Per gentile concessione del Dr. P. Zucali

Transcription

1 La seconda linea di trattamento: scenario attuale e prospettive future Paolo Andrea Zucali Dipartimento di Oncologia HUMANITAS CANCER CENTER Rozzano - Milano

2 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-TT Prior mtor-tttt 4% 89% 7% Market shares for 1 st -line systemic treatment in mrcc (% of treated patients) Source: Kantar Health online survey on 75 Oncologists treating mrcc November 2010 (excluding patients on clinical trials)

3 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior Prior VEGF-TT Prior mtor-tttt CYTOKINES 4% 89% 7% Market shares for 1 st -line systemic treatment in mrcc (% of treated patients) Source: Kantar Health online survey on 75 Oncologists treating mrcc November 2010 (excluding patients on clinical trials)

4 TKI Inhibitors after cytokines failure Agent Phase of study N ORR (%) mpfs (months) mos (months) SUNITINIB II II n.r SORAFENIB vs placebo 1 III vs 2 P< vs 2.8 P< vs 15.2 P=0.146 PAZOPANIB vs placebo 2 III vs vs 4.2 P< vs 20.5 P=0.224 AXITINIB vs Sorafenib 3 III vs 9 P= vs 6.5 P< Escudier B, et al. N Engl J Med 2007; 364: Sternberg C, et al. JCO Rini B, et al. Lancet 2011

5 SORAFENIB (TARGET Trial) OS in the cytokine-pretreated population Escudier et al. JCO 2009

6 PAZOPANIB PFS in the cytokine-pretreated subpopulation 1.0 Median PFS (months) Proportion progression-free Placebo 4.2 Pazopanib 7.4 Hazard ratio (95% CI) 0.54 (0.35, 0.84) p value (1-sided) < % reduction in risk of progression or death with pazopanib treatment compared with placebo 0.0 Number at risk, n Pazopanib Placebo Time (month) Pazopanib Placebo Sternberg et al. J Clin Oncol 2010

7 AXITINIB PFS in the cytokine-pretreated subpopulation Rini et al. Lancet 2011

8 mrcc: second line Prior CYTOKINES

9 mrcc: second line Prior CYTOKINES SORAFENIB PAZOPANIB AXITINIB* LEVEL OF EVIDENCE 1 GRADE A RECOMMENDATION

10 mrcc: second line Prior CYTOKINES SORAFENIB PAZOPANIB AXITINIB* SUNITINIB LEVEL OF EVIDENCE 1 GRADE A RECOMMENDATION LEVEL OF EVIDENCE 2 GRADE B RECOMMENDATION *Not yet clinical applicable

11 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted THERAPIES Prior mtor-targeted THERAPIES

12 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior VEGF-targeted mtor-targeted THERAPIES THERAPIES Prior CYTOKINES Prior mtor-targeted THERAPIES

13 mrcc: second line Prior mtor-targeted THERAPIES

14 mrcc: second line Prior mtor-targeted THERAPIES CLINICAL TRIALS

15 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted THERAPIES Prior mtor-targeted THERAPIES

16 mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted VEGF-targeted THERAPIES THERAPIES Prior mtor-targeted THERAPIES

17 mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) 1st Line Bevacizumab+IFNα

18 mrcc: second line 1st Line Bevacizumab+IFNα TKI mtor

20 Bevacizumab Sunitinib Phase II trial PRIMARY END-POINT: ORR 61 SECONDARY END-POINTS: PFS, Response duration, OS, Safety mpfs PR 23% SD 59% Median response duration 44.1 wks OS 47.1 wks Safety (Grade 3 AEs): fatigue 34%; hypertension 18%; HFSR 10% SUNITINIB MAY ACT AT SIGNALLING PATHWAYS INVOLVED IN BEVA-RESISTANCE Rini et al. J Clin Oncol 2008

21 Bevacizumab Axitinib vs Sorafenib Rini BI, et al. Lancet 2011;378: *One-sided log-rank test stratified by ECOG PS

22

23 mrcc: second line after bevacizumab Total patients with 1 treatment VEGF inhibitors IFN + Bevacizumab (AVOREN) (n=327) IFN + placebo (AVOREN) (n=322) 180 (55) 202 (63) Sunitinib 83 (25) 92 (29) 43 45% % Sorafenib 60 (18) 50 (16) Bevacizumab 10 (3) 12 (4) Other 7 (2) 6 (2) mtor inhibitors 14 (4) 6 (2) Cytokines 32 (10) 52 (16) Chemotherapy 28 (9) 47 (15)

24 Final results of AVOREN trial Escudier B, et al. Cancer 2010 OS OS Patients with mrcc (n=649) Stratification by: Country MSKCC risk group Bracarda S, et al. BJUI :1 Avastin + IFN-a2a (n=327) IFN-a2a + placebo (n=322) 23.3 m 21.3 m + TKIs 35% (n=113) + TKIs 37% (n=120) 38.6 m 33.6 m

26 RECORD1: PFS for pts treated with everolimus after bevacizumab + IFN Central Radiology Review Investigator Assessment PFS, progression-free survival; CI, confidence internal. Hutson T. et al. ESMO 2009; abstr P-7136

27 mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) 1st Line Bevacizumab+IFNα

28 mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) TKI mtor

29 AFINITOR (RECORD-1 Trial) Study Design N = 416 Stratification Prior VEGFr-TKI: 1 or 2 MSKCC risk group: favorable, intermediate, or poor RANDOMISATION (2:1) Everolimus 10mg/day + BSC (n = 277) Upon Disease Progression Placebo + BSC (n = 139) Study Unblinded Safety Interim Analysis 2nd Interim Analysis Data Cut- Off: 15-Oct-07 End of Double- Blind Analysis Data Cut-Off: 28-Feb-08 Survival Follow-Up: 15-Nov patients randomized between December 2006 and November 2007 Analysis cut-off: Feb-28-08, based on 266 PFS events 2nd interim analysis based on cut-off:15-oct-07, efficacy boundary crossed with 410 patients/191 PFS events (Motzer et al. Lancet. 2008;372: ), complete study unblinded on 28-Feb-08

30 PFS by Treatment Central Radiology Review Probability, % Hazard ratio = % CI [0.25, 0.43] Median PFS Everolimus: 4.90 mo Placebo: 1.87 mo Log rank P value = <0.001 Everolimus (n = 277) Placebo (n = 139) > 25 % 0 Patients at risk Everolimus Placebo Months

31 RECORD-1 Subgroup Analysis of PFS (Central Radiology Review) HR P value n Central review 0.33 < Investigator review MSKCC risk Favorable Intermediate Poor Previous treatment Sorafenib only Sunitinib only Both <.001 <.001 < <.001 <.001 < Age < 65 years 0.34 < years 0.33 < Sex Sex Male 0.32 < Female 0.39 < Region USA and Canada 0.29 < Europe 0.38 < Japan and Australia 0.18 < In favor of everolimus In favor of placebo Analysis on Feb 2008 data cutoff. Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):

32 Everolimus was as effective after 2 TKIs as it was after 1 TKI 1. Motzer RJ, et al. Cancer 2010;116(18): Hutson TE, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 7136.

33 Selected Adverse Events irrespective of causality Everolimus (n=274) Placebo (n=137) Event, % All Grades Grade 3/4 All Grades Grade 3/4 Stomatitis 44 4/<1 8 0/0 Infections (total) 37 7/3 18 1/0 Asthenia 33 3/<1 23 4/0 Fatigue 31 5/0 27 3/<1 Diarrhea 30 1/0 7 0/0 Rash 29 1/0 16 0/0 Nausea 26 1/0 19 0/0 Mucosal inflammation 19 1/0 1 0/0 Edema peripheral 25 <1/0 8 <1/0 Dyspnea 24 6/1 15 3/0 Pneumonitis 14 4/0 0 0/0 Updated information from Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):

34 Laboratory Abnormalities irrespective of causality Everolimus Placebo (n = 274) (n = 137) Event, % All Grades Grade 3/4 All Grades Grade 3/4 Hematology Anemia 92 12/1 79 5/<1 Lymphopenia 51 16/2 28 5/0 Thrombocytopenia 23 1/0 2 0/<1 Chemistry Hypercholesterolemia 77 4/0 35 0/0 Hypertriglyceridemia 73 <1/0 34 0/0 Hyperglycemia 57 15/<1 25 1/0 Elevated creatinine 50 1/0 34 0/0 Updated information from Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):

35 Medical optimization of TORisel (MoTOR): A multicenter, phase II evaluation of Torisel as II-line treatment for metastatic RCC patients progressing after cytokine therapy, tyrosine kinase, or angiogenesis inhibitors Primary Endpoint: PFS rate at 6 mos Entire series: mpfs 4.0 mos (95% CI: ) Sunitinib pretreated: mpfs 4.6 mos (95% CI: ) 18/57 pts free from progression at 6 mos in the sunitinibpretreated group. PRIMARY ENDPOINT WAS MET GIR-2 study

36 mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) TKI mtor

37 TKI-TKI Sequence: many retrospective and few prospective phase II trials Hutson et al. Clin Rev Oncol 2011

38 TKI-TKI Sequence: no cross-resistanceresistance SUNITINB SORAFENINB mpfs or TTP: mos SORAFENINB SUNITINB mpfs or TTP: mos Hutson et al. Clin Rev Oncol 2011

39 AXIS TRIAL

40 AXIS Study Design Patients with clear cell metastatic RCC and RECIST PD after 1 prior systemic firstline regimen: Sunitinib, Bevacizumab + IFN-α, Temsirolimus, or Cytokine(s) 1:1 Axitinib 5 mg BID* (n=361) PRIMARY END-POINT: PFS Sorafenib 400 mg BID (n=362) Randomization stratified by ECOG PS and type of prior treatment * Starting dose 5 mg BID with option for dose titration to 10 mg BID 4 0

41 Progression-free Survival: all population (IRC Assessment) Progression-Free Survival (probability) Subjects at risk, n Axitinib Sorafenib IRC = Independent Review Committee Time (months) mpfs, mo 95% CI Axitinib Sorafenib , , 5.6 P< (log-rank) Stratified HR (95% CI: 0.544, 0.812) Rini BI, et al. Lancet 2011

42 Rini BI, et al. Lancet 2011;378: *One-sided log-rank test stratified by ECOG PS

43 Rini BI, et al. Lancet 2011;378: *One-sided log-rank test stratified by ECOG PS

44 AXITINIB PFS in the TKI-pretreated subpopulation Rini et al. Lancet 2011

45

46 AXIS trial: Final Overall Survival

47 AXIS trial: Final Overall Survival

48 Per Per gentile concessione del del Dr. Dr. P. P. Zucali

49 Per Per gentile concessione del del Dr. Dr. P. P. Zucali

50 Axitinib Dose Titration in AXIS Trial Starting dose 5 mg BID n=359 (100%) Dose reduction <5 mg BID n=88 (25%) No dose change 5 mg BID n=139 (39%) Mean duration: 161 days Dose escalation >5 mg BID n=132 (37%) Highest titration to 7 mg BID n=60 (17%) Mean duration (7 mg BID): 92 days Highest titration to 10 mg BID n=71 (20%) Mean duration (10 mg BID): 127 days Patients whose dose increased and then reduced n=71 (20%) No substantial difference in ability to dose titrate >5 mg BID based on prior treatment, ethnicity, gender, or region 50

51 Progression-free Survival Survival Distribution Function Axitinib 5 mg BID Axitinib >5 mg BID Sorafenib PFS (months) 51

52 Summary of Treatment-emergent, All-Causality Adverse Events 5 mg BID a (n=227) Axitinib Dose, n (%) >5 mg BID b (n=132) Any AEs 216 (95.2) 126 (95.5) Diarrhea 120 (52.9) 77 (58.3) Decreased appetite 66 (29.1) 57 (43.2) Nausea 60 (26.4) 56 (42.4) Fatigue 89 (39.2) 51 (38.6) Hypertension 97 (42.7) 48 (36.4) Hypothyroidism 22 (16.7) 47 (20.7) Dysphonia 71 (31.3) 40 (30.3) Asthenia 36 (15.9) 38 (28.8) Palmar-plantar erythrodysesthesia syndrome 63 (27.8) 35 (26.5) Proteinuria 28 (12.3) 11 (8.3) a No total daily dose of axitinib >5 mg BID, b 1 total daily dose of axitinib >5 mg BID. 52

53 Summary of PFS by Duration of Prior Sunitinib PFS, months (95% CI), [n] <3 mo vs 3 mo <6 mo vs 6 mo <9 mo vs 9 mo Axitinib 4.5 (2.7, NR) [22] 4.8 (4.5, 6.5) [170] 4.6 (2.8, 8.3) [48] 4.8 (3.6, 6.5) [144] 4.5 (2.8, 6.4) [90] 6.3 (4.6, 6.7) [102] Sorafenib 2.8 (1.4, 15.7) [21] 3.7 (2.8, 4.7) [173] 2.8 (1.6, 3.7) [62] 4.6 (2.9, 4.9) [132] 2.9 (2.8, 4.6) [87] 4.6 (2.9, 4.9) [107]

54 PFS by Prior Response to Sunitinib: Axitinib vs Sorafenib Arms Axitinib Sorafenib Non-responders Responders n mpfs mo % CI Non-responders Responders n mpfs mo % CI Probability of PFS Time (months) Time (months) 0

55 mrcc: second line Prior VEGF-targeted THERAPIES TKI mtor AXITINIB LEVEL OF EVIDENCE 1 GRADE A RECOMMENDATION EVEROLIMUS LEVEL OF EVIDENCE 1 GRADE A RECOMMENDATION SU-SO SO or SO-SUSU LEVEL OF EVIDENCE 2 GRADE B RECOMMENDATION

56 BEST SEQUENCE: TKI-TKI or TKI-mTOR? Suggestions for clinical practice

57 The Optimal Sequence TKI VEGF Inhibitor 1 Phase III data mtor Inhibitor Limited data? TKI VEGF Inhibitor 1 TKI VEGF Inhibitor 2 mtor Inhibitor Phase III data Phase III data

58 Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified

60 Clinical practice: primary recfractory pts 1. Vickers MM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Abs. ASCO GU 2011; Albiges L, et al. (manuscript submitted)0

61 Clinical practice: primary recfractory pts Phase III study PD as best response Bevacizumab 20% Pazopanib 18% Sunitinib 12% Sorafenib 20% 1. Vickers MM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Abs. ASCO GU 2011; Albiges L, et al. (manuscript submitted)0

62 Clinical practice: primary recfractory pts Large retrospective series (the mrcc International Data-Base Consortium, as well as the French-Italo-British cooperative study) 1-3 : 2 PFS TKI 2 PFS mtor OS from 2 line Heng 2,8 mo 2,0 mo 7,4 mo Albiges 6,6 mo 5,0 mo 5,9 mo in TKI-primary refractory patients (i.e., a mtor inhibitor) 1. Vickers MM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Abs. ASCO GU 2011; Albiges L, et al. (manuscript submitted)0

63 Relative Potencies of TKIs in RCC 1. Eskens FALM, et al. In: Proceedings of the 99th Annual Meeting of the AACR. San Diego, CA: AACR; Abstract LB Nakamura K, et al. Cancer Res. 2006;66(18): Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25(7):

64 REACT trial RAD001 Expanded Access Clinical Trial in RCC Pts with mrcc intollerant of, or progressed while on, VEGFR-TKI therapy EVEROLIMUS treatment duration by prior therapy All PD on prior VEGFR-TKI Intolerant Treated with Treated with to prior only 1 prior only prior VEGFR-TKI VEGFR-TKI sunitinib n Treatment duration (wks) Larkin JMG, ASCO GU 2012

68 AXIS versus RECORD-1 1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378: Bex A., Lancet 2011

69 RECORD1: a real 2nd line trial? (more than 75% of pts in RECORD-1 received everolimus as 3rd+ Line) Patients received a median of 2 prior antineoplastic medications Per gentile Motzer concessione RJ, Cancer del Dr P. Zucali

70 Second line: mtor vs TKI 2100 pts VEGF-targeted therapy 1st LINE 645 pts VEGF-targeted therapy 818/2100 pts -541 pts VEGF-TT -277 pts mtor-tttt 2nd LINE 216/645 pts -192 pts VEGF-TT -24 pts mtor-tttt Heng et al. ASCO GU 2012 Vickers et al. Urology 2010

71 Second line: mtor vs TKI Vickers et al. Urology 2010 VEGF-TT VEGF-TT vs VEGF-TT mtor-tt HR for death: 0.833* (p 0.10) *adjusted for: Heng poor criteria, non-clear cell histology Heng et al. ASCO GU 2012

72 Second line: mtor vs TKI in long responders From a large retrospective European cooperative series1, we now know that: in those patients who have had a clear-cut and long-lasting benefit from a first-line TKI, (either another TKI, or a mtor inhibitor) 1 This is probably due by the fact that in RCC is so heavily dependant on angiogenesis, inhibiting mtor ultimately results in a continuous, even though indirect, inhibition of angiogenesis. 1. Eladi R, et al. (manuscript in preparation)

73 No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified

75 DIFFERENT TOXICITY PROFILES TKI mtor inhibitor TKI

76 PROFILI DI TOSSICITA

77

80 In the absence of PREDICTIVE BIOMARKERS..

81 Tolerability Profiles Can Help to Guide Selection of Treatment: Patient-related Factors and Comorbidities Patient with reduced EF Patient with nutrition disorders Patients with impaired mobility Consider the patient's profession Consider comedications (drug interactions) Chronic obstructive pulmonary disease Thromboembolic disease Diabetes Mellitus

82 Clinical trials!

83 Second-line therapy: ongoing trials Trial Prior treatment Design End-point Status SWITCH Phase III NCT Sorafenib Sunitinib Vs Sunitinib Sorafenib PFS Recruiting (n=346) RECORD-3 Phase III NCT Everolimus Sunitinib Vs Sunitinib Everolimus PFS Recruiting (n=390) Pazopanib Bevacizumab START Phase II NCT Pazopanib Everolimus Everolimus Pazopanib Everolimus Bevacizumab Bevacizumab Everolimus TTF Recruiting (n=240) Bevacizumab Pazopanib Phase III NCT TKIs Bevacizumab Vs Beva + Eve OS Recruiting (n=700) Phase III NCT Sunitinib Temsirolimus Vs Sorafenib PFS Recruiting (n=480)

84 VEGFR and mtor pathways

85 Alternate Angiogenic Signalling Pathways Afford Novel Targets in RCC

86 FGF mediates escape from anti-vegf therapy FGF2 is expressed by numerous tumor types and exerts its proangiogenic activity by interacting with TK receptors, heparan-sulfate proteoglycans, and integrins expressed on the endothelial cell surface Early phase: VEGFR2 blockade transiently stops tumor growth and decreases vascularity Casanovas O, et al. Cancer Cell 2005;8: Late phase: Reactivation of angiogenesis after anti-vegfr VEGFR2 therapy through FGF activation leads to tumorprogression

87 Horizontal Inhibition May Delay Development of Resistance

88 DOVITINIB Demonstrates Activity in Heavily Pretreated mrcc Patients Angevin E et al. ASCO Abs 3057.

89 Phase III Dovitinib in mrcc (third line)

90 AMG-386, an Angiopoeitin Antagonist With Antitumour Efficacy

91 Phase 2: AMG Sorafenib Increases Response but not PFS Over Sorafenib in RCC

92 PI3K/Akt/mTOR Signalling Figure adapted from Rini BI, Atkins MB. Lancet Oncol. 2009;10:

93 PERIFOSINE, an Oral Alkylphospholipid, Shows Clinical Benefit in Refractory mrcc

94 HGF/cMET Signalling ARQ-197 Foretinib ORR 13.5%; PFS 9.3 mos; 1yr OS 70% papillary RCC. Pts METmut+ PR 50%; DCR 100%. Cabozantinib (XL187) PR 24%; DCR 68%; tumor shrinkage 86% in refractory RCC. Choueiri et al. ASCO GU 2012

95 Immunotherapy?

96 Immunotherapy: ongoing trials Target Drug Class Development phase Blockade of T-cell regulation PD-1 antibody MDX-1106 Fully human mab Phase II CTLA-4 antibody Ipilimumab Fully human IgG1 mab Phase III (melanoma) Inhibition of tumor-induced T-cell function TGF-beta GC1008 Fully human mab Phase I TGF-beta AP12009 Fully human mab Phase I T-cell activation CD137 BMS Monoclonal Ab Phase I Cytokines Interleukin-21 Recombinant molecule Phase II (melanoma) Dendritic cell activation Toll-like receptor HYB-2055 TLR-9 agonist Phase II Dendritic celltumor fusions AGS-003 Dendritic cell-based immunotherapy Phase III

97 Conclusions After a first-line Cytokine therapy, TKIs (Level 1: pazopanib, axitinib, sorafenib; level 2: sunitinib) are the first options. After a first-line mtor-targeted therapy, patients should be included in clinical trials. After a first-line VEGF-targeted therapy, in the absence of specific comparative trials, another TKI or a mtor-inhibitor are both reasonable treatment options. No specific sequences emerged, to date, as the ideal ones. A continuous inhibition of angiogenesis appears to be key in this peculiar cancer. However, new targets should be explored (i.e. cmet, PI3K, FGFr, Angiopoietin/Tie2).

98 Grazie per l attenzione