1 / 28

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

kele
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related