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Treatment Beyond Progression- is there a new standard of care for wt kras ?

Treatment Beyond Progression- is there a new standard of care for wt kras ? . Heinz-Josef Lenz Associate Director, Clinical Research Kathryn Balakrishnan Chair for Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery Co-Leader GI Oncology Program

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Treatment Beyond Progression- is there a new standard of care for wt kras ?

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  1. Treatment Beyond Progression-is there a new standard of care for wtkras? Heinz-Josef Lenz Associate Director, Clinical Research Kathryn Balakrishnan Chair for Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery Co-Leader GI Oncology Program USC/Norris Comprehensive Cancer Center

  2. Options for wtkras…wt .. • Continue Anti VEGF therapy (bevacizumab, aflibercept) • Switch to anti EGFR AB

  3. Hallmarks of Cancer – Therapeutic Targeting Self-sufficiency in growth signals EGFR inhibitors Proapoptotic BH3 mimetics Evading apoptosis Insensitivity to antigrowth signals Acquired Functional Capabilities of Cancer Cells Cyclin-dependent kinase inhibitors Inhibitors of VEGF signaling Sustained angiogenesis Tissue invasion and metastasis Inhibitors of HGF/c-Met Limitless potential to replicate Telomerase inhibitors VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor. Hanahan D, et al. Cell. 2011;144:646-674. 15

  4. Genetic Changes in CRC Cancer Genome Atlas Network. Nature. 2012;487:330-337.

  5. Genomics: Cancer Genome Atlas Cancer Genome Atlas Network. Nature. 2012;487:330-337.

  6. VEGF expression throughout tumour life cycle1 Pre-clinical data suggest continuous VEGF suppression is key to achieving and maintaining tumour control2 bFGF TGFb-1 bFGF TGFb-1 bFGF TGFb-1 bFGF VEGF VEGF VEGF VEGF VEGF PIGF PD-ECGF TGFb-1 PIGF PIGF PD-ECGF Pleiotrophin Tumour evolution VEGF = vascular endothelial growth factor bFGF = basic fibroblast growth factor TGFb-1 = transforming growth factor b-1 PD-ECGF = platelet-derived endothelial cell growth factor 1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 2005 2. Bagri et al. Clin Cancer Res 2010

  7. VEGF-A, VEGF-B, and PlGF are involved in multiple pathways of angiogenic response BM PROGENITORS LEUKEMIC CELL Proliferation, Migration, Survival DENDRITIC CELL Suppression ofantigen recognition MACROPHAGE Recruitment and activationRelease of angiogenic factors VEGF-A VEGF-A PlGF sVEGFR-1 VEGF-B STROMAL CELLPERICYTE, SMC MigrationProliferation TUMOR CELL Proliferationand migrationChemoprotection VEGF-A VEGFR-1 VEGFR-2 ENDOTHELIAL CELL Survival, Migration, Proliferation Adapted from Fischer. Nat Cancer Rev. 2008;8:942–956.

  8. 5 Courtesy of Heinz-Josef Lenz, MD.

  9. Pharmacologic Approaches to Blocking Angiogenesis THREE GENERAL MECHANISMS OF ANGIOGENESISINHIBITORS THAT BLOCK THE VEGF PATHWAY Intracellular Extracellular VEGFR-2 Tumorcell VEGF • Block VEGF receptor • Anti-VEGFR-2 TKIs(sunitinib, etc) • Neutralize VEGF • Aflibercept • Bevacizumab • Block VEGFexpression • Erlotinib • Cetuximab • Panitumumab ANGIOGENESIS INHIBITORS 1. Avastin PI. 2010. Genentech Inc. 2. Holash. PNAS. 2002;99:11393–11398. 3. Sutent PI. 2010. 4. Nexavar PI. 2010. 5. Votrient PI. 2010. 6. Petit. Am J Pathol. 1997;151:1523–1530. 7. Tarceva PI. 2010. 8. Erbitux PI 2010. 9. Vectibix PI. 2010 Neutralizing VEGF activity(e.g., bevacizumab, aflibercept)1,2 Inhibition of receptorkinase activity (e.g., sunitinib,sorafenib, pazopanib, etc.)3-5 Reducing expression of VEGFby inhibiting tumor growth pathways(e.g., anti-EGFR therapies)6-9

  10. VEGF-TRAP TG-403 PlGF VEGF-B VEGF-C BEVACIZUMAB* VEGF-A VEGF-D 18F1 1121B Tyrosine Kinase Inhibitors Sunitinib* Sorafenib* Pazopanib* Axitinib* Motesanib Cedirinib Brivanib Many, many others VEGF Targeted Agents in the Clinic or In Clinical Trials Do we see improved outcomes in patients treated with agents that target PlGF/VEGFR-1? NRP-1/ NRP-2 VEGFR-3 (Flt-4) NRP-2 VEGFR-1 (Flt-1) VEGFR-2 (Flk- 1/KDR) Vasculogenesis Angiogenesis Lymphangiogenesis Ellis, Hicklin Nat Rev Ca. 2008 * FDA approved agents

  11. Biomarker profiles may indicate resistance against VEGF inhibition • Patients treated with FOLFOXIRI-bevacizumab* were screened for VEGF, PlGF levels Loupakis F et al, BJC, 2011, 104: 1262-9 * Masi G et al, Lancet Oncol, 2010: 11, 845-52

  12. Cytokine increase on BEV therapy Kopetz et al., JCO 2010

  13. EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) 13 Aflibercept 4 mg/kg IV+ FOLFIRI q 2 weeks 600 pts mCRC afterfailure of an oxaliplatinbased regimen R 1:1 Placebo + FOLFIRIq 2 weeks Stratification factors: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) 600 pts 30% of patients had prior BEV PIs: Allegra, Van Cutsem

  14. VELOUR: phase III trial of second-line aflibercept plus FOLFIRI – efficacy (ITT) OS* PFS† Aflibercept + FOLFIRI (n=612) Placebo + FOLFIRI (n=614) Aflibercept + FOLFIRI (n=612) Placebo + FOLFIRI (n=614) 1.0 1.0 HR*=0.82 p=0.0032 HR*=0.76 p=0.00007 0.8 0.8 PFS estimate1 OS estimate1 0.6 0.6 0.4 0.4 6.9 4.7 12.1 13.5 0.2 0.2 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 3336 39 Time (months) Time (months) 0 0 Improvement in OS and PFS with aflibercept appears to be independent of prior treatment with bevacizumab 2L aflibercept plus FOLFIRI significantly improved OS and PFS compared with FOLFIRI *Stratified, cut-off date = February 7, 2011 †Stratified, cut-off date = May 6, 2011 Van Cutsem, et al. JCO 2012

  15. Aflibercept: VELOUR Phase III: OS and PFS Stratified by PriorBevacizumab Overall Survival 0 1 2 3 Favors aflibercept Favors placebo Progression-Free Survival 0 1 2 3 Favors aflibercept Favors placebo Adapted from Van Cutsem E, et al. J ClinOncol. 2012 Sep 4. [Epub ahead of print].

  16. Primary Endpoint Allegra Abstract #3505

  17. Response Rates Van Cutsem et al., JCO 2012

  18. Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events • AEs leading to treatment discontinuation: • AFL: 26.6% • PL: 12.1% Van Cutsem et al., JCO 2012

  19. EGF Receptor: A Rational Target for CRC Therapy Ligand: AREG, EREG EGFR-TK Target for EGFT-TK inhibitor pY GRB2 pY SOS P13K RAS RAF pY STAT MEK AKT PTEN MAPK Gene transcription Cell-cycle progression P P Cyclin D1 MYC JUN FOS Cyclin D1 MYC Proliferation/maturation Survival (anti-apoptosis) Chemotherapy/radiotherapy resistance Invasion and metastasis Angiogenesis Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.

  20. IRI OX OX OX OX OX IRI IRI 1st Line 2nd Line

  21. PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS WT mCRC 0.7 Cetuximab Panitumumab 0.6 0.5 0.4 0.3 0.2 1- HR NORDIC VII2 COIN3 PICCOLO6 CRYSTAL5 0.1 Amado8 CO.179 PRIME4 1817 0 –0.1 N01471 –0.2 –0.3 Salvage (single agent) Adjuvant 1L 2L 1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. JCO 2010; 5. Van Cutsem, et al. JCO 2011; 6. Seymour, et al. ASCO 20117. Peeters, et al. JCO 2010; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008

  22. 181 vs EPIC A Sobrero et al. GI Symposium 2012 A Sobrero et al. J Clin Oncol 2008. 26:2311-2319.

  23. 181: FOLFIRI +/- PanitumumabPFS and OS PFS OS 100 Panitumumab + FOLFIRI (n=303) Panitumumab + FOLFIRI (n=238) FOLFIRI alone (n=294) FOLFIRI alone (n=248) 80 Hazard ratio (95% CI): 0.92 (0.78, 1.10) P-value: 0.37 Hazard ratio (95% CI): 0.82 (0.69, 0.97) P-value: 0.023 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months Months Median (95% CI), months 6.7 (5.8, 7.4) 4.9 (3.8, 5.5) Median (95% CI), months 14.5 (13.0, 16.1) 12.5 (11.2, 14.2) Panitumumab + FOLFIRI Panitumumab + FOLFIRI FOLFIRI alone FOLFIRI alone * PFS “on treatment” HR = .73; p= .001 Adapted from: A Sobrero et al. GI Symposium 2012

  24. SWOG 0600/iBET: A Phase III of Irinotecan and Cetuximab With or Without Bevacizumabin Patients With mCRC That Progressed During First-Line TherapyGold, Grothey et al.. Second line R A N D O M I Z E mCRC KRAS wild-type previously treated with Bevacizumab and oxaliplatin- based CT (n=1260) Bevacizumab 5 mg/kg + (FOLFIRI or Irinotecan + Capecitabine) PD Cetuximab + (FOLFIRI or Irinotecan + Capecitabine) N = 68 CT + dual biologic arm removed • Primary endpoint: OS • Secondary endpoints: PFS, objective tumor response, tolerability, and safety • June 2007 – October 2010

  25. PEAK study: FOLFOX + Pmab vs. FOLFOX + Beva SchwartzbergL et al ASCO 2013

  26. CO.20 Trial: Cetuximab +/- BrivanibK-Ras WT Chemo-refractory CRC Siu et al

  27. Conclusions • Anti Angiogenesis Therapy effective through all lines of therapy (1.4 months!) • Not only kras exon 12/13 but all other codons and nras may be used to select patients for second line anti EGFR Therapies (prior to resistant!?) • Emergent Mechanisms of Resistance in EGFR and VEGF pathways may be a key for combination therapies

  28. Are All KRAS Mutations Created Equal? – G13D Pooled analysis of OPUS and CRYSTAL Tejpar et al., ASCO 2011

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