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Sequential treatment in metastatic kidney cancer

Sequential treatment in metastatic kidney cancer. GIUSEPPE DI LORENZO. Medical Oncology Division University Federico II of Naples. …From 1990 to 2012. Bevacizumab + IFN 5. Temsirolimus 4. High dose interleukin-2 1. Pazopanib 7. Everolimus 6. Sorafenib 2.

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Sequential treatment in metastatic kidney cancer

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  1. Sequential treatment in metastatickidneycancer GIUSEPPE DI LORENZO MedicalOncologyDivision University Federico II ofNaples

  2. …From 1990 to 2012 Bevacizumab + IFN5 Temsirolimus4 High dose interleukin-21 Pazopanib7 Everolimus6 Sorafenib2 Sunitinib3 Tivozanib 2008 2005 2006 2007 2009 2009 2011 2012 2010 1992–2005 IFN- Axitinib8(FDA) • Fyfe G et al. J Clin Oncol 1995; 13: 688-696. • Escudier B et al. N Engl J Med 2007; 356: 125-134. • Sutent. Summary of Product Characteristics. 2010. • Hudes G et al. N Engl J Med 2007; 356: 2271-2281. 5. EscudierB et al. Lancet 2007; 370: 2103-2211. 6. Afinitor. Summary of Product Characteristics. 2010. 7. Sternberg CN et al. J ClinOncol2010; 28: 1061-1068. 8. Rini et al. Lancet 2011; 378: 1931-39

  3. Improved survival 1.0 0.8 0.6 Proportion surviving 0.4 0.2 0 5 0 1 2 3 4 6 7 8 9 10 YearsfromTx start Trends in survival for metastatic RCC patients treated on trials at MSKCC: at 5 years: 20 % vs 5-7% survivors

  4. Howtochoose first line treatment Prognosticprofile (Motzer/Heng ) Good-intermediaterisk : Standard Options sunitinib,pazopanib,beva+IFN, (tivozanib)sorafenib, HD IL-2,observation Poorrisk: temsirolimus,sunitinib,BSC

  5. Howtochoose first line treatment Toxicityprofile, QoLand comorbidities

  6. Howtochoose first line treatment Physicianexperience

  7. Howtochoose first line treatment Patientpreference

  8. Howtochoose first line treatment Histology

  9. First-line and following treatment • Manypatientsreceivedsunitinibworldwide • The useofpazopanibislimitedbutgrowing

  10. SECOND LINE Secondlinetherapyfollowingpriorcytokines: fewpts 5-10% Secondlinetherapyfollowingpriortarget-therapy: the maiority

  11. Secondlinetherapyfollowingpriorcytokines: • Sorafenib: level 1 evidence(PFS improvement vs IFN) • Pazopanib: level 1 evidence(PFS improvement vs placebo) • Tivozanib: PFS improvement vs sorafenib

  12. SECOND-LINE afterTKIs TKI? or MTOR?

  13. Sequential treatment in kidney cancer

  14. RECORD-1 Phase III Study Design: Everolimusvs Placebo After Progression on a VEGFR-TKI R A N D O M I Z A T I O N 2:1 Everolimus + Best Supportive Care (n = 277) • Stratification • n = 416 • Previous VEGFR-TKI: 1 or 2 • MSKCC risk group Placebo + Best Supportive Care (n = 139) Motzer RJ, et al. Cancer 2010

  15. RECORD-1 100 Median PFS Everolimus (n = 277): 4.9 mos Placebo (n = 139): 1.9 mos HR: 0.33 95% CI: 0.25-0.43 Log rankP < .001 80 60 PFS (%) 40 20 0 0 2 4 6 8 10 12 Months Motzer RJ, et al. Cancer 2010

  16. RECORD-1 HR P Value N Central review Investigator review MSKCC risk Favorable Intermediate Poor Previous treatment Sorafenib only Sunitinib only Both Age <65 yrs ≥65 yrs Sex Male Female Region US and Canada Europe Japan and Australia 0.30 0.31 0.35 0.25 0.39 0.29 0.30 0.28 0.32 0.29 0.29 0.36 0.24 0.37 0.10 < .0001 < .0001 < .0001 < .0001 .009 < .0001 < .0001 < .0001 < .0001 < .0001 < .0001 .002 < .0001 < .0001 .001 410 410 118 231 61 119 184 107 259 151 317 93 130 251 29 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 In favor of everolimus In favor of placebo Motzer RJ, et al. Lancet. 2008;372:449-456.

  17. Everolimus: a real 2nd line? RECORD-1 EVE 3rd/4th line 1st line 2nd line (3rd line) n = 108 2 VGFR-TKI ± 1 other prior therapy 79% EVE 3rd line 1st line 2nd line n = 219 VEGF-TKI + 1 other prior therapy most commonly cks 2nd line EVE 1st line VGFR-TKI n = 89 21% Motzer RJ, et al. Cancer 2010

  18. AxitinibvsSorafenibas Second-line Therapy for Metastatic Renal Cell Carcinoma:Results of the Phase 3 AXIS Trial Axitinib 5 mg BID* R A N D O M I Z E Potent and selective second-generation inhibitor of VEGFR-1, 2, 3 Treatment-refractory metastatic RCC Primary endpoint: PFS Secondaryanalyses:effect of dose titration and previous first-line treatment duration and response on axitinib efficacy Sorafenib 400 mg BID *Starting dose 5 mg BID with option for dose titration to 10 mg BID

  19. Patient Characteristic

  20. Patient Characteristic 1) Motzer RJ, et al. J Clin Oncol 1999;17:2530-40; 2) Heng DY et al. J Clin Oncol 2009;27:5794-9

  21. Best response by RECIST (IRC assessment) *Axitinib vs Sorafenib: P = 0.0001

  22. Progression-free Survival(IRC Assessment) mPFS, mo 95% Cl 1.0 Axitinib Sorafenib 6.7 4.7 6.3 - 8.6 4.6 - 5.6 0.9 0.8 P<0.0001 (log-rank) Stratified HR 0.665 (95% Cl 0.544-0.812) 0.7 0.6 0.5 Progression-Free Survival (probability) 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Time (months) Subjects at risk, n Axitinib 361 256 202 145 96 64 38 20 10 1 0 Sorafenib 362 224 157 100 51 28 12 6 3 1 0 IRC = Independent Review Committee

  23. PFS by Prior Regimen

  24. How to select second line therapy? • No direct comparisonbetweenaxitinib and everolimus • Toxicitywith first-line VEGFi agent • Response or Duration of responsewith first-line TKI • No data for mTORi mTORi

  25. SECOND-LINE: Head to head TKI VS MTOR

  26. INTORSECT*: Hutson, Escudier, ESMO 2012 RANDOMIZE • Patients with mRCC and PD on 1st-line sunitinib • (N=512) • Stratification factors: • Duration of sunitinib therapy (≤ or >6 mo) • MSKCC risk group • Histology (clear cell or non–clear cell) • Nephrectomy status Temsirolimus 25 mg IV weekly† (n=259) Treat until PD, unacceptable toxicity, or discontinuation for any other reason Sorafenib 400 mg oral BID† (n=253) N=512 112 sites in 20 countries 1:1 First patient randomized: September 25, 2007; last patient randomized: January 31, 2012. Data cutoff: May 4, 2012. At present, 2 patients are on study. *ClinicalTrials.gov Identifier: NCT00474786. †Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg); sorafenib (to 400 mg/day then every other day). BID, twice daily; IRC, independent review committee; IV, intravenous; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; PD, progressive disease; PFS, progression-free survival. 30

  27. INTORSECT: Progression-Free Survival Median PFS,months 1.0 95% CI 4.28 4.01, 5.43 0.9 Temsirolimus 3.91 2.80, 4.21 Sorafenib 0.8 P=0.1933 (log-rank) 0.7 Stratified HR: 0.87 0.6 (95% CI: 0.71, 1.07) PFS (probability) 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 Time (months) Patients at risk, n Sorafenib 252 72 22 11 6 0 Temsirolimus 259 96 28 9 5 0 CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival. 31

  28. INTORSECT: Overall Survival Median OS,months 95% CI 1.0 12.27 10.13, 14.80 Temsirolimus 0.9 16.64 13.55, 18.72 Sorafenib 0.8 P=0.014 (log-rank) Stratified HR: 1.31 0.7 (95% CI: 1.05, 1.63) 0.6 Overall Survival (probability) 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 Time (months) Patients at risk, n Sorafenib 253 158 74 34 13 0 Temsirolimus 259 132 54 22 8 0 CI, confidence interval; HR, hazard ratio; OS, overall survival. 32

  29. EUR UROL 2012

  30. Take Home Messages:Refractorydisease Options: • Axitinib++ • Everolimus++ • Sorafenib+ • Sunitinib • Dovitinib? Choicebased on: • Side-effectswith first line + • Good-risk/poorriskassessment+ • Comorbidity and age+ • Response and durationof first line • Site ofdisease • Histology

  31. Potentialfactorstocustomizesecond-line • Toxicityprofile

  32. Everolimus: adverse events *Significant difference between sum of grade ¾ events for everolimus and palcebo groups (P < .05) Motzer RJ, et al. Lancet. 2008;372:449-456.

  33. Axitinib: Adverse events*

  34. Potentialfactorstocustomizesecond-line • good/poorprognosis

  35. GOOD PROGNOSIS: generallyabletoundergo multiple linesoftherapies POOR PROGNOSIS: no multiple lines TKI MTOR

  36. Potentialfactorstocustomizesecond-line • Age

  37. Hazard Ratios for PFS by Prognostic Factors and Baseline Characteristics Baseline factor n Axitinib benefit Sorafenib benefit ECOG performance status 1 327 ECOG performance status 0 396 Sunitinib-containingregimen 389 Bevacizumab-containing regimen 59 Temsirolimus-containing regimen 24 Cytokine-containing regimen 251 White 547 176 Non-white 523 Male Female 200 Age <65 years 476 Age ≥65 years 247 306 MSKCC favorable MSKCC intermediate/poor 417 Asia 152 Europe 357 North America 186 Other region 28 0.0 1.0 2.0 3.0 Hazard Ratio (95% Cl)

  38. Incidence in elderlypatients and the total studypopulationofadverseevents and laboratoryabnormalities (allgrades)* BSC = best supportive care. *Regardlessof relation to treatment, occurring in >10% ofallpatients in the everolimusarm.

  39. Dose reductions, dose interruptions and concomitantmedications in elderlypatients and the total studypopulation

  40. Potentialfactorstocustomizesecond-line • Priorresponseto TKI

  41. INVESTIGATING TREATMENT SEQUENCES: A STEP FORWARD Thirdline

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