La seconda linea di trattamento: scenario attuale e prospettive future Paolo Andrea Zucali Dipartimento di Oncologia HUMANITAS CANCER CENTER Rozzano - Milano
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)
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)
TKI Inhibitors after cytokines failure Agent Phase of study N ORR (%) mpfs (months) mos (months) SUNITINIB II II 105 107 34 20 8.3 8.2 n.r. 19.8 SORAFENIB vs placebo 1 III 903 10 vs 2 P<0.001 5.8 vs 2.8 P<0.001 17.8 vs 15.2 P=0.146 PAZOPANIB vs placebo 2 III 135 29 vs 3 7.4 vs 4.2 P<0.001 22.9 vs 20.5 P=0.224 AXITINIB vs Sorafenib 3 III 251 19 vs 9 P=0.0001 12.1 vs 6.5 P<0.0001 - - 1 Escudier B, et al. N Engl J Med 2007; 364:115 124 2 Sternberg C, et al. JCO 2010 3 Rini B, et al. Lancet 2011
SORAFENIB (TARGET Trial) OS in the cytokine-pretreated population Escudier et al. JCO 2009
PAZOPANIB PFS in the cytokine-pretreated subpopulation 1.0 Median PFS (months) Proportion progression-free 0.8 0.6 0.4 0.2 Placebo 4.2 Pazopanib 7.4 Hazard ratio (95% CI) 0.54 (0.35, 0.84) p value (1-sided) <0.001 46% reduction in risk of progression or death with pazopanib treatment compared with placebo 0.0 Number at risk, n Pazopanib Placebo 0 5 10 15 20 Time (month) 135 67 Pazopanib Placebo 75 16 37 7 18 5 Sternberg et al. J Clin Oncol 2010
AXITINIB PFS in the cytokine-pretreated subpopulation Rini et al. Lancet 2011
mrcc: second line Prior CYTOKINES
mrcc: second line Prior CYTOKINES SORAFENIB PAZOPANIB AXITINIB* LEVEL OF EVIDENCE 1 GRADE A RECOMMENDATION
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
mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted THERAPIES Prior mtor-targeted THERAPIES
mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior VEGF-targeted mtor-targeted THERAPIES THERAPIES Prior CYTOKINES Prior mtor-targeted THERAPIES
mrcc: second line Prior mtor-targeted THERAPIES
mrcc: second line Prior mtor-targeted THERAPIES CLINICAL TRIALS
mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted THERAPIES Prior mtor-targeted THERAPIES
mrcc: second line SECOND-LINE SYSTEMIC THERAPY Prior CYTOKINES Prior VEGF-targeted VEGF-targeted THERAPIES THERAPIES Prior mtor-targeted THERAPIES
mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) 1st Line Bevacizumab+IFNα
mrcc: second line 1st Line Bevacizumab+IFNα TKI mtor
mrcc: second line 1st Line Bevacizumab+IFNα TKI mtor
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
Bevacizumab Axitinib vs Sorafenib Rini BI, et al. Lancet 2011;378:1931-9. *One-sided log-rank test stratified by ECOG PS
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)
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 2010 1:1 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
mrcc: second line 1st Line Bevacizumab+IFNα TKI mtor
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
mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) 1st Line Bevacizumab+IFNα
mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) TKI mtor
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-08 416 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;372:449 456), complete study unblinded on 28-Feb-08
PFS by Treatment Central Radiology Review Probability, % 100 80 60 40 20 Hazard ratio = 0.33 95 % 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 0 2 4 6 8 10 12 14 Months 277 192 115 51 26 10 1 0 139 47 15 6 2 0 0 0
RECORD-1 Subgroup Analysis of PFS (Central Radiology Review) HR P value n Central review 0.33 <.001 416 Investigator review MSKCC risk Favorable Intermediate Poor Previous treatment Sorafenib only Sunitinib only Both 0.32 0.31 0.32 0.44 0.25 0.34 0.32 <.001 <.001 <.001.007 <.001 <.001 <.001 416 120 235 61 124 184 108 Age < 65 years 0.34 <.001 263 65 years 0.33 <.001 153 Sex Sex Male 0.32 <.001 322 Female 0.39 <.001 94 Region USA and Canada 0.29 <.001 130 Europe 0.38 <.001 251 Japan and Australia 0.18 <.001 35 0 0.2 0.4 0.6 0.8 1 1.2 1.4 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):4256-4265.
Everolimus was as effective after 2 TKIs as it was after 1 TKI 1. Motzer RJ, et al. Cancer 2010;116(18):4256 4265. 2. Hutson TE, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 7136.
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):4256-4265.
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):4256-4265.
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: 2.7-5.3) Sunitinib pretreated: mpfs 4.6 mos (95% CI: 2.8-6.5) 18/57 pts free from progression at 6 mos in the sunitinibpretreated group. PRIMARY ENDPOINT WAS MET GIR-2 study
mrcc: second line 1st Line TKIs (Sunitinib-Sorafenib-Pazopanib) TKI mtor
TKI-TKI Sequence: many retrospective and few prospective phase II trials Hutson et al. Clin Rev Oncol 2011
TKI-TKI Sequence: no cross-resistanceresistance SUNITINB SORAFENINB mpfs or TTP: 8.5-12.0 mos SORAFENINB SUNITINB mpfs or TTP: 12.5-19.019.0 mos Hutson et al. Clin Rev Oncol 2011
AXIS TRIAL
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
Progression-free Survival: all population (IRC Assessment) Progression-Free Survival (probability) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Subjects at risk, n Axitinib Sorafenib IRC = Independent Review Committee 0 2 4 6 8 10 Time (months) mpfs, mo 95% CI Axitinib Sorafenib 6.7 4.7 6.3, 8.6 4.6, 5.6 P<0.0001 (log-rank) Stratified HR 0.665 (95% CI: 0.544, 0.812) 12 14 16 18 20 361 256 202 145 96 64 38 20 10 1 0 362 224 157 100 51 28 12 6 3 1 0 Rini BI, et al. Lancet 2011
Rini BI, et al. Lancet 2011;378:1931-9. *One-sided log-rank test stratified by ECOG PS
Rini BI, et al. Lancet 2011;378:1931-9. *One-sided log-rank test stratified by ECOG PS
AXITINIB PFS in the TKI-pretreated subpopulation Rini et al. Lancet 2011
AXIS trial: Final Overall Survival
AXIS trial: Final Overall Survival
Per Per gentile concessione del del Dr. Dr. P. P. Zucali
Per Per gentile concessione del del Dr. Dr. P. P. Zucali
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
Progression-free Survival Survival Distribution Function 1.00 0.75 0.50 0.25 0.00 Axitinib 5 mg BID Axitinib >5 mg BID Sorafenib 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 PFS (months) 51
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
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]
PFS by Prior Response to Sunitinib: Axitinib vs Sorafenib Arms Axitinib Sorafenib 1.00 0.80 Non-responders Responders n 145 47 mpfs mo 4.8 4.6 95% CI 4.2 6.7 2.8 6.3 1.00 0.80 Non-responders Responders n 143 52 mpfs mo 3.0 4.7 95% CI 2.8 4.6 2.9 6.6 Probability of PFS 0.60 0.40 0.60 0.40 0.20 0.20 0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Time (months) Time (months) 0
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
BEST SEQUENCE: TKI-TKI or TKI-mTOR? Suggestions for clinical practice
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
Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
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
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
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
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; 2008. Abstract LB-201. 2. Nakamura K, et al. Cancer Res. 2006;66(18):9134-9142. 3. Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25(7):884-896.
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 1367 1267 363 895 742 Treatment duration (wks) 14 14.1 13.1 13.7 13.1 Larkin JMG, ASCO GU 2012
Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
Clinical practice No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
AXIS versus RECORD-1 1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9. Bex A., Lancet 2011
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. 2010 P. Zucali
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
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
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)
No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
DIFFERENT TOXICITY PROFILES TKI mtor inhibitor TKI
PROFILI DI TOSSICITA
No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
No response Intolerance Short term benefit Long term benefit Porta C, et al. EJMCO 2010 Eisen T, modified
In the absence of PREDICTIVE BIOMARKERS..
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
Clinical trials!
Second-line therapy: ongoing trials Trial Prior treatment Design End-point Status SWITCH Phase III NCT00732914 Sorafenib Sunitinib Vs Sunitinib Sorafenib PFS Recruiting (n=346) RECORD-3 Phase III NCT00903175 Everolimus Sunitinib Vs Sunitinib Everolimus PFS Recruiting (n=390) Pazopanib Bevacizumab START Phase II NCT01217931 Pazopanib Everolimus Everolimus Pazopanib Everolimus Bevacizumab Bevacizumab Everolimus TTF Recruiting (n=240) Bevacizumab Pazopanib Phase III NCT01198158 TKIs Bevacizumab Vs Beva + Eve OS Recruiting (n=700) Phase III NCT00474789 Sunitinib Temsirolimus Vs Sorafenib PFS Recruiting (n=480)
VEGFR and mtor pathways
Alternate Angiogenic Signalling Pathways Afford Novel Targets in RCC
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;8:299-309 Late phase: Reactivation of angiogenesis after anti-vegfr VEGFR2 therapy through FGF activation leads to tumorprogression
Horizontal Inhibition May Delay Development of Resistance
DOVITINIB Demonstrates Activity in Heavily Pretreated mrcc Patients Angevin E et al. ASCO 2010. Abs 3057.
Phase III Dovitinib in mrcc (third line)
AMG-386, an Angiopoeitin Antagonist With Antitumour Efficacy
Phase 2: AMG 386 + Sorafenib Increases Response but not PFS Over Sorafenib in RCC
PI3K/Akt/mTOR Signalling Figure adapted from Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
PERIFOSINE, an Oral Alkylphospholipid, Shows Clinical Benefit in Refractory mrcc
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
Immunotherapy?
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-663513 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
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).
Grazie per l attenzione