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

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  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