New strategies and future of target therapy in advanced kidney cancer
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1 New strategies and future of target therapy in advanced kidney cancer
2 VHL Gene Inactivation VHL Complex Disrupted VHL Protein HIF1-a, HIF2-a Accumulation VEGF PDGF TGF-α, CXCR4 Angiogenesis Endothelial stabilization Autocrine Growth Stimulation
3 Other Recurrent Mutations/Alterations Histone modification gene mutatations SETD2 (histone H3 methyltransferase) JARID1C (histone H3 demethylase) UTX (histone H3 demethylase) Chromatin remodeling complex mutations PBRM1 Ubiquitin E3 ligase complex alterations SPOP overexpression in 99% ccrcc Dalgliesh, et al; Nature, 2010 Varela, et al; Nature, 2011 Liu, et al, Science, 2009
4 Proportion Surviving Not All Patients With mrcc Are The Same Risk factors are: no prior nephrectomy KPS <80 low HGB high corrected calcium high LDH 0 risk factors (164 patients, 30 alive) 1 or 2 risk factors (348 patients, 23 alive) 3, 4, or 5 risk factors (144 patients, 1 alive) Years Following Systemic Therapy Motzer et al JCO; 17:
5 RCC Algorithm: 2011 Setting Prognosis Therapy (Level 1) Other Options ( Level 2) Untreated Good or Intermediate Risk Poor Risk Sunitinib Bev./IFNA Pazopanib Temsirolimus Observation HD IL2 Sorafanib Other VEGF pathway inhib. Cytokine Sorafanib Pazopanib Other VEGF pathway inhib. Previously Treated VEGFR TKI Everolimus Other VEGF pathway inhib. Temsirolimus mtor inhib. VEGF pathway inhib.
6 TREATMENT - METASTATIC: IL2 Cytokine Working Group trial HD IL2 vs sc IL2/IFNA HD IL2: 600,000 IU/kg q8 o x 14 doses sc IL2/IFNA: 5 x 10 6 IU/m 2 4d/wk IL2; 5 x10 6 IU/m 2 2d/wk sc IL2/IFNA HD IL2 Pt number Deaths 1 1 CR 3 8 (p= 0.21) PR 6 14 Resp. Duration 15 mo 24 mo (p=0.18) Med. Surv. 13 mo 17 mo (p = 0.21) Durable 3 yr CR 0 7 (p=0.01) Selection criteria Non-clear cell have minimal to no benefit Suggestion that post-vegfr TKI treatment has higher toxicity and lower efficacy
7 VEGF Pathway Targeted Therapy AG X Sunitinib Sorafenib Pazopanib Axitinib X X Molecular Targets : TKI s * Also inhibits c-raf
8 Kinase Interaction Map Sorafenib Sunitinib Karaman, et al Nature Biotech. 26:127, 2008
9 Available VEGF Pathway Inhibitors Agent(s) Comparator Context of Definitive Trial(s) No Prior Therapy Bevacizumab/IFNA IFNA X Sunitinib IFNA X Prior IL2 or IFNA Sorafenib Placebo X Pazopanib Placebo X X Prior VEGF Pathway Axitinib* Sorafenib X Tivozanib* Sorafenib X X *Data pending
10 Other VEGFR/PDGFR Inhibitors AG (Axitinib, Pfizer) Phase II previously untreated: RR = 46% Phase II sorafenib refractory patients: RR = 23% (Rini, JCO, 2009) Phase III vs sorafenib in sunitinib refractory pts positive AZ2171 (Cedirinib, Astra-Zeneca) Phase II previously untreated: RR = 38% AV-951 (Tivozanib, Aveo) Phase II previously untreated: RR = 35% Phase III vs sorafenib in progress (1 st line) Your favorite drug company Has at least 1 VEGFR/PDGFR inhibitor on the shelf
11 Prognostic Factors With VEGF Pathway Targeted Therapy 645 pts, therapy naïve, 3 US/4 Canadian centers Median OS: 22 mo Independent prognostic factors for OS Hgb < LLN Corrected Ca > ULN Karnofsky PS < 80% Interval since diagnosis <1 yr Neutrophils > ULN Plt > ULN Overall survival (median) 0 factors: > not reached (75% >2 yr) 1-2 factors: 27 months 3-6 factors: 9 months Heng, et al, JCO 2009
12 CALGB Eligibility Criteria Confirmed metastatic RCC with a component of clear cell histology Karnofsky PS 70% ST RA TIF Y RA ND O MI ZE IFNA 9 MU TIW Measurable or evaluable disease (by RECIST) IFNA 9 MU TIW + No prior systemic treatment Adequate end-organ function Bevacizumab 10 mg/kg IV q d1 and d15 No CNS metastases BP < 160/90 with meds No DVT within 1 year or arterial thrombotic event within 6 months Prior nephrectomy not required Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)* * Motzer R et al., JCO 20(1), 2002
13 Kaplan-Meier Progression-Free Survival Progression-Free Survival Probability INF BEV/IFN, Stratified log-rank p< Median PFS 8.4 months Median PFS 4.9 months HR= 0.71 (95% CI= ) Time(months) Number of Patients at Risk IFN BEV/IFN
14 Overall Survival (probability) Kaplan-Meier Overall Survival Curves by Treatment Arm IFN BEV/IFN Stratified log-rank p= BEV/IFN: Median OS 18.3 months IFN: Median OS 17.4 months Time(months) Number of Patients at Risk IFN BEV/IFN
15 (1:1) Randomization Sunitinib v. IFNA Phase III Eligibility Clear cell histology No prior therapy Good performance status Adequate laboratories Stratify LDH (<1.5 vs >1.5 x upper limit of normal [ULN]) ECOG PS 0 vs 1 Presence vs absence of nephrectomy Sunitinib, 50 mg po qd q 4/6 wks IFNA 3 9 MU TIW PFS = 1 o Endpoint Motzer, NEJM 356:115,
16 Overall Survival Probability Final Overall Survival Sunitinib (n=375) Median: 26.4 months (95% CI: ) IFN-a (n=375) Median: 21.8 months (95% CI: ) ndeath/nrisk Sunit ndeath/nrisk IFN-a Hazard Ratio = (95% CI: ) p =0.051 (Log-rank) Total Death Sunitinib 190 IFN-a Time (months) / / / / / 61 4 / / / / / / 53 1 / 1
17 Sorafenib Phase III Study Major inclusion Failure of 1 prior therapy PS = 0-1 Low/Interm. MSKCC risk Stratification Motzer criteria Country Sorafenib 400 mg bid Placebo Major endpoints PFS (a=0.01) Survival (a=0.04) 1:1 Randomization (n~884) Escudier, et. al. NEJM, 2007
18 OS (% patients) TARGET: Final OS Analysis 16 Months Post-Crossover: Intent-to-Treat Sorafenib (n=451) = 17.8 months Placebo (n=452) = 15.2 months HR (sorafenib/placebo) = % CI: P =.146* Time from randomization (months) 561 events *Non-significant; O Brien Fleming threshold for statistical significance a=0.037 Escudier
19 VEGF Pathway Toxicities Cardiac Hypertension Reversible Posterior Leukoencephalopathy MI CVA CHF Integument Hand/Foot Mucositis Diarrhea Systemic Fatigue Dysgeusia Metabolic Liver toxicity Hypothyroidism
20 VEGF Pathway Inhibitors Summary Not clear which inhibitor to use first Statistically significant improvements in PFS Minimal or no improvements in OS in trial setting Epidemiologic studies suggest greater OS benefit Due to cross-over or introduction of multiple inhibitors simultaneously?? Can have significant toxicity
21 mtor Inhibitors Sirolimus (Rapamycin) Temsirolimus (CCI-779) Everolimus (RAD001)
22 mtor Inhibitors Agent Context of Definitive Trial Comparator No Prior Therapy Temsirolimus* IFNA X Prior VEGF Pathway Everolimus Placebo X *Poor prognosis only, included non-clear cell
23 Phase 3 Study of TEMSR and IFN in Advanced RCC 626 patients with advanced metastatic RCC with poor-risk features 209 sites (26 countries) Stratification by: Geographic Regions: WEU + AU + CA (22%) US (30%) EEU + Other (48%) Nephrectomy: Yes (67%) No (33%) R A N D O M I Z E IFN: escalating to 18 MU SC TIW TEMSR: 25 mg IV QW TEMSR: 15 mg IV QW + IFN: 6 MU TIW n = 207 n = 209 n = 210 Hudes, et al. ASCO 2006,
24 Probability of Survival Overall Survival by Treatment Arm Parameter Comparisons TEMSR Arm 2 Arm 2:Arm 1 TEMSR + IFN Arm 3 Arm 3:Arm 1 Log-Rank p Arm 2: Temsirolimus Arm 1: IFN Arm 3: IFN + Temsirolimus Time from Randomization, Months
25 Everolimus RStudy Conduct A N = 416 Stratification Prior VEGFr TKI: 1 or 2 MSKCC risk group: favorable, intermediate, or poor N D O M I Z A T I O N 2:1 Safety Interim analysis Everolimus + BSC (n = 277) Upon Disease Progression Placebo + BSC (n = 139) 416 patients randomized between December 2006 and November 2007 Analysis cut-off: February 28, 2008, based on 266 PFS events 2nd Interim analysis data cut-off: 15 OCT 2007, N=410 End of double blind analysis data cut-off: 28 FEB nd interim analysis based on cut-off: 15 October 2007, efficacy boundary crossed with 410 patients/
26 Progression-Free Survival
27 mtor Inhibitor Toxicity Metabolic Hyperglycemia Hyperlipidemia Increased Creatinine Integument Diarrhea Mucositis Pruritic Rash Systemic Fatigue Edema Pneumonitis Infectious risks Hematologic Thrombocytopenia
28 mtor Inhibitor Summary Modest activity Small survival benefit in poor prognosis first line therapy with temsirolimus PFS benefit in post-vegfr TKI setting with everolimus Can have significant toxicity
29 XL Roziglitazone Cabozantinib is administered daily at a starting dose of 175 mg; Rosiglitazone 4 mg Day 22 4/9 patients with a partial response Related AEs Grade 3 severity: fatigue (1 pt), amylase and lipase increased and hypophosphatemia (1 pt), and hyponatremia and hypophosphatemia (1 pt)
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32 TORAVA Study Toxicity Fatigue, nausea, vomiting, hypertension appeared to be synergistic in between bevacuizumab and temsirolimus 3.4% death rate on study in arm A, compared to no deaths seen in arms B or C 41% of patients in arm A discontinued therapy due to toxicity
33 Bevacizumab +High Dose IL-2 49 patients enrolled from 8 centers Bevacuzimab administered at 10 mg/kg days 1, 15, 43, 57, 71, 85 and 99 HD IL-2 (600,000 IU/KG) on days 1, 15, 85, 99
34 HD IL 2 + Bevacizumab: Response Response N (%) Complete Response 4(8) Partial Response 10(20) Stable Disease 21(43) Progressive Disease 13(27) Withdrawn from study 1(2) Median PFS Median Survival 9 mos 24.6 mos
35 Pending Large Trials (a partial list) (20,000 pts US + Europe/yr; 5% clinical trials = 1000 pts/yr) Adjuvant Sorafenib v. Sunitinib v. Placebo x 1 yr (ECOG) - complete Sorafenib 1y v. Sorafenib 2y v. Placebo (MRC) Sunitinib v. Placebo 1yr (Pfizer) Pazopanib v. Placebo 1 yr (GSK) Everolimus v. Placebo 1 yr (SWOG) Untreated metastatic Pazopanib versus Sunitinib (GSK) complete Tivozanib versus Sorafenib (Aveo) complete Bev v. Bev/Tem v.stem/sor v. Tem/Sor (ECOG) - complete Bev/IFNA v. Bev/Temsirolimus (Pfizer) Bev/IFNA v. Bev/Everolimus (Novartis) Nephrectomy Sunit v. Sunit Nephrectomy Sunit (EORTC) Prior Sunitinib Axitinib v. Sorafenib (Pfizer) - complete/ positive Temsirolimus v. Sorafenib (Pfizer) - complete Everolimus v. Everolimus/Bev (CALGB)
36 HD IL 2 + Bevacizumab: Toxicity Adverse events were as expected when either drug was given alone One death from pulmonary embolus and one death from GI perforation
37 Non-Clear Cell Renal Cancer Activity with both VEGFR TKI and mtor inhibitors in retrospective and small phase 2 trials Degree of activity less than in clear cell Degree of patient benefit unknown Retrospective analysis of temsirolimus study suggests enhanced benefit in non-clear subset No central pathology review Is this a subtype or poor differentiated effect?
38 Conclusions New targets need to be identified for non clear cell carcinoma Combinations of TKI s appear to be too toxic. Results of randomized phase III trials are awaited
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