Renal Cell Carcinoma
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1 Renal Cell Carcinoma Sequencing in renal cancer: two options for the same problem (TKImTOR) Viktor Grünwald Clinic for Hematology, Hemostasis, Oncology and Stemcelltransplantation Prof. Viktor Grünwald Medical School Hannover
2 Milestones of recent clinical development in mrcc (ASCO presentations) Sorafenib 2 nd line Zytokine Sunitinib Temsirolimus 1 st line IFN+Bev 1 st line Everolimus 2 nd line TKI Pazopanib 1 st /2 nd line TKI nd line Axitinib 1 st line (Tivozanib)
3 Tyrosine kinase inhibitors Targets of various TKI in RCC approved or in development Activity in biochemical assays indicated as IC50 [nm] FGF- R1 PDGF- R PDGF- R VEGF- R1 (Flt-1) VEGF-R2 (Flk-1, Kdr) VEGF-R3 (Flt-4) Sunitinib RAF Sorafenib Pazopanib Axitinib Nintedanib Flt3 26 Dovitinib Tivozanib ,001 0,001 0,001 - Mendel DB, et al. Clin Cancer Res Jan;9(1): LaMontagne, et al. Angiogenis. 2009;12(3): Kumar R, Mol Cancer Ther Jul;6(7): Gilbert JA, Pancreas Apr;42(3): Kitigawa D, et al. Genes Cells Feb;18(2): Eisen T et al, ASCO 2013, #4506 X: Target molecule *: inhibits other receptors, too e.g. FLT 3
4 The VEGF inhibition at its max.
5 1 st line: clearcell RCC Sunitinib - A Pazopanib - A BEV-IFN - A Temsirolimus*- A IFN/IL2 -C Sunitinib -A Pazopanib - A BEV-IFN - A Temsirolimus*- A Sorafenib $ -B IL-2 - C IFN alpha - D *poor risk only. indivudal cases $ if other TKI contraindicated option for poor risk. B Escudier et al. Annals of Oncology 23, vii65 vii71 doi: /annonc/mds227. Ljungberg, B. et al. Eur Urol 58, doi: /j.eururo
6 1 st line activity of licensed agents good/intermediate risk Study Sunitinib (COMPARZ) Pazopanib (COMPARZ) BEV-IFN (AVOREN) OS (mo.) PFS (mo.) ORR (%) 29,3 9, ,4 8, ,3 10,2 31 independent assessment. *investigator based assessment Motzer et al. ESMO Escudier et al. JCO (13):
7 1 st line choice defines your sequence BEV/IFN AXI, SOR, PAZ or EVE $ EVE PAZ EVE* SOR SU AXI or EVE** SOR or EVE $ a subgroup of RECORD-1 included failure after BEV/IFN *no prospective phase III data available, yet (only subgroups of GOLD study) **sorafenib ma be an option in selected cases
8 49 yo female patient Complains of pain of the left shoulder Imaging studies show osseous lesion Thorax scan without additional lesions Bone scan shows another lesion at the right os ileum
9 CT-guided biopsy of the left scapula Pathology of left scapula suggestive for clear cell carcinoma
10 Abdominal scan shows primary lesion How would you proceed? 1. Nephrectomy first 2. Palliative radiotherapy first 3. Palliative systemic therapy first
11 Hypofractionated RTX to hip/scapula Initiation of ZA What to do next? 1. Take out the kidney 2. Start systemic therapy 3. Start zolodronic acid and wait for progression
12 Follow-up on CT scan (3 mo.) New thoracic lesions: lymphnodes Parenchymal (small, dissiminated)
13 How to proceed? 1. Take out the kidney 2. Desperate surgery 3. Systemic treatment 4. Active surveillance because pts. is asymptomatic
14 What would be your prime choice for 1st line systemic therapy 1. Bevacizumab/IFN 2. Sunitinib 3. Pazopanib 4. Temsirolimus
15 Minor response to sunitinib (2 cycles)
16 Early response is prognostic relevant Seidel, C. et al. (2013) British Journal of Cancer. doi: /bjc Krajewski et al. (2011). European Urology, 59(5), doi: /j.eururo
17 Post-progression survival (PPS) depends on initial PFS v Négrier et al. (2014). EJC, 50(10), doi: /j.ejca
18 What now? 1. Continue sunitinib 2. Take out the kidney 3. Ablative treatment of the kidney 4. Treatment interruption and wait for progression
19 30% tumor necrosis after sunitinib Lymphnode RCC metastasis after sunitinib treatment
20 Sunitinib-associated (recall) pneumonitis: dose-reduction after 6 mo. of SU Seidel et al. (2010). Annals of Oncology, 21(10), doi: /annonc/mdq444
21 Case: Progressive disease after 10 mo. on sunitinib Next line of therapy? Everolimus Axitinib Sorafenib Temsirolimus
22 ESMO guidelines 2014 Escudier et al. Annals of Oncology 2104, 25 Suppl 3(suppl 3), iii49 iii56. doi: /annonc/mdu259
23 Phase III data after sunitinib failure Trial Agent PFS (mo.) OS (mo.) ORR (%) RECORD-1 EVE vs. 4.9 va vs $ 1.8 vs. 0 placebo AXIS AXI vs. SOR 4.8 vs vs vs. 8 INTORSECT TEM vs. SOR 4.3 vs vs vs. 8 SWITCH-1 SOR vs. SU 2.8 (vs. 5.4) (30.2 vs. 31.5)* 7 (vs. 18) *from 1 st line, includes cross-over $ cross-over allowed Motzer RJ et al. Cancer. 2010;116: Rini BI et al. Lancet. 2011;378: Hutson TE et al. Ann Oncol. 2012;23: abstract 918. Michel et al. ASCO GU 2014
24 2 nd line: TKI vs. mtori Busch et al. EUR UROL 2011 PFS OS * More intrinsic resistance in TKI-TKI arm (PFS 1 st line: 6,6 vs. 10,6 Mo.)
25 Systemic review of 2 nd line choices Dranitsaris et al. (2013). Journal of Cancer Research and Clinical Oncology, 139(11), doi: /s
26 Case: everolimus treatment Very good tolerability Duration of treatment: 7.8 mo. Resection of isolated CNS metastasis postop. hypofractionated stereotactic RTX (40 Gy) lumbal surgery due to progressive lesion
27 Case: Follow-up Failure of dovitinib (2 mo. of Rx) Re-exposure everolimus 3 mo. progressive disease Whole brain and lumbal RTX due to recurrences Overall survival 26.9 mo. since start of sunitinib
28 2 nd line when to switch?
29 8 Mo. on pazopanib: pain right shoulder Tasks: surgery? RTX? Bisphosphonates? Change systemic approach?
30
31
32 Non-target progression is a prognostic factor (RECORD-1) Stein et al. (2013). European Urology, 64(6), doi: /j.eururo
33 Baseline tumorburden predicts OS 1-cm increase in TB: increases risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% CI ; P < 0.001) Increase in risk of death by 5% (HR: 1.05; 95% CI ; P < 0.001). Iacovelli et al. (2012). BJU International, 110(11), doi: /j x x
34 Response over time (SLD depicted) Treatment beyond progression mm ,8 mo. pazopanib -25% * 5 mo. pazopanib Zoledronic acid +16% +20% pause * +63% *new symptomatic bone metastasis
35 2 nd line meta-analysis: different PFS, but similar OS outcome OS PFS Duran et al. IBJU 2013;39(6):
36 Licensed options in 2 nd line
37 PFS: Everolimus - RECORD-1 central review Proportion surviving, % Everolimus (n=277; Median PFS: 4.90 mo) Placebo (n=139; Median PFS: 1.87 mo) HR = 0.33 (95% CI: 0.25, 0.43) Log-rank P< Month Motzer, et al. Cancer. 2010
38 RECORD-1: no OS benefit 76% cross over Motzer, R.J. et al. Cancer 116, doi: /cncr
39 AXIS: PFS after failure of sunitinib Rini et al. Lancet 2011;378:
40 AXIS: response based on prior therapy prior agent AXI (%) SOR (%) Risk Ratio Sunitinib Cytokine Bevacizumab Temsirolimus P one-sided Covhran-Mantel-Haerszel test stratified by ECOG Escudier et al. ESMO 2011
41 AXIS: no OS benefit despite lack of crossover (patients after sunitinib failure) Motzer et al. Lancet Oncol 2013Vol 14
42 Risk adapted survival AXIS RECORD-1 Motzer et al. (2010). Cancer, 116(18), doi: /cncr Motzer et al. (2013). Lancet Oncology, 14(6), doi: /s (13)
43 Cross-trial comparison between Axitinib and Everolimus PFS both with modest activity Higher response rate with Axitinib More GI-toxicity with sequential TKI use Caveat: cross-trial comparison
44 Alternative choices
45 INTORSECT: Progression-Free Survival (IRC Assessment) Temsirolimus Sorafenib Median PFS, months % CI 4.01, , 4.21 PFS (probability) P= (log-rank) Stratified HR: 0.87 (95% CI: 0.71, 1.07) Patients at risk, n Sorafenib Temsirolimus Time (months) CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival. Hutson et al. JCO 2013
46 INTORSECT: Overall Survival Overall Survival (probability) Patients at risk, n Sorafenib Temsirolimus Temsirolimus Sorafenib Median OS, months Time (months) % CI 10.13, , P=0.014 (log-rank) Stratified HR: 1.31 (95% CI: 1.05, 1.63) CI, confidence interval; HR, hazard ratio; OS, overall survival. Hutson et al. JCO 2013
47 INTORSECT response rate PR -CR TEM N=259 8% 0% SOR N=253 8% <1% SD 61% 60% PD 23% 24% Missing 7% 7% CI, confidence interval; HR, hazard ratio; OS, overall survival. Hutson et al. ESMO 2012: #918
48 Selected mtor inhibitor differences 1-5 Oral Bioavailability Active Metabolite Route of Administration Dose and Schedule Everolimus Sustainable None Oral 10 mg once daily 2 Temsirolimus Poor; extensive first-pass metabolism 1 Metabolised to active sirolimus IV 25 mg, infused over minutes, once weekly 3 PK/PD Paramete r AUC, mean (SD) C max, mean (SD) t 1/2, mean (SD) Oral Everolimus Daily* (10 mg) (231) ng-h/ml 61 (17) ng/ml IV Temsirolimu s Weekly* (34 mg) (809) ng-h/ml 2200 (798) ng/ml 30 (8) h 22.3 (6.1) h *Studies conducted in patients with advanced solid tumours. Across all patients receiving oral everolimus weekly (5 70 mg). 1. Buckner JC et al. Invest New Drugs. 2010;28: Afinitor [package insert]. Novartis Pharmaceuticals Corporation; Torisel [package insert]. Pfizer; O'Donnell A et al. J Clin Oncol. 2008;26: Raymond E et al. J Clin Oncol. 2004;22: This presentation is for scientific discussion only Please do not distribute following this meeting
49 RECORD-1, AXIS and INTORSECT: patient characteristics Performance status Good/intermed iate/ poor MSKCC risk Prior nephrectomy Liver metastases Prior 1 TKI therapy RECORD-1 1,2 AXIS 3,4 INTORSECT 5 KPS 70% ECOG PS 0-1 ECOG PS % / 56% / 14% 40% / 54% / 2% (ASCO) 28% / 37% / 33% (Lancet) 18% / 69% / 12% 97% 91% 86% 33% 28% Not reported 21% 54% 100% received 1 (sunitinib) 1. Motzer RJ et al. Cancer. 2010;116: Calvo E et al. Eur J Cancer. 2012;48: Rini BI et al. Lancet. 2011;378: Rini BI et al. J Clin Oncol. 2011;29: abstract Hutson TE et al. Ann Oncol. 2012;23: abstract 918. This presentation is for scientific discussion only Please do not distribute following this meeting
50 How to pick the drug in 2 nd line?
51 Duration of previous therapy is not predictive in 2 nd line 1 st line PFS (mo.) INTORSECT TEM (n=259) SOR (n=253) SOR (n=194) AXIS AXI (n=192) Sunitinib < 6 Mo Sunitinib > 6 Mo. HR 0.8 ( ) CI95% ( ) CI95% ( ) Hutson et al. ESMO Rini et al. ASCO GU 2012 HR 0.9 ( ) CI95% ( ) CI95% ( )
52 Prior response not predictive in retrospective series p= mo. 5.1 mo. Seidel et al. EJC 2012
53 ORR: no correlation for previous response The overall objective rate was 22% for first-line therapy and 11% for second-line therapy ORR to second-line therapy did not differ by response to first-line therapy No association between first- and second-line ORR observed (chi-squared trend test, P =.17) 60% 50% 40% 30% 20% 10% 0% CR2 PR2 SD2 PD2 CR1/PR 1% 13% 36% 50% SD1 1% 9% 50% 40% PD1 0% 11% 34% 55% Al-Marrawi MY et al. Target Oncol. 2013; 8:203-9.
54 1 st line PFS: not predictive in 2 nd line No correlation between first- and second-line PFS observed (Pearson correlation coefficient 0.025; P =.59) Second-line PFS, mo First-line PFS Versus Second-line PFS Pearson correlation coefficient 0.025; P = First-line PFS, mo Al-Marrawi MY et al. Target Oncol. 2013; 8:203-9.
55 VEGF-sensitivity correlates with good prognosis 46,8 MO. 12,1 MO. Retrospective analysis n=119 Seidel et al. Eur J Cancer 2012 vol. 48 (7) pp
56 Case: 41 y/o caucasian male Synchronous lung mets. MSKCC: intermediate left nephrectomy Refractory RCC: 3 mo. sunitinib 3 mo. everolimus 1 mo. dovitinib 2 mo. sorafenib death 11 mo. after diagnosis
57 Toxicity spectrum varies between TKI and mtori Hutson et al. JCO 2013
58 Drug Delivery INTORSECT (Safety Population) Dose interruptions, % Due to AEs, % Temsirolimus (n=249) Sorafenib (n=252) Median relative dose intensity, % Discontinuations due to treatment-related AEs,* % *Adverse events related to treatment as determined by investigators. AE, adverse event. Hutson et al. JCO 2013
59 AE: selected class effects in 2 nd line (%) RECORD-1 $ INTORSECT AXIS Pl EVE TEM SOR SOR AXI Stomatitis * 14* Exanthema Dyspnea Dysphonia Hypertension HFS Diarrhea *Mukositis. $ AE 10%. AE >25%
60 PISCES: patient s preference differs from AE incidence Better quality of life Less fatigue Less taste change Pazopanib (n=153) Sunitinib (n=148) Alle Grade Grad 3/4 Alle Grade Grad 3/4 29% 4% 30% 5% Less mucositis/stomatitis Less nausea/vomiting 33% <1% 30% 0 14% <1% 16% <1% Less hand-foot syndrome Better appetite Less stomach pain Less diarrhoea 42% <1% 32% <1% Other Less hair colour change Pazopanib preferred (n=80) Sunitinib preferred (n=25) Escudier B, et al. ASCO 2012; abstract Patients
61 2 nd line phase III studies: pick the winner INTORSECT RECORD-1 AXIS TEM SOR EVE Pl SOR AXI ORR (%) PFS (mo) OS (mo.) discont.* (%) diarrhea (%) *wegen AE. TEM: Temsirolimus. EVE: Everolimus. SOR: Sorafenib. AXI: Axitinib. Pl: Placebo.
62 mtor inhibitors and TKIs have distinct safety profiles 62 TKIs and mtori have distinct safety profiles. 1-3 Hypertension, GI-AEs, and hand-foot syndrome are more frequent with VEGFr-TKIs 4 Pneumonitis and metabolic effects (glucose, lipids) are more frequent with mtor inhibitors Motzer RJ et al. Cancer. 2010;116: Pfizer Inc. FDA Oncologic Drugs Advisory Committee Briefing Document (NDA ). CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ucm htm. Accessed January 28, Motzer RJ et al. N Engl J Med. 2007;356: Eisen T et al. J Natl Cancer Inst. 2012;104: Calvo E, Escudier, B, Motzer RJ, et al. Eur J Cancer. 2012;48:
63 Sequential studies
64 Tivozanib improves efficacy in Rxnaive patients Motzer, R.J. et al. Journal of Clinical Oncology doi: /jco
65 TIVO-1: 2 nd line treatment compensates for inferior 1 st line PFS 2 nd line VEGFR 63% 2 nd line VEGFR 13% Motzer, R.J. et al. Journal of Clinical Oncology doi: /jco
66 Lessions from TIVO-1 Sorafenib is the weakest TKI 2 nd line therapy may compensate for inferior 1 st line treatment 2 nd line treatment may improve OS Do cross-over trials properly
67 RECORD-3: Sequential therapy in RCC Motzer et al ASCO 2013 #4504 EVE-SUN (N=238) SUN-EVE (N=233) HR (95% CI) P value* 1 st line PFS (Mo.)* (2 nd line Therapie) 7,9 (5,6-8,2) 54% 10,7 (8,2-11,5) 52% 1,43 (1,15-1,77) - 2 nd line PFS OS (Mo.) 22,4 (19,7-NR) 32,0 (20,5-NR) 1,24 (0,94-1,64) - *primary endpoint, non-inferiority design
68 RECORD-3: 1 st line PFS Death in 1 st line EVE (n=238) 37 (40%) SU (n=233) 22 (24%) Time to deterioration HR 1.45 favoring sunitinib Motzer et al. (2014). Journal of Clinical Oncology, JCO doi: /jco
69 mtor a target for later lines of therapy Cumulative event-free probability (%) Everolimus (events/n = 182/238) Sunitinib (events/n = 158/233) K-M Median PFS (mo) Everolimus Sunitinib Hazard Ratio = 1.43 Two-sided 95% CI [1.15, 1.77] Number of patients still at risk Time (months) Everolimus Sunitinib Motzer, et al. Cancer Motzer R et al. Oral Presentation ASCO 2013; #4504
70 Overall Survival (interim analysis) Motzer et al. (2014). Journal of Clinical Oncology, JCO doi: /jco
71 Everolimus toxicity AE, % Everolimus 1 st line n = 238 Everolimus 2 nd line n =99 All Grades Grade 3/4 All Grades Grade 3/4 Everolimus 2 nd line n=274 All Grades Grad e 3/4 Stomatitis 53 6/0 25 1/0 40 3/0 Fatigue 45 8/1 32 9/2 20 3/0 Diarrhea 38 4/1 13 1/0 17 1/0 Cough 38 2/0 21 1/0 12 0/0 Rash 37 2/0 19 0/0 25 1/0 Nausea 34 2/0 15 2/0 15 0/0 Decreased appetite 29 3/0 23 3/0 16 1/0 Anemia 28 11/ /0 91 9/1 Peripheral edema 28 <1/0 16 1/0 NR NR Dyspnea 25 6/1 21 5/1 8 1/0 Dysgeusia 21 0/0 7 0/0 NR NR Vomiting 21 2/0 9 2/0 12 0/0 Constipation 19 <1/0 11 0/0 NR NR Hypertension 10 4/0 3 1/0 NR NR Hand-foot s. 6 <1/0 2 0/0 NR NR Motzer, R.J.et al. Lancet 2008: 372, doi: /s (08) Motzer et al. (2014). JCO doi: /jco Modified from: Motzer R et al. Oral Presentation ASCO 2013; #4504
72 SWITCH R ECOG 0/1 Sunitinib 1:1 Sorafenib Sorafenib Sunitinib Total PFS* N=365 CT: q3 mo. Response according to RECIST 1.0 *superiorty design for SOR-SU Michel et al. ASCO GU 2014
73 Primary endpoint <50% entered 2 nd line PFS probability (%) Total progression-free survival Median (one-sided n 95% CI) PFS, months So Su (>11.5, <15.0) Su So (>10.5, <17.2) HR: 1.01 (one-sided 95% CI: <1.27) p value for superiority= No. patients Months from randomization So Su Su So Intent-to-treat population Michel et al. 2014
74 Secondary endpoints Survival probability (%) Overall survival Median (one-sided n 95% CI) OS, months So Su (>23.3, <36.9) Su So (>23.6, <50.1) HR: 1.00 (one-sided 95% CI: <1.30) p value for superiority= No. patients Months from randomization So Su Su So Intent-to-treat population OS, overall survival Michel et al. 2014
75 2nd-line progression-free survival PFS probability (%) Limitations: Imbalance between arms for patients initiating protocol-defined 2nd-line therapy No randomization immediately prior to 2nd-line Months from randomization n Median (95% CI) PFS, months So Su (>3.0, <5.5) Su So (>2.7, <2.9) HR: 0.55 (one-sided 95% CI: <0.74) p value for superiority < No. patients So Su Su So Intent-to-treat population Michel et al. 2014
76 Tumour response and disease control* So Su Su So p value 1st-line n=177 n=176 Complete response, % Partial response, % Stable disease, % Disease control rate**, % nd-line n=103 n=76 Complete response, % Partial response, % Stable disease, % Disease control rate**, % Modified intent-to-treat population; only patients who received 1 dose of study drug in the respective line were included *Response evaluation based on investigator assessment; **Disease control rate = complete response + partial response + stable disease Michel et al. 2014
77 Treatment-emergent AEs* So Su Su So So 1st-line (n=177) Su 2nd-line (n=103) Su 1st-line (n=176) So 2nd-line (n=76) All G 3/4 All G 3/4 All G 3/4 All G 3/4 Any Diarrhoea HFSR Fatigue Hypertension Alopecia Rash Nausea Loss of appetite Pain Stomatitis Thrombocytopenia Safety population; data are %; G, grade; HFSR, hand foot skin reaction *AEs in >20% of patients in either arm, or grade 3/4 in >3% of patients in either arm Michel et al. 2014
78 SWITCH This is a negative study No central review for CTs Total PFS is not a usefull endpoint and should be avoided Sorafenib has poorer performance compared to sunitinib in 1 st and 2 nd line Patients who drop out after 1 st line may have tolerability issues i.e. 2 nd line is not better tolerated (same as in RECORD-3) For tolerability, data has to be shown for the same cohort in 1 st and 2 nd line
79 Caveat of current sequential trials RECORD-1 RECORD-3* SWITCH $ Pl n=137 EVE n=274 1 st n=238 2 nd n=99 1 st n=177 2 nd n=76 Stomatitis (%) Exanthema (%) NR Dyspnea (%) NR NR Fatigue (%) Cough (%) NR NR Diarrhea (%) Discont. to AE * Everolimus only. $ Sorafenib only
80 PFS in untreated patients PFS line prior Rx N VEGF ,8 Mo VEGF ,2 Mo. 2. IFN 67 TARGET 2,8 Mo. 2. IFN 452 RECORD-1 1,9 Mo. >2. TKI/IFN 139 Escudier et al. (2007). The New England Journal of Medicine, 356(2), doi: /nejmoa Motzer et al. (2008). The Lancet, 372(9637), doi: /s (08) Sternberg et al. (2010). Journal of Clinical Oncology, 28(6), doi: /jco
81 GOLD trial: defining the 3 rd line (ESMO I,B recommendation) Motzer et al. (2014). Lancet Oncology, doi: /s (14)
82 Novel concepts
83 RECORD-1, AXIS and TARGET: cumulative toxicity Based on a comparison of AXIS and TARGET, there appears to be cumulative toxicity when 2 TKIs are given sequentially RECORD-1 1 AXIS 2 TARGET 3 Interruptio ns Placebo Everolimus Axitinib Sorafenib Sorafenib 11% 38% 77% 80% 21% Reductions 1% 7% 31% 52% 13% 1. Motzer RJ et al. Cancer. 2010;116: Rini BI et al. Lancet. 2011;378: Escudier B et al. N Engl J Med. 2007;356: This presentation is for scientific discussion only Please do not distribute following this meeting
84 ANZUP 0901: EVERSUN 1 x Sunitinib 50 mg 4-2 Regime 1 x Everolimus 10 mg 5-1 Regime 1 x Sunitinib 50 mg 4-2 Regime... CT CT N=55 I : PFR 6 Mo. PFR 6Mo. : 53% ORR: 13% PFS: 8 Mo. OS: 17 Mo. Davis et al. J Clin Oncol 32, 2014 (suppl 4; abstr 438)
85 Dual inhibition of PI3K + mtor is not beneficial Disconti nuation* GDC % Everolimus 12% *due to AE Powles et al. ASCO 2014
86 OS: even better outcome for everolimus Powles et al. ASCO 2014
87 Is there a predicitve biomarker? A. Best % Change From Baseline (Tumor SLD) IHC PTEN IHC Low PTEN IHC High No Alteration High Low Any Alteration Everolimus PTEN NGS* VHL PBRM1 PIK3CA PTEN TP53 Powles et al. ASCO 2014
88 Maybe but why does it work in everolimus only? Progression Free Survival VHL Evero Any Alteration (n=22) Evero None (n=9) Progression Free Survival Evero High (n=28) Evero Low (n=9) HR (GDC-0980) 0.53 (0.23, 1.22) HR (Everolimus) 0.53 (0.22, 1.24) 0.0 Time (Months) Time (Months) Powles et al. ASCO 2014
89 mtor or TSC mutations in 3/5 patients Voss et al. CCR 2014
90 PD-L1 expression is associated with poor prognosis in RCC Thompson et al. Proc Natl Acad Sci USA 2004;101:
91 Pick the winner strategy: nivolumab in previously treated RCC Arm mg/kg nivolumab IV Q3weeks Screen for eligibility Randomize a 1:1:1 (treatment arms blinded) Arm 2 2 mg/kg nivolumab IV Q3weeks Treat until progression or intolerable toxicity Arm 3 10 mg/kg nivolumab IV Q3weeks ClinTrials.gov NCT a Stratified by MSKCC prognostic score (0 vs 1 vs 2/3) and number of prior lines of therapy in the metastatic setting (1 vs >1). Motzer et al. ASCO 2014 #5009
92 Progression-free survival (%) Number of patients at risk Progression-free survival Median PFS, months (80% CI) 0.3 mg/kg 2.7 (1.9, 3.0) 2 mg/kg 4.0 (2.8, 4.2) 10 mg/kg 4.2 (2.8, 5.5) Stratified trend test P value Time (months) 0.3 mg/kg mg/kg mg/kg mg/kg (events: 48/60) 2 mg/kg (events: 43/54) 10 mg/kg (events: 45/54) Symbols represent censored observations. 92 Motzer et al. ASCO 2014 #5009
93 Overall survival (%) Overall survival by MSKCC risk group 100 and number of prior treatments Risk group Favorable (events: 25/56) Intermediate (events: 40/70) Poor (events: 32/42) Time (months) Median OS, months (95% CI) Favorable NR (24.9, NR) Intermediate 20.3 (13.4, NR) Poor 12.5 (8.1, 18.6) NR, not reached; Symbols represent censored observations. Overall survival (%) Number of prior treatments 1 Prior treatment (events: 22/46) 2 Prior treatments (events: 75/122) Time (months) Median OS, months (95% CI) 1 NR (19.8, NR) (13.4, 26.0) Motzer et al. ASCO 2014 #5009
94 Current phase III trials in 2 nd or 3 rd line agent endpoint N METEOR BMS NCT Cabozantinib Everolimus Nivolumab Everolimus PFS (OS) 650 OS 822
95 Conclusions Sequential therapy with TKI and mtori are the backbone of therapy in mrcc 2 nd line therapies are modestly active and exert a distinct toxicity profile Molecular diagnostics will be key in the future Immunotherapies exert clinical activity and are the next step in the treatment algorithm
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