinib vs Nivolumab Stukalin et al GU ASCO 2018
IMDC Real World Evidence: 2 nd line Cabozantinib vs Nivolumab Stukalin et al GU ASCO 2018
Case Presentation 67M IMDC favorable risk metastatic RCC to pancreas (largest 2.7 cm) and liver (largest 4 cm) Original nephrectomy clear cell RCC Oct 1994 Biopsy proven liver mets: clear cell RCC First-line sunitinib Aug 2012 - Nov 2013 Dose reduced to 37.5mg 4/2 Best response SD but eventual PD (15 months) Case Provided by D Heng
Case Presentation Second-line cabozantinib Jan 2014-Feb 2017 On METEOR trial, excellent disease response Central necrosis followed by tumor regression Breaks and dose reduction to 40mg for diarrhea Liver lesions 6.4 cm max and pancreatic lesions 4.4 cm max. Had PR, but eventual PD THREE YEARS later Case Provided by D Heng
Patient on Cabozantinib Case Provided by D Heng
Case Presentation Third-line Axitinib Mar 2017 to Apr 2017 Did not tolerate due to diarrhea, fatigue, volume depletion even at dose reduction of 2mg bid Continued disease progression (PD) Fourth-line Nivolumab May 2017 to November 2017 Stable disease Eventual referral to palliative care Case Provided by D Heng
EVOLVING TREATMENT ALGORITHM
How do we choose therapy? IMDC risk group IV vs oral therapy Patient preference Side effect profiles Contraindications
Metastatic Renal Cell Carcinoma: Evolving Treatment Algorithm Future? Present Past Sunitinib/ Pazopanib Everolimus/ Axitinib Therapy not previously used FAV risk (~25%) Pazopanib/ Sunitinib Cabozantinib/ Nivolumab Axitinib/ Lenvatinib + Eve Therapy not previously used INT/POOR risk (~75%) Ipilimumab / Nivolumab Therapy not previously used (see above) Therapy not previously used Composite Predictive Biomarker Immune Therapy VEGF Ipilimumab Nivolumab Cabozantinib Sun/Pazo etc mtor Everolimus Temsirolimus @DrDanielHeng
Metastatic Renal Cell Carcinoma ADVANCING PRECISION MEDICINE
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PBRM1 LOF Mutations Enrich for Benefit From Anti PD-1 Therapy Whole exome sequencing of 35 clear cell RCCs treated with anti PD-1 Validated in additional 63 patients Miao D, et al. Science. 2018;359:801-806. 50
The Future 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 6 9 0 6 9 PD-L1 <1% HR = 1.00 (0.74 1.36) 3 12 15 18 21 24 27 30 PD-L1 1% HR = 0.48 (0.28 0.82) 3 12 15 18 21 24 27 30 PBRM1 LOF mutations for PD-1 inhibitors Miao D, et al. Science. 2018;359:801-806. CheckMate 214 Motzer RJ, et al. N Engl J Med. 2018;378:1277-1290. TSC1/TSC2/mTOR for mtor inhibitors Kwiatkowski DJ, et al. Clin Cancer Res. 2016;22:2445-2452. 51
Conclusions Small steps toward precision IMDC criteria can be used PDL1 testing not helpful yet mrcc is still addicted to angiogenesis: importance of VEGF inh Patient selection is key for cytoreductive nephrectomy Biomarkers remain elusive, but stay tuned 52
THANK YOU! daniel.heng@ahs.ca @DrDanielHeng