1 / 40

Metastatic Colon Cancer: Today’s and Tomorrow’s Target

Metastatic Colon Cancer: Today’s and Tomorrow’s Target. Tanios Bekaii-Saab, MD Medical Director, GI Oncology The Ohio State University-James Cancer Hospital. May regress existing microvasculature 1,2

Audrey
Download Presentation

Metastatic Colon Cancer: Today’s and Tomorrow’s Target

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. Metastatic Colon Cancer: Today’s and Tomorrow’s Target Tanios Bekaii-Saab, MD Medical Director, GI Oncology The Ohio State University-James Cancer Hospital

  2. May regress existing microvasculature1,2 • Direct and rapid changes include a significant reduction in microvascular density, as seen in preclinical models1-3 3 1 • May normalize surviving mature vasculature3-5 • Reversal of structural and functional abnormalities may improve the vasculature’s • capacity for drug delivery, as seen in preclinical models3-5 May inhibit vessel regrowth and neovascularization2,3,6 2 Anti-VEGF Agents’ Proposed Mechanisms of Action Based on Preclinical Models 1. Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60:5565-5570. ; 2. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.; 3. Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680.; 4. Jain RK. Science. 2005;307:58-62.; 5. Tong RT, Boucher Y, Kozin S, et al. Cancer Res. 2004;64:3731-3736.; 6. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.

  3. First-Line Bevacizumab in MCRC: Progression-Free Survival AVF2107g NO16966 BICC-C TREE-2 a b c PFS or TTP (mo) aP<0.001; bP=0.0023; cP=0.003 vs mIFL. Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510; Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.

  4. First-Line Bevacizumab in MCRC: Overall Survival AVF2107g NO16966 BICC-C TREE-2 b a OS (mo) aP<0.001; bP=0.0769. Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510; Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.

  5. NO66: Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy: PFS OS CapeOx/FOLFOX4 + bevacizumabn=699; 513 events CapeOx/FOLFOX4 + bevacizumabn=699; 420 events CapeOx/FOLFOX4 + placebon=701; 547 events CapeOx/FOLFOX4 + placebon=701; 455 events HR=0.83 (97.5% CI, 0.72-0.95) HR=0.89 (97.5% CI, 0.76-1.03) P=0.0023 P=0.0769 Proportion of patients Proportion of patients 8.0 9.4 19.9 21.3 Months Months Saltz et al. J Clin Oncol. 2008;26:2013.

  6. PIIR study of FOLFOX/Sunitinib vs FOLFOX/bevacizumab Hecht et al , ASCO 2010 Higher toxicity with sunitinib

  7. VEGFR TKI’s in CRC >10,000 Courtesy of Scott Kopetz

  8. EGFR Activation Blood Vessel Metastatic Spread EGFR Activation Tumor Angiogenesis Angiogenesis Cell Survival Tumor Proliferation Rowinsky EK. Annu Rev Med. 2004;55;433. Ritter CA, Arteaga CL. Semin Oncol 2003;30;3. Mendelsohn J. J Clin Oncol, 2002;20;1S. Herbst RS, Shin DM, Cancer, 2002;94;1593-1611. Woodburn JR. Pharmacal Ther. 1999;82;241.

  9. Colon Cancer Has Many Biologic Subsets That Differ in Response to EGFR-Targeted Agents EREG or AREG Low expression of EGFR ligands → decreased response to EGFR targeted agents EGFR Mutant KRAS → decreased response to EGFR-targeted agents PIP1 PI3K KRAS PTEN PTEN loss of expression → decreased response to EGFR-targeted agents Mutant BRAF → ?decreased response to EGFR-targeted agents PIP3 BRAF Signaling to the nucleus

  10. COIN Trial design Maughan et al Arm A 815 5FU or capecitabine 5FU or capecitabine CONTINUOUS CT until progression, toxicity or patient choice oxaliplatin oxaliplatin Arm B 815 cetuximab CONTINUOUS CT until progression, toxicity or patient choice • >80% patients genotyped for KRAS, NRAS and BRAF • 43% KRAS mutation; 4% NRAS mutation; 8% BRAF mutation . Maughan et al; Abs 3502, ASCO 2010

  11. OS and PFS among KRAS wild-type patients 1.00 HR point estimate = 1.038 95% CI = (0.90, 1.20) Χ2 = 0.18; p = 0.68 HR point estimate = 0.959 95% CI = (0.84, 1.09) Χ2 = 0.27; p = 0.60 0.75 0.50 Survival 0.25 Arm A (OxFp) Arm A (OxFp) Arm B (OxFp + cetux) Arm B (OxFp + cetux) 0.00 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (months) Time (months) Overall Survival Progression-free Survival Maughan et al; Abs 3502, ASCO 2010

  12. Disease progression FOLFOX • Total n = 1,183 • Stratification by: • Geographic Region • EGOG performance (0,1/2) Enrollment Screening End of study End of Treatment Long term Follow up FOLFOX + panitumumab Disease progression PRIME Study – FOLFOX +/- Panitumumab in 1st Line mCRC Study Description Hypothesis Endpoints The addition of panitumumab to chemotherapy (FOLFOX) will increase progression-free survival (PFS) compared to chemotherapy (FOLFOX) alone as first-line treatment of mCRC among subjects with wild-type KRAS tumors and subjects with mutant KRAS tumors. Primary Endpoint: PFS Secondary Endpoints: OS, ORR, TTP, DOR, Safety Tertiary/Exploratory Endpoints: TTR, Biomarkers, PRO A Randomized, Multicenter, Phase 3 Study to Compare the Efficacy of Panitumumab in Combination with Oxaliplatin/ 5-fluorouracil/ leucovorin to the Efficacy of Oxaliplatin/ 5-fluorouracil/ leucovorin Alone in Patients with Previously Untreated Metastatic Colorectal Cancer 12

  13. WT KRAS: Progression-Free Survival

  14. WT KRAS: Overall Survival (Interim Analysis)

  15. Summary of published Phase III 1st line CT + anti-EGFR combination data in KRAS WT patients 1. Van Cutsem E, et al Eur J Can (suppl):a6.077, 3. Update from ECCO-ESMO , 2. Bokemeyer C, et al. Eur J Can(Supp)a6.079, 3. Saltz L, et al. J Clin Onc 2008;26:2013-2019, 4. Douillard et al ESMO 2009

  16. Summary of 2nd line CT + anti-EGFR combination data in KRAS WT patients

  17. Conclusions • The current standard of care for first line treatment of eligible patients with MCRC remains F-based chemotherapy + Bevacizumab. • Is Bevacizumab optimally used in combination with chemotherapy? • + FOLFIRI/XELIRI: Yes ( 5 mg/Kg qowk/7.5 mg/Kg q3wks) • + XELOX  Yes (7.5 mg/Kg q3wks) • + FOLFOX Unclear in first line at 5 mg/Kg qowk – ?10 mg/Kg qowk? (ECOG 3200) • Effect of bevacizumab on PFS and OS is independent of KRAS status • In advanced CRC, evidence suggests that treating to progression may improve survival. • Balance effect with added risk of toxicity

  18. Conclusions • A role for EGFR inhibitors in first line treatment of select patients with potentially resectable disease is justifiable (KRAS WT). • Anti-EGFR antibody therapy when added to oxaliplatin based therapy for patients with KRAS mutant tumors might be detrimental with respect to RR, PFS and OS. When combined with irinotecan , there is no added benefit to justify the added toxicities. • Are EGFR inhibitors optimally used in combination with chemotherapy? • + Irinotecan  Cetuximab: Yes  Panitumumab: Yes • + Oxaliplatin  Cetuximab: No  Panitumumab: Yes • Can Bevacizumab be safely combined with anti-EGFR mAbs? • + Cetuximab: No ( 1st line (CAIRO-2) • + Panitumumab: No (PACCE)

  19. COIN : Mutations in Kras, Nras, Braf: distribution and prognostic significance Prognostic effect of mutational status NRAS-mut n=50 (4%) KRAS-mut n=565 (43%) Arm A Arm B 12 “All-wt” n=581 (44%) BRAF-mut n=102 (8%) Median PFS (months) 6 39 0 11 18 102 554 12 Total n=1316 (81%) Median OS (months) 6 0 40 30 2-year OS (%) 20 10 0 297 362 57 268 367 45 N: 340 815 289 366 815 292 Mutation status: BRAF mutation All patients Any mutation KRAS wild-type KRAS mutation All wild-type

  20. Mutations in Kras, Nras, Braf: distribution and prognostic significance Prognostic effect of mutational status Arm A Arm B 12 Median PFS (months) 6 0 BRAF mutation: poorest prognosis KRAS wt: superior prognosis compared to KRAS mut 18 12 Median OS (months) 6 0 40 30 2-year OS (%) 20 10 0 297 362 57 268 367 45 N: 340 815 289 366 815 292 Mutation status: BRAF mutation All patients Any mutation KRAS wild-type KRAS mutation All wild-type

  21. Conclusions Strong prognostic effect of KRAS, BRAF and NRAS mutation status independent of the use of cetuximab Limitation  No observation arm ( not really feasible)

  22. N0147 : Is K-ras prognostic in FOLFOX treated patients?

  23. BRAF status is prognostic for OS but not RFS KRAS BRAF Relapse free survival (RFS) Overal survival (OS) Roth, A. D. et al. J Clin Oncol; 28:466-474 2010

  24. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status C. Bokemeyer, C.-H. Köhne, P. Rougier, C. Stroh, M. Schlichting, E. Van Cutsem • In this pooled analysis, a significant improvement in OS is demonstrated for patients with KRAS WT tumors receiving cetuximab plus chemotherapy vs. chemotherapy alone • Patients with BRAF mutations appear to benefit from cetuximab, although a mutation in BRAF would appear to be an indicator of poor prognosis  BRAF is perhaps prognostic but not necessarily predictive.

  25. KRAS mutation: Predictive and/or prognostic ? PREDICTIVE – response to therapy KRAS mutation predicts non-response to EGFR inhibitor antibodies PROGNOSTIC – outcome independent of treatment NO: PETACC 3 3rd line Cetuximab / Panitumumab monotherapy trials CAIRO-2 – 1st line oxaliplatin / bevacizumab +/- cetuximab stage IV PACCE – 1st line chemo / bevacizumab +/- panitumumab stage IV YES: RASCAL – stage II/III colon cancer FOCUS – 1st line sequential treatment stage IV COIN – 1st line oxaliplatin / cetuximab stage IV N0147 – Adjuvant FOLFOX +/- cetuximab MAYBE: CRYSTAL – 1st line FOLFIRI / cetuximab stage IV

  26. BRAF mutation: Predictive and/or prognostic ? • BRAF mutation is present in less than 10% of MCRC • BRAF mutation does not predict for EGFR resistance • BRAF mutation is prognostic for overall survival in MCRC ( including relapsed disease). • BRAF , TTR and tumor site predict for survival after relapse in patients with stage II and III CRC.

  27. Future Biologics

  28. Hedgehog Inhibitors • (Abstr 3530): Safety Analysis of a randomized phase II trial of hedgehog pathway inhibitor GDC-0449 (vesmodegib) versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC) • Authors: Bendell, Hart, Firdaus, Gore, Hermann, Mackey, Graham, Zerivitz, Low, Berlin

  29. Hedgehog Hedgehog Overexpression Mutation SMO Celium Cell Membrane Patched Mutation GDC-0449 Gli Activated Gli SuFu Inactive SMO Pathway Mechanism: Unknown Mutation Nuclear Membrane Hedgehog Gene Targets: GLI1, BCL2, SNAIL, etc Proliferation and survival Stem Cell Maintenance Angiogenesis

  30. FOLFOX/ or FOLFIRI/B + GDC-0449 1Von Hoff, NEJM 2009 • Results: some concerning signals in tox data • More deaths in the GDC-0449 arm (4 vs 0) • Two sudden deaths; two pneumonias (unusual cause of death for colorectal patients?) • All deaths occurred before the median PFS for 1st line CRC (days 91, 95, 155, 231) • Slightly less exposure to conventional chemo and biologics in experimental arms • No PK interactions (preliminary) • Added toxicities consistent with phase I trial1

  31. Perifosine (abstr 3531): Final results of a randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients with second- or third-line metastatic colorectal cancer (mCRC) Authors: Richards, Nemunaitis, Vukelja, Hagenstad, Campos, Letzer, Hermann, Sportelli, Gardner, Bendell

  32. Perifosine O N = • What is perifosine? • Oral alkylphospholipid • Related to miltefosine (FDA approved for breast CA cutaneous mets, and leishmaniasis), which has significant GI side effects • Mechanism of action is complex/unclear. Interacts with cell membrane and inhibits AKT (indirectly?). Also inhibits NF-ĸB; facilitates degradation of mTOR pathway members; activates JNK (apoptotic) pathway. • Phase I studies • Phase I (daily dosing, 3 on, 1 off) in solid tumors (Eur J Ca 2002) • n=22, diarrhea and vomiting dose-limiting, MTD 200 mg/day • ½ life 105 hr; 11 CRC patients, no responses • Phase I (weekly dosing) in solid tumors (Eur J Ca 2010) • n=36, diarrhea/vomiting, RP2D = 600 mg/wk • linear PK, ½-life 80 – 120 hr range, no responses P O O O

  33. Capecitabine +/- perifosine • Small trial (n=38; interim analysis, no power calculation provided but primary endpoint TTP) • Toxicity profile as expected; perifosine appeared to add fatigue, diarrhea, nausea, anemia. Also surprising rate of g3/4 HFS (30%) in combo arm • Improvement in • Response rate (4 pts v 1 pt, n=35 total), most >1 yr (Only one response was in 5-FU refractory) • Time to progression (28 v. 11 weeks, HR=0.28) • Overall survival (17.7 v 10.9 mos, HR=0.41)

  34. Results: capecitabine +/- perifosine ALL EVALUABLE PATIENTS 5-FU REFRACTORY PATIENTS Median TTP: P-CAP: 28 weeks [95% CI (12, 48)] Median TTP: CAP: 11 weeks [95% CI (9, 15.9)] p-value = 0.0012 Median TTP: P-CAP: 18 weeks [95% CI (12, 36)] Median TTP: CAP: 10 weeks [95% CI (6.6, 11)] p-value = 0.0004 Hazard ratio: 0.284 (0.127, 0.636) Hazard ratio: 0.186 (0.066, 0.521) Richards, ASCO 2010

  35. Signaling Pathway Target:PI3K Ligands PIP2 PIP3 p85 PI3K p110 Growth Factor Receptor PI3K inhibitors (XL147, GDC-0941, PX-866, SF1126, BEZ235) AKT inhibitors (perifosine?, MK-2206 GSK2141795, SR13668, XL418, GSK690693) AKT Blocking the Pathway mTOR mTOR inhibitors (sirolimus, temsirolimus, everolimus, AP23573, AZD8055, OSI-027, palomid 529)

  36. Combining Biologics ?

  37. Double-Targeting EGFR EGFR Compensatory overexpression of EGFR? Tyrosine Kinase Inhibitor Monoclonal Antibody Endocytosis of EGFR EGFR

  38. Dual Targeting • EGFR + VEGFR ( mAB)  No Go • VEGF + mTOR  early signals • EGFR + VGFRR ( TKI)  Too toxic • Etc …

  39. Conclusions • Revealing the many molecules and pathways that go awry in tumor cells has and will allow us to develop precise strategies to attack cancer • Thousands of new drugs are being studied for cancer therapy • We are moving to an era of predictive testing (enrichment strategies) and thus away from trial and error. • Kras mutational status and effectiveness of EGFR inhibitors • The example of Panitumumab and Cetuximab • Global gene expression profile as a tool to select targets

More Related