Renal Cell Carcinoma: Navigating a Maze of Choices

Transcription

1 Renal Cell Carcinoma: Navigating a Maze of Choices Sumanta Kumar Pal, M.D. Associate Professor Department of Medical Oncology & Experimental Therapeutics Co-Director, Kidney Cancer Program City of Hope Comprehensive Cancer Center August 11, 2018

2 Disclosures Relevant financial relationships in the past twelve months by presenter or spouse/partner. Consultant: Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, BMS, Astellas speakers bureau: Genentech The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

3 Debates in RCC Therapy Is HD IL-2 appropriate for everyone? Sunitinib or sorafenib? Everolimus or sorafenib? Cabozantinib, nivolumab or lenvatinib/ everolimus? Goals of therapy: 1. Live longer (ideally with a cure!) 2. Live better First Line Debate Temsirolimus for poor risk? Axitinib or everolimus? Nivo/ipi or cabozantinib or bev/atezo? Second Line Debate

4 A Banner Year for Immunotherapy in RCC ESMO 2017: Nivolumab/Ipilimumab vs Sunitinib Primary Analysis SITC 2017: Nivolumab/Ipilimumab vs Sunitinib Subset Analysis GUCS 2018: Bevacizumab/Atezolizumab vs Sunitinib Primary Analysis

5 CheckMate 214: Study design Treatment-naïve advanced or metastatic clear-cell RCC Measurable disease KPS 70% Tumor tissue available for PD-L1 testing Patients Randomize 1:1 Stratified by IMDC prognostic score (0 vs 1 2 vs 3 6) Region (US vs Canada/Europe vs Rest of World) Treatment Arm A 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for four 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 Escudier et al ESMO 2017

6 Overall Survival (Probability) Co-primary endpoint OS: IMDC intermediate/poor risk Median OS, months (95% CI) NIVO + IPI NR (28.2 NE) No. at Risk NIVO + IPI SUN 0 Outcome 3 6 NIVO + IPI N = N = 847 SUN N = 422 Confirmed ORR, a % (95% CI) 42 (37 47) 27 (22 31) Confirmed BOR, a % Complete response Partial response Stable disease Progressive disease Unable to determine/not reported 9 b P < b SUN 26.0 (22.1 NE) Hazard ratio (99.8% CI), 0.63 ( ) P < Months Escudier et al ESMO 2017

7 Exploratory endpoint ORR and PFS: IMDC favorable risk N = 249 a Outcome NIVO + IPI N = 125 SUN N = 124 Confirmed ORR, b % (95% CI) 29 (21 38) 52 (43 61) P = PFS, c median (95% CI), months 15.3 ( ) 25.1 (20.9 NE) HR (99.1% CI) 2.18 ( ) P < Escudier et al ESMO 2017

8 Patient disposition: All treated patients NIVO + IPI N = 547 SUN N = 535 Treatment discontinuation, % Reasons for treatment discontinuation, % Disease progression Study drug toxicity Adverse event unrelated to study drug Other Median duration of therapy (95% CI), months 7.9 ( ) 7.8 ( ) Median doses received (range), no. Nivolumab Ipilimumab 14 (1 63) 4 (1 4) NA NA Median daily dose (range), mg/day NA 31 (14 50) In the NIVO + IPI arm, 79% of patients received all four doses of IPI Median follow-up was 25.2 months Escudier et al ESMO 2017

9 Secondary endpoint Treatment-related adverse events: All treated patients NIVO + IPI N = 547 SUN N = 535 Event, % Any grade Grade 3 5 Any grade Grade 3 5 a Treatment-related adverse events in 25% of patients Fatigue Pruritus 28 <1 9 0 Diarrhea Nausea 60% of patients treated with NIVO 20 + IPI required 2 systemic 38 1 Hypothyroidism corticosteroids for an 16 adverse <1 event 25 <1 Decreased appetite Dysgeusia <1 Stomatitis Hypertension 2 < Mucosal inflammation Palmar-plantar erythrodysesthesia syndrome Treatment-related AEs leading to discontinuation, % Treatment-related deaths n = 7 b n = 4 c a Two patients had grade 5 cardiac arrest. b Pneumonitis, immune mediated bronchitis, lower GI hemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. c Cardiac arrest (n = 2), heart failure, multiple organ failure Escudier et al ESMO 2017

10 Progression-Free Survival (Probability) Exploratory endpoint PFS by PD-L1 expression: IMDC intermediate/poor risk PD-L1 <1% (n = 562) PD-L1 1% (n = 214) Median PFS, months (95% CI) Median PFS, months (95% CI) NIVO + IPI 11.0 ( ) SUN 10.4 ( ) HR (95% CI) 1.00 ( ) P = NIVO + IPI 22.8 (9.4 NE) SUN 5.9 ( ) HR (95% CI) 0.48 ( ) P = No. at Risk NIVO SUN Months Months

11 Overall Survival (Probability) Motzer et al SITC OS by tumor PD-L1 expression: IMDC intermediate/poor risk PD-L1 <1% (n = 562) PD-L1 1% (n = 214) Median OS (95% CI), months NIVO + IPI NR (28.2 NE) SUN NR (24.0 NE) HR (95% CI), 0.73 ( ) P = Median OS (95% CI), months NIVO + IPI SUN NR (NE NE) 19.6 (14.8 NE) HR (95% CI), 0.45 ( ) P < No. at Risk Months NIVO + IPI SUN Months

12 A Banner Year for Immunotherapy in RCC ESMO 2017: Nivolumab/Ipilimumab vs Sunitinib Primary Analysis SITC 2017: Nivolumab/Ipilimumab vs Sunitinib Subset Analysis GUCS 2018: Bevacizumab/Atezolizumab vs Sunitinib Primary Analysis

13 Study Design Key Eligibility: Treatment-naive advanced or metastatic RCC Clear cell and/or sarcomatoid histology KPS 70 Tumor tissue available for PD-L1 staining Stratification: MSKCC risk score Liver metastases PD-L1 IC IHC status (< 1% vs 1%) a N = 915 R 1:1 Atezolizumab 1200 mg IV q3w b + Bevacizumab 15 mg/kg IV q3w b Sunitinib 50 mg/day orally (4 wk on, 2 wk off) a 1% IC: 40% prevalence using SP142 IHC assay; b No dose reduction for atezolizumab or bevacizumab. Presented by: Dr. Robert Motzer 13

14 PFS (PD-L1+ & ITT) Co-Primary Endpoint 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 Median PFS, mo (95% CI) Atezo + Bev 11.2 (9.6, 13.3) Sunitinib 8.4 (7.5, 9.7) HR, 0.83 (95% CI: 0.70, 0.97) Consistent PFS results in PD-L1+ & ITT population by investigator review. PFS assessed by investigators. Minimum follow-up, 12 mo. Median follow-up, 15 mo. Presented by: Dr. Robert Motzer 14

15 Objective Response Rate Secondary Endpoint Confirmed ORR, % 95% CI Atezo + Bev n = % (35, 50) PD-L1+ Sunitinib n = % (28, 42) Complete response 9% 4% Partial response 34% 30% PD-L1+ Median DOR, mo (95% CI) Ongoing Responders, n (%) Atezo + Bev NR (12.4, NR) 49 (65%) Sunitinib 12.9 (9.8, NR) 34 (53%) Higher CR rates than associated with VEGF-TKIs. Stable disease 32% 35% Progressive disease 19% 21% Not evaluable a 7% 10% NR, not reached. a Including patients with no post-baseline tumor assessment. ORR assessed by investigators in patients with measurable disease at baseline. Minimum follow-up, 12 mo. Median follow-up, 15 mo. Presented by: Dr. Robert Motzer 15

16 Treatment-related AEs > 5% difference between arms and 20% frequency in either arm Atezo + Bev Sunitinib Secondary Endpoint Diarrhea PPE Hypertension Fatigue Nausea Dysgeusia Decreased appetite Mucosal inflammation Stomatitis Asthenia Discontinuation rate due to AEs lower with bev/atezo; 16% of patients required steroids. Vomiting Proteinuria All-grade AEs Grade 3-4 AEs All-grade AEs Grade 3-4 AEs 60% 50% 40% 30% 20% 10% 0 10% 20% 30% 40% 50% 60% PPE, palmar-plantar erythrodysesthesia. Presented by: Dr. Robert Motzer 16

17 PFS and ORR by IRC Secondary Endpoint Median PFS, mo (95% CI) Stratified HR (95% CI) Confirmed ORR, % (95% CI) Atezo + Bev n = (6.9, 12.5) 36% (29, 44) PD-L1+ PD-L1- a ITT 0.93 (0.72, 1.21) Sunitinib n = (6.1, 11.1) 33% (26, 40) Atezo + Bev n = (8.3, 13.3) 32% (26, 37) 0.84 (0.67, 1.04) Sunitinib n = 277 b 8.4 (7.4, 10.1) 30% (25, 36) Atezo + Bev n = (8.3, 11.5) 33% (29, 38) 0.88 (0.74, 1.04) Sunitinib n = (7.0, 9.7) 31% (27, 36) CR rate 15% 8% 8% 6% 11% 7% IRC and INV assessment of PFS benefit was generally consistent in the ITT population; however, results differed from INV assessment in patients with PD-L1+ disease Investigators, IRC reviewers and the sponsor were blinded to PD-L1 status a PD-L1 negative tumors had a PD-L1 IC IHC expression < 1%. b n = 276 for ORR. Presented by: Dr. Robert Motzer 17

18 Overall Survival in ITT & PD-L1+ Co-Primary Endpoint Atezo + Bev Sunitinib ITT Median OS, mo (95% CI) Not reached Not reached HR, 0.81 (95% CI: 0.63, 1.03) P = 0.09 PD-L1+ Median OS, mo (95% CI) Atezo + Bev Not reached Sunitinib 23.3 (21.3, NR) HR, 0.68 (95% CI: 0.46, 1.00) OS data are immature; 29% of patients had an OS event at data cutoff OS data are immature; 30% of patients had an OS event at data cutoff Minimum follow-up, 12 mo. Median of follow-up, 15 mo. Event/patient ratio: 27% for atezo + bev, 31% for sunitinib. The OS analysis did not pass the P value boundary of alpha = at the first interim analysis. Presented by: Dr. Robert Motzer 18

19 Immotion151 vs CheckMate214 CheckMate214 Immotion151 Duration of doublet therapy Toxicity Benefit across risk strata Mature OS data Impressive CR rate Impressive CR rate OS trend PFS EP positive

20 Immotion151 vs CheckMate214 CheckMate214 Immotion151

21 Probability of PFS Choueiri et al ESMO 2017 PFS per IRC and Overall Survival Median PFS No. of Events Cabozantinib (N=79) 8.6 mo 43 Sunitinib (N=78) 5.3 mo 49 HR=0.48 (95% CI: ), p= (2-sided) Subgroup Analyses of PFS per IRC No. at risk Cabozantinib Sunitinib Time Since Randomization (Months) Data cutoff : PFS, Sep 15, 2016; OS, July 1, 2017; IRC, Independent Review Committee; IMDC, International Metastatic RCC Database Consortium. Favors cabozantinib Favors sunitinib Overall Survival (OS) HR=0.80 (95% CI: ); p=0.29 (2-sided) Median OS: Cabozantinib 26.6 mo, Sunitinib 21.2 mo 21

22 Algorithm incorporating emerging first-line options Treatment First-Line Second-Line Good risk Bevacizumab/Atezolizumab Cabozantinib Cabozantinib* Nivolumab Intermediate/Poor-risk CHMP ruled against Bevacizumab/Atezolizumab approval of nivolumab/ipilimumab! Cabozantinib Nivolumab/Ipilimumab Cabozantinib* Nivolumab * For special populations (e.g., bony metastatic disease)

23 Beyond the current debate Is HD IL-2 appropriate for everyone? Sunitinib or sorafenib? Everolimus or sorafenib? Cabozantinib, nivolumab or lenvatinib/ everolimus? TKI + PD-1/-L1 Ab? First Line Debate Temsirolimus for poor risk? Axitinib or everolimus? Nivo/ipi or cabozantinib or bev/atezo? Second Line Debate

24 Does biology matter? Agent Immunomodulatory Properties Sunitinib Reduces peripheral MDSCs, reverses type 1 T-cell suppression, decreases Tregs Pazopanib Prompts evolution of MDSC subtype; non-responders have elevated MDSCs Axitinib Biology may matter, but we will have clinical data regardless. Induces differentiation of monocytic MDSCs toward an antigen-presenting phenotype Cabozantinib Induces tumor cell death via CXCR4-dependent neutrophil recruitment Bevacizumab Decreases peripheral Tregs 1 Ko et al CCR 2009; 2 Pal et al J Urol 2015; 3 Du Four et al Oncoimmunol 2015; 1 Patnaik et al Cancer Disc 2017; 3 Thomas et al Cancer Immunol Immunother 2017

25 % Progression Free % Progression Free % Progression Free Objective of combination therapy TKI IO TKI + IO? Time Time Time

26 Axitinib + Pembrolizumab * Stable disease or partial response not confirmed, or no follow-up scans available. ORR=objective response rate Presented by: Michael B Atkins, MD 26

27 Axitinib + Pembrolizumab Median time to response was 2.8 months (range ) Median duration of tumor response was 18.6 months (95% CI 15.1 not reached) Median PFS 20.9 months (95% CI 15.4 NE) Median OS NR CI=confidence interval; PD=progressive disease Presented by: Michael B Atkins, MD 27

28 Cabozantinib/Nivolumab +/- Ipilimumab Presented by: Dr. Rosa Nadal (PI: Dr. Andrea Apolo) 28

29 Tivozanib + Nivolumab Presented by: Dr. Bernard Escudier 29

30 The current landscape Motzer et al ASCO GU 2018; Lee et al ESMO 2017; Choueiri et al ASCO 2017; Atkins et al ASCO GU 2018; Nadal et al ASCO GU 2018

31 Define Recommend Dose Understanding activity of PD-L1 inhibitors in rare subtypes Cabozantinib with Atezolizumab Dose Expansion RCC with clear cell histology who have not received prior systemic anticancer therapy Dose escalation UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy, or RCC (clear cell, non-clear cell) with or without prior systemic anticancer therapy UC with progression on or after platinumcontaining chemotherapy UC not eligible for cisplatin-based chemo and no prior platinum-based chemotherapy UC eligible for cisplatin-based chemotherapy with no prior platinum-based chemotherapy We need you! Dose Escalation in ncrcc Planned NCT : A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors

32 Phase III Assessments of VEGF + CPI Combinations in RCC Control Sunitinib Sunitinib Sunitinib Sunitinib Sunitinib Sunitinib Comparator Nivolumab/Ipilimumab Bevacizumab + Atezolizumab Axitinib + Pembrolizumab Lenvatinib + Everolimus vs Lenvatinib/Pembrolizumab Axitinib + Avelumab Cabozantinib/Nivolumab

33 Sunitinib Nivolumab Could increasing crossover from sunitinib to nivolumab blunt OS? Margin of benefit in OS ~20% of patients on control arm crossed over from sunitinib to nivolumab in Immotion151 Time

34 Forthcoming Phase III Trials

35 Beyond the current debate Is HD IL-2 appropriate for everyone? Sunitinib or sorafenib? Everolimus or sorafenib? Cabozantinib, nivolumab or lenvatinib/ everolimus? TKI + PD-1/-L1 Ab? First Line Debate Temsirolimus for poor risk? Axitinib or everolimus? Nivo/ipi or cabozantinib or bev/atezo? Second Line Debate Future Debates: Will adjuvant therapy change the preferred upfront regimen?

36 My Take on Adjuvant Therapy with VEGF inhibitors S-TRAC shows benefit in DFS balanced with duration of treatment Favors Adjuvant Therapy Favors Observation PROTECT and ASSURE fail to meet primary endpoint No study shows a compelling signal of OS benefit Motzer et al J Clin Oncol 35, 2017 (suppl; abstr 4507)

37 1:1 Randomization Adjuvant Immunotherapy for RCC? Atezolizumab Adjuvant (An SUO-CTC Trial) Key Eligibility (n=664) High risk OR limited metastasis s/p metastasectomy s/p nephrectomy 12 weeks No evidence of residual disease Clear cell or sarcomatoid histology Stratification Factors Disease stage (T2/T3a vs. T3b/c/T4/N+ vs metastasectomy) PD-L1 (IC0 vs IC1/2/3) Region (US/Canada vs ROW) Atezolizumab 1200 mg IV q3wk x 16 cycles Placebo q3wk x 16 cycles We need you! NCT : A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection

38 Beyond the current debate Is HD IL-2 appropriate for everyone? Sunitinib or sorafenib? Everolimus or sorafenib? Cabozantinib, nivolumab or lenvatinib/ everolimus? TKI + PD-1/-L1 Ab? First Line Debate Temsirolimus for poor risk? Axitinib or everolimus? Nivo/ipi or cabozantinib or bev/atezo? Second Line Debate Future Debates: 1. Role for VEGF or IO alone? 2. Non clear cell disease? 3. Focus on optimizing VEGF-directed therapy?

39 KEYNOTE-427: A role for CPI monotherapy? McDermott et al ASCO 2018

40 KEYNOTE-427: A role for CPI monotherapy? McDermott et al ASCO 2018

41 SWOG 1500 for mprcc PI: S. Pal (City of Hope) Translational PI: B. Shuch (Yale) BISQFP funding for genomic characterization Requires 41 pts/arm 164 pts total Assuming 10% ineligibility 180 pts total We need you! NCT : A Randomized, Phase II Efficacy Assessment of Multiple MET Kinase Inhibitors (Cabozantinib [NSC #761968], Crizotinib [NSC #749005], Savolitinib [NSC #785348], and Sunitinib [NSC #736511]) in Metastatic Papillary Renal Carcinoma (PAPMET)

42 HOPE 218: An FDA Mandated Study (PI: Pal) N = 306 Key Inclusion Criteria Advanced clear cell RCC Progression on/after 1 prior VEGF-targeted treatment Prior PD-1/PD-L1 inhibitor treatment is allowed Measurable disease KPS 70 R 1:1 Lenvatinib 18 mg qd + Everolimus 5 mg qd Lenvatinib 14 mg qd + Everolimus 5 mg qd Heng (Calgary) Puente (Spain) On Cycle 2 Day 1: Lenvatinib will be escalated to 18 mg qd if no intolerable G2 or G3/G4 AEs or SAEs are observed in the first 28 days Stratification by: MSKCC prognostic groups (favorable, intermediate and poor risk) Prior PD-1/PD-L1 treatment (yes, no) 42

43 Thank you! City of Hope / Beckman Research Institute Tanya Dorff, MD (Head, GU Medical Oncology) Ravi Salgia, MD (Chair,Medical Oncology) GU Fellows: Paulo Bergerot, MD; Cris Bergerot, PsyD; Nazli Dizman, MD; Jacob Adashek; Meghan Salgia Feel free to or call me for trials!