Linee guida terapeutiche oncologiche Francesco Massari U.O.C. di Oncologia Medica d.u. Azienda Ospedaliera Universitaria Integrata Verona 1 YOUNG SPECIALIST RENAL CARE Verona, 07-08 Marzo 2014
Clinical guidelines are only one option for improving the quality of care. Clinical guidelines make sense when practitioners are unclear about appropriate practice and when scientific evidencecanprovideananswer.theyareapoorremedyin other settings. When clinicians already know the information contained in guidelines, should redirect their efforts to identify the specific barriers, beyond knowledge, that stand in the way of behavior change. SH Woolf et al., BMJ 1999
Current treatment Algorithm for mrcc therapy HISTOLOGY SETTING RISK GROUP STANDARD THERAPY OPTION Clear-cell Favourable/Inter mediate risk Sunitinib (Motzer, NEJM 2007) Bevacizumab+ INFa (Escudier, Lancet 2007) Pazopanib (Sternberg, J Clin Oncol 2010) Cytokine(IL-2HD) Sorafenib I Line Poor-risk Temsirolimus (Hudes, NEjM 2007) Sunitinib Sorafenib II Line Post cytokines Sorafenib ( Escudier, NEJM 2007) Pazopanib Axitinib (Rini, Lancet 2011) Sunitinib Post TKIs Everolimus (Motzer, Lancet, 2008) Axitinib (Rini, Lancet 2011) Sorafenib Non clear-cell Clinical trial Temsirolimus Ciccarese C, Massari F. 2013 Sunitinib Sorafenib
First-line treatment for clear cell mrcc: guidelines Favourable and Intermediate risk AIOM 1 ESMO 2 NCCN 3 EAU 4 Sunitinib (pos. forte) Bevacizumab + IFNα (pos. debole) Sunitinib (IA) Bevacizumab + IFNα (IA)* Sunitinib (cat.1) Bevacizumab + IFNα (cat.1) Sunitinib (1b) Bevacizumab + IFNα (1b) Pazopanib (pos. debole) Pazopanib (IIB)* Pazopanib (cat.1) Pazopanib (1b) Sorafenib IL-2 High-dose IL-2 Temsirolimus Sorafenib Clinical trial IL-2 Poor risk Temsirolimus (pos. debole) Temsirolimus (IA)* Temsirolimus (cat.1) Temsirolimus (1b) Sunitinib 1 Linee GuidaAIOM 2013; 2 Escudier B, et al. Ann Oncol2012 3 NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer v.2.2014; 4 Ljungberg B, et al. 2013; *Corrigendum Ann Oncol 24(6): vi171, 2013
First-line treatment for clear cell mrcc: AIOM guidelines AIOM guidelines 2013
First-line treatment for clear cell mrcc: AIOM guidelines Modified by R. Passalacua, AIOM guidelines 2013
Bevacizumab + Interferon-α in 1st-line
Why choosing Sunitinib? 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 Hazard Ratio=0.538 (95% CI 0.439, 0.658) p<0.000001 IFN-α Median 5.1 months (95% CI 3.9-5.6) 0 5 10 15 20 25 30 Time (months) Sunitinib Median 11.0 months (95% CI 10.7-13.4) No. at Risk Sunitinib: 375 240 156 54 10 1 IFN-α: 375 124 46 15 4 0 Level of evidence: 1; grade of recommendation: A Motzer RJ et al., NEJM 2007
Sunitinib works in all risk groups Risk Group* % Median PFS (months) Sunitinib (n=375) IFN-a (n=375) Favorable (0 risk factor) 35 14.5 7.9 (95% CI) (11.3 16.8) (7.0 10.5) Intermediate (1-2 risk factors) 56 10.6 3.8 (95% CI) (8.2 10.9) (3.6 4.0) Poor ( 3 risk factors) 6 3.7 1.2 (95% CI) (2.0 9.8) (1.0 2.4) *Motzer et al. J Clin Oncol 2002;20:289-96; Risk factors associated with shorter survival were: low hemoglobin, high corrected calcium, high LDH, poor performance status, and an interval of <1 yr from diagnosis to treatment Motzer RJ, et al., NEJM 2007
Why choosing Pazopanib? Proportion Progression-Free 1.0 0.8 0.6 0.4 0.2 0.0 Pazopanib Placebo 0 5 10 15 20 Months Hazard Ratio = 0.46 95% CI (0.34, 0.62) P value < 0.0000001 Median PFS Pazopanib: 9.2 mo Placebo: 4.2 mo Sternberg, J Clin Oncol 2010
First-line treatment for clear cell mrcc: AIOM guidelines AIOM guidelines 2013
COMPARZ Trial: Study design Phase 3, randomized, noninferiority trail, designed to compared the efficacy and safety of pazopanib and sunitinib in patients with mrcc as first-line treatment. KEY ELIGIBILITY CRITERIA: Advanced or metastatic RCC Clear-cell histologic component No prior systemic therapy Measurable disease KPS >70 Adequate organ function Stratification Factors: KPS 70/80 vs 90/100 Prior nephrectomy Baseline LDH R A N D O M I Z E 1 : 1 PAZOPANIB 800 mg/qd continuous dosing Dose reductions to 600 mg or 400 mg SUNITINIB 50 mg qd 4wk on/2wk off Dose reductions to 37.5 mg or 25 mg 1100 pts (183 asiatics) Motzer RJ et al., NEJM 2013; 369(8): 722-31
COMPARZ TRIAL: EFFICACY RESULTS PAZOPANIB SUNITINIB HR Median PFS (IRC) 8.4 months 9.5 months Median OS* 28.4 months 29.3 months 1.047 (95%CI 0.898-1.220) 0.908 (95%CI 0.762-1.082) ORR (IRC) 31% 25% p=0.032 Median duration of the treatment 8 months 7.6 months Dose reductions 44% 51% Discontinuations due toaes 24% 19% * Interim analysis Motzer RJ et al. ESMO 2012 (abst.lba8) -Motzer RJ et al., NEJM 2013; 369(8): 722-31
COMPARZ has changed the guidelines? EscudierB, et al. Ann Oncol2012 ; Corrigendum Ann Oncol24(6): vi171, 2013
COMPARZ has changed the guidelines? EAU 2013 EAU 2010 LjungbergB, et al. 2013; LjungbergB, et al. 2010
Phase 3 Trial Temsirolimus in Poor-risk mrcc HudesG et al. N EngJ Med. 2007
Temsirolimus: Overall Survival HudesG et al. N EngJ Med. 2007
Current treatment Algorithm for mrcc therapy HISTOLOGY SETTING RISK GROUP STANDARD THERAPY OPTION Clear-cell Favourable/Inter mediate risk Sunitinib (Motzer, NEJM 2007) Bevacizumab+ INFa (Escudier, Lancet 2007) Pazopanib (Sternberg, J Clin Oncol 2010) Cytokine(IL-2HD) Sorafenib I Line Poor-risk Temsirolimus (Hudes, NEjM 2007) Sunitinib Sorafenib II Line Post cytokines Sorafenib ( Escudier, NEJM 2007) Pazopanib Axitinib (Rini, Lancet 2011) Sunitinib Post TKIs Everolimus (Motzer, Lancet, 2008) Axitinib (Rini, Lancet 2011) Sorafenib Non clear-cell Clinical trial Temsirolimus Ciccarese C, Massari F. 2013 Sunitinib Sorafenib
Current treatment Algorithm for mrcc therapy II Line Post cytokines Sorafenib ( Escudier, NEJM 2007) Pazopanib Axitinib (Rini, Lancet 2011) Sunitinib Post TKIs Everolimus (Motzer, Lancet, 2008) Axitinib (Rini, Lancet 2011) Sorafenib Ciccarese C, Massari F. 2013
Second-line treatment for clear cell mrcc: guidelines Second-line after TKI AIOM 1 ESMO 2 NCCN 3 EAU 4 Everolimus (pos. forte) Sorafenib (pos. debole) Axitinib(IB)* Everolimus(IIA) Axitinib(cat.1) Everolimus(cat.1) Sorafenib(cat.2) Sunitinib(cat.2) Axitinib(1b) Everolimus(1b) Sorafenib(1b) Seond-line after cytokines Sorafenib (pos. forte) Pazopanib (pos. debole) Sunitinib (pos. debole) Axitinib(IA) Sorafenib(IA) Pazopanib(IIA) Sunitinib(IIIA) Axitinib(cat.1) Sorafenib(cat.1) Pazopanib(cat.1) Sunitinib(cat.1) Axitinib(1b) Sorafenib(1b) Pazopanib(1b) 1 Linee Guida AIOM 2013; 2 Escudier B, et al. Ann Oncol 2012 3 NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer v.2.2014; 4 Ljungberg B, et al. 2013; *Corrigendum Ann Oncol 24(6): vi171, 2013
Second-line treatment for clear cell mrcc: AIOM guidelines Modified by R. Passalacua, AIOM guidelines 2013
Everolimus has level I evidence in 2 nd line
RECORD-1: Everolimus vs. placebo Patientswith: Metastatic RCC with clear cell component; Measurable disease; Progressive disease on or within 6 months of treatment with sunitinib, sorafenib, or both; Prior bevacizumab and cytokines permitted; Adequate performance status, blood counts, and serum chemistry. R 2:1 Everolimus 10 mg/day. Treat until PD, unmanageable AEs or withdrawal of consent. Stratification factors: Prior VEGFrTKI: 1 or 2 MSKCC risk group: favorable, intermediate, or poor Placebo N=362 Primary endpoint: PFS Secondary endpoints: OS, ORR, safety, QoL 1. Motzer, et al. Lancet 2008;372:449-56; 2. Motzer et al. Cancer 2010;116:4256-65
RECORD-1: Everolimus vs. placebo Progression Free Survival Overall Survival 81% of pts crossed over from pbo to everolimus. 1. Motzer, et al. Lancet 2008;372:449-56; 2. Motzer et al. Cancer 2010;116:4256-65
RECORD-1: a real II line trial? (more than 75% of pts in RECORD-1 received everolimus as 3rd+ Line) 1 st Line 2 nd Line 3 rd Line mtor 4 th Line n = 82 5 th Line 1 st Line 2 nd Line 3 rd Line mtor 4 th Line n = 104 79% 1 st Line 2 nd Line mtor 3 rd Line n = 141 1 st Line mtor 2 nd Line n = 89 21% Patients received a median of 2 prior antineoplastic medications 1. Motzer, et al. Lancet 2008;372:449-56; 2. Motzer et al. Cancer 2010;116:4256-65; 3. Calvo E, et al. Eur J Cancer 2011.
Axitinib has level I evidence in 2 nd line
AXIS Trial: Axitinib vs. Sorafenib Patientswith mrcc and PD Histologically-confirmedmRCC with clear-cell component Failure of prior first-line regimen containing 1 of: -Sunitinib - Bevacizumab +IFN-α - Temsirolimus - Cytokine(s) Stratification factors: Prior regimen ECOG PS (0 vs 1) R 1:1 Axitinib 5 mg b.i.d. Sorafenib 400 mg oral BID (n=253) N=723 Treat until PD, unmanageable AEs or withdrawal of consent. Primary endpoint: PFS Secondary endpoints: OS, ORR, safety, QoL Motzer RJ et al. Lancet Oncol 2013
AXIS Trial: Axitinib vs. Sorafenib PFS in overall population PFS in Sunitinibpretreated population Rini BI et al. Lancet Oncol 2011
AXIS Trial: Axitinib vs. Sorafenib OS in overall population OS in Sunitinibpretreated population Crossover from sorafenib to axitinib was not allowed. Motzer RJ et al. Lancet Oncol 2013
Sorafenib has now level I evidence in 2 nd line, too
INTORSECT Trial: Temsirolimus vs. Sorafenib PatientswithmRCC and PD on 1 st line sunitinib(n=512) Stratification factors: Durationofsunitinib therapy( or >6 mo) MSKCC riskgroup Histology(clear cell or non-clear cell) Nephrectomy status R 1:1 Temsirolimus 25 mg IV weekly (n=259) Sorafenib 400 mg oral BID (n=253) Treat until PD, unacceptable toxicity, or discontinuation for any other reason N=512 Primary endpoint: PFS Secondary endpoints: OS, ORR, duration of response, safety, QoL HutsonTE, et al. JClinOncol. 2013
INTORSECT Trial: Temsirolimus vs. Sorafenib Hutson T, ESMO 2012
Current treatment Algorithm for mrcc therapy HISTOLOGY SETTING RISK GROUP STANDARD THERAPY OPTION Clear-cell Favourable/Inter mediate risk Sunitinib (Motzer, NEJM 2007) Bevacizumab+ INFa (Escudier, Lancet 2007) Pazopanib (Sternberg, J Clin Oncol 2010) Cytokine(IL-2HD) Sorafenib I Line Poor-risk Temsirolimus (Hudes, NEjM 2007) Sunitinib Sorafenib II Line Post cytokines Sorafenib ( Escudier, NEJM 2007) Pazopanib Axitinib (Rini, Lancet 2011) Sunitinib Post TKIs Everolimus (Motzer, Lancet, 2008) Axitinib (Rini, Lancet 2011) Sorafenib Non clear-cell Clinical trial Temsirolimus Ciccarese C, Massari F. 2013 Sunitinib Sorafenib
Current treatment Algorithm for mrcc therapy Non clear-cell Clinical trial Temsirolimus Sunitinib Sorafenib Ciccarese C, Massari F. 2013
nccrcc Treatment Options Are Limited Efficacy and safety data are inconclusive Patients usually excluded from pivotal trials 1 No targeted therapies currently approved for nccrcc Evidence-based treatment guidelines are limited 2,3,4 Clear guidance is lacking; optimal treatment strategy remains to be determined 5 1. Schrader AJ et al. BJU Int. 2008;101:1343-1345. 2. NCCN. Clinical Practice Guidelines in Oncology for Kidney Cancer. V 2.2014. 3. Escudier B et al. Ann Oncol. 2012; 4. Ljungberg B et al. Eur Urol. 2013; 5. Singer EA et al. Target Oncol. 2010;5:119-129.
Conclusion and open questions Limit of Guidelines which refer to studies very selected in terms of methodology, inclusion and exclusion criteria Discrepancies in guidelines: how to assess them? In what may be useful and how we can use them in clinical practice? Where there are many differences in efficacy or toxicity there is no question, but where the results are similar or almost similar?
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