Metastatic Renal Cell Cancer: Evidence Based Treatment Manuela Schmidinger Medical University of Vienna, Austria
Disclosures Honoraria for lectures or advisory boards from: Pfizer, Roche, BMS, Novartis, Ipsen, Astellas, AVEO, Exilixis, EISAI, Eusa Pharma
Topics First- and second-line treatment according to the current guidelines (ESMO 2016) First-and second-line treatment of mrcc in the near future (ESMO 2018 guidelines)
IMDC Risk Groups in mrcc 0 RF: favorable; 1-2 RF s: intermediate; 3+ RF s poor risk Heng DY et al., Lancet Oncol 2014
F I R S T L I N E S E C O N D L i n e 1 st -Line treatment NOW ESMO Clinical Practice Guidelines 2016*; CC-Good/ intermediate risk Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] Option: High-dose IL2 [III, C] Sorafenib [II, B] Bevacizumab + low-dose IFN [III, B] Post TKI s Nivolumab (IA) MCBS 5 Cabozantinib (IA) Option Axitinib (IIB) Everolimus (IIB) Sorafenib (IIIB) CC- Poor risk Standard: Temsirolimus [II, A] Non-cc Standard: Sunitinib [II, B] Favorable/intermediate Option: risk: use the agent your are Sunitinib [II, B] most Sorafenib familiar [III, B] with Poor risk: preference Pazopanib for VEGFR-TKI s [III, B] rather than temsirolimus Option: Temsirolimus [III, B] Sorafenib [III, B] Pazopanib [III, B] Everolimus [III, B] Escudier B, et al. Ann Oncol. 2016;27(suppl 5):v58-v68.
F I R S T L I N E S E C O N D L i n e 2 nd -Line treatment NOW ESMO Clinical Practice Guidelines 2016*; CC-Good/ intermediate risk Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] Option: High-dose IL2 [III, C] Sorafenib [II, B] Bevacizumab + low-dose IFN [III, B] Post TKI s Nivolumab (IA) MCBS 5 Cabozantinib (IA) Option Axitinib (IIB) Everolimus (IIB) Sorafenib (IIIB) CC- Poor risk Standard: Temsirolimus [II, A] Option: Sunitinib [II, B] Sorafenib [III, B] Pazopanib [III, B] Non-cc Standard: Sunitinib [II, B] Option: Temsirolimus [III, B] Sorafenib [III, B] Pazopanib [III, B] Everolimus [III, B] Escudier B, et al. Ann Oncol. 2016;27(suppl 5):v58-v68.
Treatment Options and Questions for 2 nd - Line Treatment Decisions 1. What is available and reimbursed in my country??? 2. Is all of this still appropriate in 2018??? Axitinib Sorafenib Cabozantinib Everolimus Nivolumab
What is appropriate for 2 nd -line 2018? Axitinib Sorafenib Choueriri T et al., New Engl J Med 2015 But... Motzer R et al., New Engl J Med 2015 Motzer RJ et al., Lancet 2015 1. Tamburini J et al., Blood 2009 2. Chiarini F et al., Cancer Res 2010 3. Kang SA et al., Science 2013 4. Gewirtz DA et al., Cancer Res 2014 Cabozantinib Everolimus Nivolumab Loser in three randomized trials CheckMate 025 METEOR HOPE Poor pro-apoptotic activity, being mainly cytostatic Do not target all mtorc1 outputs 1-4 S6K1-dependent feedback-loops that lead to reactivation of RTK, PI3K/Akt and Ras/Raf/MEK/ERK signaling 3
Progression-free Survival Randomized phase II trial: Lenvatinib+Everolimus vs Everolimus vs Lenvatinib 2 nd -Line 1.0 0.8 0.6 0.4 0.2 0.0 Number at risk Objective Response Lenvatinib/Everolimus (n = 51) Lenvatinib (n = 52) Everolimus (n = 50) Objective response rate, % 43 27 6 95% CI 29 58 16 41 1 17 Best overall response, % Complete 2 0 0 Partial 41 27 6 Stable disease 41 52 62 Progression 4 6 24 Not evaluated 12 15 8 Median duration of objective response, (months) 13.0 7.5 8.5 95% CI 3.7 NE 3.8 NE 7.5 9.4 NE, not estimable. Primary Endpoint: Progression-free Survival Lenvatinib/Everolimus vs Everolimus HR 0.40 (95% CI 0.24 0.68); P < 0.001 Lenvatinib vs Everolimus HR 0.61 (95% CI 0.38 0.98); P = 0.048 Median, mos (95% CI) Lenvatinib/Everolimus 14.6 (5.9 20.1) Lenvatinib 7.4 (5.6 10.2) Everolimus 5.5 (3.5 7.1) 0 3 6 9 12 15 18 21 24 Time (mos) Lenvatinib/Everolimus 51 41 27 23 16 10 5 1 0 Lenvatinib 52 41 29 20 11 6 4 1 0 Everolimus 50 29 15 11 7 3 1 0 0 Motzer RJ, et al. Lancet Oncology 2015; 16: 1473 1482
Progression-free survival (probability) What is appropriate for 2 nd -line 2018? Axitinib Sorafenib Cabozantinib Nivolumab AXIS: Axitinib significantly prolonged PFS versus sorafenib 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Subjects at risk, n Axitinib Sorafenib 0.0 0 2 4 6 8 10 12 14 16 18 20 Time (months) mpfs, months Axitinib 6.8 Sorafenib 4.7 95% CI 6.3 8.6 4.6 5.6 P<0.0001 (log-rank) Stratified HR 0.665 (95% CI :0.544 0.812) 361 256 202 145 96 64 38 20 10 1 0 362 224 157 100 51 28 12 6 3 1 0 Rini B, et al. ASCO 2011
Decision in second-line IO or TKI? Tyrosine kinase inhibition Restoring T-cell function by blocking PD-1-PD-L1 interaction Axitinib Cabozantinib 1 Nivolumab 2 Not investigated versus nivolumab or cabozantinib PFS in favorable risk population: 13.9 (95%CI 7.8-17.7) vs 4.7 (3.5-6.7) months 3 1.Choueiri T et l, New Engl J Med 2015 2.Motzer R et al., New Engl J Med 2015 3.Bracarda S et al., ASCO GU 2018, abstract 589 Significant benefits in ORR Just PFS another OS TKI? 60% dose reductions Significant benefits in ORR OS QoL
1) 2 nd -Line CABOZANTINIB How strong is the rationale for using a MET-AXL-VEGF-inhibitor in second line? Tumours first respond to VEGF(R)-inhibitors: stasis/ regression, loss of vasculature Induction of a hypoxic microenvironment 1 (occurrence of resistance, epithelial to mesenchymal transition) Various VEGF-independent mechanisms enable revascularisation and progression > Switching to an agent that does not primarily target VEGF VEGF=vascular endothelial growth factor Paez-Ribes M, et al. Cancer Cell 2009;15(3);220 231.
Cabozantinib: VEGF-MET-AXL inhibition Is additional HGF VEGF-inhibition provided by Gas6 Cabozantinib Cabozantinib MET necessary? Tumour cell VHL inactivation AXL Increased MET and AXL expression has been associated with poor prognosis and resistance to VEGFR inhibitors in VEGF Tumour progression 1,2 Growth, invasion, metastasis Resistance to VEGFR inhibition Tumour angiogenesis Cabozantinib is an oral, small molecule inhibitor of tyrosine kinases including MET, VEGF receptors and AXL 3,4 RCC 1,2 GAS6=growth arrest-specific 6; HGF=hepatocyte growth factor; RCC=renal cell carcinoma; VEGF=vascular endothelial growth factor; VEGFR=vascular endothelial growth factor receptor; VHL=von Hippel Lindau 1. Zhou L, et al. Oncogene 2016;35(21):2687 2697; 2. Ciamporcero E, et al. Mol Cancer Ther 2015;14(1):101 110; 3. Yakes FM, et al. Mol Cancer Ther 2011;10(12):2298 2308; 4. Choueiri TK, et al. New Engl J Med 2015;373(19):1814 1823.
Targeting MET-AXL and VEGF simultaneously is a strategy that addresses both: the mechanisms of (primary or secondary) resistance to VEGF-inhibition such as MET- AXL upregulation the potentially regained sensitivity of the tumor to VEGF, because resistance is of temporary nature 1.Hammers HJ, et al. Mol Cancer Ther 2010;9(6):1525 1535. 2. Zhou L, et al. Oncogene 2016;35(21):2687 2697; 3. Ciamporcero E, et al. Mol Cancer Ther 2015;14(1):101 110; 4. Yakes FM, et al. Mol Cancer Ther 2011;10(12):2298 2308;
METEOR: Cabozantinib versus Everolimus 1 Overall Survival Hazard ratio 0.66 (95% CI 0.53-0.83), P=0.0003 ASCO 2016 Median OS mo (95% CI) No. at Risk Cabozantinib 330 318 296 264 239 178 105 41 6 3 0 Everolimus 328 307 262 229 202 141 82 32 8 1 0 No. of Deaths Cabozantinib (N=330) 21.4 (18.7-NE) 140 Everolimus (N=328) 16.5 (14.7-18.8) 180 Cut-off: Dec 31, 2015 5 1. Choueiri T et al., New Engl J Med 2015
Mean change from baseline Worse Better 2) 2 nd -Line NIVOLUMAB CheckMate 025: Nivolumab versus Everolimus 1 CheckMate 025: HRQoL Mean change from baseline in HRQoL scores by FKSI-DRS: descriptive analysis Nivolumab 6 4 2 0-2 -4 Everolimus -6 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104 Number of patients at risk c b Treatment visit (week) 361 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20 Everolimus 343 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9 Adapted from Cella et al, 2016. a Significant improvement (P<0.05) from baseline in FKSI-DRS for nivolumab. b Significant improvement (P<0.05) in FKSI-DRS mean change from baseline scores between nivolumab and everolimus arms. c Significant deterioration (P<0.05) from baseline in FKSI-DRS for everolimus. Note:o ytimepoi ts heredata ereavai ab efor 5 patie ts arep oted. FKSI-DRS, Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms. Cella DF et al. Oral presentation at ASCO 2016. 4549. a c 139 Nivolumab Motzer RJ et al., New Engl J Med 2015
Can differences between studies help to make a treatment choice? CheckMate 025 and METEOR Comparator Population ORR and OS Disease specific details Similarities Both everolimus 71% and 72% were second line Both provide encouraging, clinically relevant and statistically significant ORR and OS outcomes Both studied in patients with bone metastases; both not studied in patients with brain metastases, non-cchistologies 1. Choueiri TK, et al. N Engl J Med 2015;373:1814 1823; 2. Choueiri TK, et al. Lancet Oncol 2016;17:917 927; 3. Motzer RJ, et al. N Engl J Med 2015;373:1803 1813. PFS Dose reduction Safety (all causality) MoA Differences Nivolumab does not significantly improve PFS, while cabozantinib provides a statistically significant superiority 60% of cabozantinib patients required dose reductions while no dose reductions were allowed in CheckMate025 However: 51% had dose delays/interruptions Cabozantinib: grades 3-4: 71% Nivolumab: grades 3-4: 53% Different targets ESMO 2017 ASK Meeting Internal Ipsen Do not distribute
Do we know yet when which mode of action is appropriate? Currently, the decision between TKI and Checkpoint inhibitor is subject to two phenomena Success even in melanoma TKI=tyrosine kinase inhibitor 1 2
Do we know yet when which mode of action is appropriate? 1) That immunotherapy should be given as early as possible Checkpoint inhibitors in metastatic renal cell carcinoma patients Results from the IMDC) 2 2) That response to first-line TKI may help to select treatment in second line Perception 1. Yip S, et al. J Clin Oncol 2017;35:(suppl. abstract 4580).
Patient GF: Treatment with cabozantinib after early progression on sunitinib Male patient, 66 years old, ECOG 0 March 2014: Nephrectomy ccrcc, pt3a, M1, G3 Synchronous skeletal metastasis, laminectomy Th3/Th4 April 2014: lung metastases, IMDC intermediate risk May 2014: Began first-line sunitinib, PFS 5 months October 2014: Began second-line cabozantinib, PFS 19 months Response to first-line TKI is a poor driver of treatment decision in second line
Can differences between studies help to make a treatment choice? CheckMate 025 and METEOR Comparator Population ORR and OS Disease specific details Similarities Both everolimus 71% and 72% were second line Both provide encouraging, clinically relevant and statistically significant ORR and OS outcomes Both studied in patients with bone metastases; both not studied in patients with brain metastases, non-cchistologies 1. Choueiri TK, et al. N Engl J Med 2015;373:1814 1823; 2. Choueiri TK, et al. Lancet Oncol 2016;17:917 927; 3. Motzer RJ, et al. N Engl J Med 2015;373:1803 1813. PFS Dose reduction Safety (all causality) MoA Differences Nivolumab does not significantly improve PFS, while cabozantinib provides a statistically significant superiority 60% of cabozantinib patients required dose reductions while no dose reductions were allowed in CheckMate025 However: 51% had dose delays/interruptions Cabozantinib: grades 3-4: 71% Nivolumab: grades 3-4: 53% Different targets ESMO 2017 ASK Meeting Internal Ipsen Do not distribute
Arguments against immunotherapy (few) When is IO less appropriate than a TKI? STRONG STRONG RATHER WEAK SHOULD BE FURTHER EXPLORED Significant difference between hyperprogressive disease and age: (66 vs 55; P=0.007) * 19% of patients older than 64 years vs 5% of patients younger than 64 * *Champiat S, et al. Clin Cancer Res 2016;23:1920 1928. WEAK
Arguments pro Immunotherapy When is IO more appropriate than a TKI?
Female patient: 63 years at diagnosis of mrcc, intermediate risk July 2013 TN right kidney: cc- RCC, pt3a, G2-3; L0, V0, R0, pnx November 2015: Nivolumab (NPP) Toxicities: 0 Complains about weight gain due to increased appetite: 7kg TKIs for metastasis in lung, mediastinal lymph nodes PFS on TKI: 21 months VEGFR-TKI- toxicities: Asthenia 3 Diarrhoea 3 Nausea 3 Last staging: December 2017, stable disease PFS Nivolumab: 25 months Excellent QoL
THE DISCUSSION ALONG TREATMENT CHOICE IN 2 ND -LINE IS GOING TO BE REDUNDANT SOON... DUE TO DRAMATIC CHANGES IN 1 ST -LINE
Topics First- and second-line treatment according to the current guidelines (ESMO 2016) First-and second-line treatment of mrcc in the near future (ESMO 2018 guidelines)
What do we need to know about the role of VEGFR-inhibitors in 1 st -Line mrcc? VEGF(R) Inhibitors haven been the 1 st -Line Standard of Care for the last 12 years They were approved based on a statistically significant benefit in PFS and ORR not based on survival benefits OS results would have been confounded anyway, due to cross over or access to a VEGF-inhibitor after progression Before 2017, Sunitinib has never been defeated by any other agent in a randomized phase III superiority trial
LBA5 CheckMate 214: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Sunitinib for Treatment-Naïve Advanced or Metastatic Renal Cell Carcinoma, Including IMDC Risk and PD-L1 Expression Subgroups Bernard Escudier, 1 Nizar M. Tannir, 2 David F. McDermott, 3 Osvaldo Arén Frontera, 4 Bohuslav Melichar, 5 Elizabeth R. CheckMate Plimack, 6 Philippe Barthelemy, 214: 7 Saby George, Study 8 Victoria Neiman, design 9 Camillo Porta, 10 Toni K. Choueiri, 11 Thomas Powles, 12 Frede Donskov, 13 Pamela Salman, 14 Christian K. Kollmannsberger, 15 Brian Rini, 16 Sabeen Mekan, 17 M. Brent McHenry, 17 Hans J. Hammers, 18 Robert J. Motzer 19 74% and 71% PD-L1 negative 1 Gustave Roussy, Villejuif, France; 2 University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA; 3 Beth Israel Deaconess Medical Center, Patients Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 4 Centro Treatment Internacional de Estudios Clinicos, Santiago, Chile; 5 Palacky University, and University Hospital Olomouc, Olomouc, Czech Republic; 6 Fox Chase Cancer Center, Philadelphia, PA, USA; 7 Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 8 Roswell Park Cancer Institute, Buffalo, Arm NY, A USA; 9 Davidoff Cancer Center, Rabin Medical Treatment-naïve Center, Petah Tikva, Israel, and Tel Aviv University, Tel Aviv, Israel; 10 IRCCS 3 mg/kg San Matteo nivolumab University Hospital IV + Foundation, Pavia, Italy; 11 Danaadvanced Farber or Cancer Institute, Brigham Randomize Women s Hospital, 1:1 and Harvard Medical School, Boston, MA, USA; 12 Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary 1 University mg/kg of ipilimumab London, Royal Free IV Q3W NHS Trust, London, UK; 13 Aarhus metastatic clear-cell University Hospital, Aarhus, Stratified Denmark; 14 by Fundación Arturo López Pérez, Santiago, for four Chile; doses, 15 British then Columbia Cancer Agency, Treatment Vancouver, BC, until RCC Canada; 16 Cleveland Clinic IMDC Taussigprognostic Cancer Institute, score Cleveland, OH, 3 mg/kg USA; 17 Bristol-Myers nivolumab Squibb, IV Princeton, Q2W NJ, USA; 18 progression Sidney Kimmel or Measurable Comprehensive disease Cancer Center, (0 vs 1 2 Johns vs Hopkins, 3 6) Baltimore, MD, USA; 19 Memorial Sloan Kettering Cancer Center, New York, NY, USA KPS 70% unacceptable Region (US vs Tumor tissue Canada/Europe vs toxicity available for PD-L1 Rest of World) Arm B testing 50 mg sunitinib orally once daily for 4 weeks (6-week cycles) Co-Primary EP:ORR, PFS OS in intermediate and poor risk (n=847) IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks Secondary EP: ORR, PFS, OS in ITT (includes favorable risk, n=249)) Exploratory EP: ORR, PFS, OS in favorable and PD-L1 pos. patients Escudier B et al., ESMO 2017 Madrid
Overall Survival (Probability) Progression-Free Survival (Probability) Duration of Response (Probability) Results Primary endpoints Co-primary endpoint: ORR ORR and DOR: IMDC intermediate/poor risk Median duration of response, Patients with ongoing Co-primary endpoint months (95% CI) response, % NIVO + IPI NR (21.8 NE) 72 SUN 18.2 (14.8 NE) 63 PFS per IRRC: IMDC intermediate/poor risk 1.0 N = 847 0.9 Median PFS, months (95% CI) NIVO + IPI SUN Outcome N = 425 N = 422 0.8 NIVO + IPI 11.6 (8.7 15.5) Confirmed ORR, a 1.0 % (95% CI) 42 Co-primary (37 47) 27 endpoint 0.7 SUN 8.4 (7.0 10.8) (22 31) 0.9 0.6 0.8 Hazard ratio (99.1% CI), 0.82 (0.64 1.05) P < 0.0001 0.5 P = 0.0331 Confirmed BOR, a 0.7 % OS: IMDC intermediate/poor risk 0.6 Complete response 9 b 1 b 0.4 0.5 Partial response 32 25 0.3 0.4 Stable disease 31 45 Median OS, months (95% CI) 0.2 0.3 Progressive disease 20 17 0.1 NIVO + IPI NR (28.2 NE) 0.2 Unable to determine/not reported 8 12 0.1 1.0 0.0 SUN 26.0 (22.1 NE) 0.0 0 6 12 18 24 0.9 No. at Risk Months airrc-assessed ORR and 0BOR by RECIST 3 v1.1; b P < 60.0001 9 12 15 18 21 24 27 30 NIVO + IPI 177 146 120 55 3 No. at Risk 0.8 Months NIVO + IPI 425 304 233 187 SUN 163 112 149 118 75 46 52 17 17 3 0 0 P < 0.0001 0.7 SUN 422 282 191 139 107 86 57 33 11 1 0 0.6 Escudier B et al., Presidential Session ESMO 0.5 2017 0.4 0.3 0.2 0.1 0.0 No. at Risk NIVO + IPI SUN 0 3 6 9 12 Hazard ratio (99.8% CI), 0.63 (0.44 0.89) 15 18 21 24 27 30 33 Months 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., ESMO 2017 Madrid
Progression-Free Survival (Probability) Results exploratory endpoints Exploratory endpoint 0.6 0.5 0.4 No. at Risk PFS by PD-L1 expression: IMDC intermediate/poor risk PD-L1 <1% (n = 562) PD-L1 1% (n = 214) Median PFS, months (95% CI) 1.0 NIVO + IPI 11.0 (8.1 14.9) SUN 10.4 (7.5 13.8) 0.9 HR (95% CI) 1.00 (0.74 1.36) 0.8 P = 0.9670 Exploratory 0.7 endpoint 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 Months NIVO 284 202 155 119 102 90 70 23 9 1 0 SUN 278 200 138 105 83 67 43 25 11 1 0 Outcome 1.0 0.9 0.8 0.7 Median PFS, months (95% CI) NIVO + IPI 22.8 (9.4 NE) SUN 5.9 (4.4 7.1) HR (95% CI) 0.48 (0.28 0.82) P = 0.0003 0.6 0.5 0.4 ORR and 0.3 PFS: IMDC favorable risk 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 Months 100 77 61 54 50 48 41 21 8 2 0 114 63 40 24 17 13 9 4 0 0 3 Exploratory endpoint Antitumor activity by tumor PD-L1 expression level Outcome NIVO + IPI N = 284 IMDC intermediate/poor risk Intention to treat PD-L1 <1% PD-L1 1% PD-L1 <1% PD-L1 1% SUN N = 278 NIVO + IPI N = 100 SUN N = 114 NIVO + IPI N = 386 SUN N = 376 NIVO + IPI N = 113 SUN N = 127 ORR, a % (95% CI) 37 (32 43) 28 (23 34) 58 (48 68) 22 (15 31) 36 (31 41) 35 (31 40) 53 (44 63) 22 (15 30) PFS, c median (95% CI), months P = 0.0252 15.3 (9.7 20.3) P < 0.0001 P = 0.879925.1 (20.9 NE) P < 0.0001 BOR, a % Complete response 7 1 HR 16 (99.1% 1 CI) 2.18 9 (1.29 3.68) 2 14 1 Partial response 30 27 42 21 27 33 39 21 Stable disease 36 47 19 40 39 43 25 43 Progressive disease 20 13 14 25 P < 0.0001 18 11 14 23 NA 7 12 9 13 7 11 8 13 a IRRC-assessed NIVO + IPI N = 125 Escudier B et al., ESMO 2017 Madrid N = 249 a SUN N = 124 Confirmed ORR, b % (95% CI) 29 (21 38) 52 (43 61) P = 0.0002
F I R S T L I N E ESMO Clinical Practice Guidelines 2018?*; Good risk Clear cell histology Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] Tivozanib Option: High-dose IL2 [III, C] Sorafenib [II, B] Bevacizumab + low-dose IFN [III, B] Intermediate/Poor risk Standard: Nivolumab+Ipilimumab Cabozantinib Option: Temsirolimus [II, A] Sunitinib [II, B] Sorafenib [III, B] Pazopanib [III, B] Non clear cell histology Standard: Sunitinib [II, B] Option: Temsirolimus [III, B] Sorafenib [III, B] Pazopanib [III, B] Everolimus [III, B] ESCUDIER B ET AL.,
F I R S T L I N E ESMO Clinical Practice Guidelines 2018?*; Good risk Clear cell histology Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] Option: High-dose IL2 [III, C] Sorafenib [II, B] Bevacizumab + low-dose IFN [III, B] Heng DY et al., Lancet Oncol 2014 Intermediate/Poor risk Standard: Nivolumab+Ipilimumab Option: Temsirolimus [II, A] Sunitinib [II, B] Sorafenib [III, B] Pazopanib [III, B] Is the patient population clear cut?
F I R S T ESMO Clinical Practice Guidelines 2018?*; Good Risk Clear cell histology Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] L I Option: N High-dose IL2 [III, C] Median E PFS: Sorafenib [II, B] Bevacizumab + low-dose Cabo: 8.2 months IFN [III, B] 95%CI, 6.2 to 8.8 months) Sun: 5.6 months (95%CI, 3.4 to 8.1) Adjusted HR for progression: 0.66, 95%CI 0.46-0.95; p=0.012 1. Choueiri TK et al., J Clin Oncol 2016; Intermediate/Poor risk Standard: Nivolumab+Ipilimumab Cabozantinib Option: Temsirolimus [II, A] Sunitinib [II, B] Sorafenib [III, B] Pazopanib [III, B] Nivo+Ipi is not the only option for intermediate and poor risk
F I R S T L I N E ESMO Clinical Practice Guidelines 2018?*; CC-Good risk Standard: Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] Option: High-dose IL2 [III, C] Sorafenib [II, B] Bevacizumab + low-dose IFN [III, B] Sunitinib better than Nivo+Ipi, but: Do these patients need immediate treatment at all? Phase II study on observation: median time on observation: 14.9 months (95% CI 10.6 25.0) 1,2 Confirmed retrospectively in 2716 patients 2 Are established TKI s the best option? Tivozanib approved 2017: highly potential VEGFR-TKI, few toxicities Is Nivo+Ipi never an option in favorable risk? What about favorable risk+pd-l1 expression (11% in 214)? PD-L1 expression predicts poor outcome from TKI 3 : should we offer a TKI or Nivo+Ipi in these 11%? 1.Rini BI et al., Lancet Oncol 2016; 2.Woldu SL et al., ASCO GU 2018, abstract 586; 3. Choueiri TK et al., Clin Cancer Res 2015
The near future is not only about Nivo+Ipi versus TKI: multiple combination trials (CPI+anti-VEGF) under way Rationale: CPI s T-cell mediated cancer cell killing may be enhanced Rationale through important for properties Combining of anti-vegf(r)-agents Atezolizumab + Bevacizumab Promotion of T-cell priming and activation via dendritic cell maturation 1-2 3. Priming and activation (APCs and T cells) 2. Cancer antigen presentation (dendritic cells/apcs) 1. Release of cancer cell antigens (cancer cell death) 4. Trafficking of T cells to tumors (CTLs) 7. Killing of cancer cells (immune and cancer cells) 5. Infiltration of T cells into tumors (CTLs, endothelial cells) 6. Recognition of cancer cells by T cells (CTLs, cancer cells) Normalization of the tumor vasculature for increased T-cell tumor infiltration 3-6 Establishing an immune-permissive tumor microenvironment by decreasing MDSC and Treg populations 6-10 Atezolizumab s T-cell mediated cancer cell killing may be enhanced through bevacizumab s reversal of VEGF-mediated immunosuppression 1. Gabrilovich DI, et al. Nat Med, 1996. 2. Oyama T, et al. J Immunol, 1998. 3. Goel S, et al. Physiol Rev, 2011. 4. Motz GT, et al. Nat Med, 2014. 5. Hodi FS, et al. Cancer Immunol Res, 2014. 6. Wallin JJ, et al. Nat Commun, 2016. 7. Gabrilovich DI, Nagaraj S. Nat Rev Immunol, 2009. 8. Roland CL, et al. PLoS One, 2009. 9. Facciabene A, et al. Nature, 2011. 10. Voron T, et al. J Exp Med, 2015. Figure Presented by: Dr. Robert Motzer adapted from Chen DS, Mellman I. Immunity, 2013. 1. Gabrilovich DI, et al. Nat Med, 1996. 2. Oyama T, et al. J Immunol, 1998. 3. Goel S, et al. Physiol Rev, 2011. 4. Motz GT, et al. Nat Med, 2014. 5. Hodi FS, et al. Cancer Immunol Res, 2014. 6. Wallin JJ, et al. Nat Commun, 2016. 7. Gabrilovich DI, Nagaraj S. Nat Rev Immunol, 2009. 8. Roland CL, et al. PLoS One, 2009. 9. Facciabene A, et al. Nature, 2011. 10. Voron T, et al. J Exp Med, 2015. Figure adapted from Chen DS, Mellman I. Immunity, 2013. 3
Combinations: highly promising... Pembro+ axi Avelumab+ axi...but they will raise more questions than answers, biased by sponsor (huge investment, urgent need for both a positive study for approval Pembro+ Lenvatinib Atezo+ bev n 52 45 30 101 14 CR% 5.8 5.5 0 7 0 PR% 65.4 52.7 63 25 64 ORR% 73.1 58.2 63 32 64.3 ASCO GU 2018 Nivo+Tivo a favorable profile within the competitor combos (> multiple endpoints...) Will not answer the questions: does every patient need a combo, which combo? Should we treat based on IMDC risk group, PD-L1 status...? Atkins MB et al., ASCO GU 2018, abstract 579 Choueiri T et al., J Clin Oncol 35, 2017 (suppl abstract 4504); Motzer RJ et al., ASCO GU 2018, abstract TPS 706 Motzer RJ et al., ASCO GU 2018, abstract 578 Escudier B et al., ASCO GU 2018, abstract 618 None of the above combinations are approved in 1L mrcc
The future of prediction? Treatment decisions based on the individual immunophenotype Kim JM et al., Ann Oncol 2016
Future Second-Line Decisions are going to be challenging After 1 st -line Nivo-Ipi After 1 st -line Combo VEGF-i+ PD(L)1-CPI After 1 st -line TKI Which TKI Sunitinib? Tivozanib? Axitinib? Cabozantinib? Any? Nivo+Ipi? TKI with more than VEGFinhibitory activity? (Cabo, Lenvatinib+Eve)? Is Nivo Mono appropriate at all after CheckMate 214??? After Sun/Tivo>TKI with more than VEGFinhibitory activity? (Cabo, Lenva+Eve)?
Conclusions After the introduction of targeted therapy 12 years ago, we now witness another paradigm shift in the treatment of mrcc: introduction of immune check point inhibitors and combinations Results from combination trials using either another CPI or targeted therapy are highly encourging, particularly with respect to the CR rate It is currently unknown 1) which combination is best; 2) which population; 3) whether combination or sequencing of novel agents provides more benefit; 4) if the type of sequence matters The future: treatment decisions based on the individual immunophenotype, transcriptom-profiling?