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Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer

Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer. Metastatic Colorectal Cancer. Axel Grothey, MD Senior Associate Consultant Division of Medical Oncology Mayo Clinic College of Medicine Rochester, MN. Case 3: First-line Colorectal Cancer.

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Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer

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  1. Challenging Cases in Cancer:Integration of Findings from ASCO 2007Colorectal Cancer Metastatic Colorectal Cancer Axel Grothey, MD Senior Associate Consultant Division of Medical Oncology Mayo Clinic College of Medicine Rochester, MN

  2. Case 3: First-line Colorectal Cancer • Patient was treated with adjuvant 5-FU/LV after R hemicolectomy for T3N1M0 stage III colon cancer • Two years later he relapses with rising CEA and 2 lung metastases plus 3 liver metastases • He is treated with modified FOLFOX6 plus bevacizumab for 12-cycles (six months) but develops grade 3 neuropathy • CT scan shows all lesions more than 50% smaller

  3. Case 3: First-line Colorectal Cancer • Which treatment option would you recommend? • Continue therapy (unchanged) • Hold all treatment until tumor progression • Stop oxaliplatin and continue therapy with 5-FU/LV and bevacizumab • Stop oxaliplatin and continue therapy with bevacizumab alone • Switch therapy to an irinotecan-based regimen

  4. Case 3: First-line Colorectal Cancer • Which treatment option would you recommend? • Continue therapy (unchanged) • Hold all treatment until tumor progression • Stop oxaliplatin and continue therapy with 5-FU/LV and bevacizumab • Stop oxaliplatin and continue therapy with bevacizumab alone • Switch therapy to an irinotecan-based regimen • Recommended approach • Stop oxaliplatin and continue therapy with 5-FU/LV and bevacizumab

  5. Pertinent Issues for Case 3 • Metachronous metastases after 2-years to lung and liver • Should always consider resectability even with extrahepatic disease • In this case situation it was deemed unresectable • Good response to chemotherapy with FOLFOX + BEV, but grade 3 neurotoxicity after 12-cycles • Should patient have a “chemo-holiday”?

  6. Definition of “Chemo-Holiday” • Stop of: • All medical therapy (chemo/biologics), no “maintenance” (OPTIMOX2) • Certain components of medical therapy, continuation of “chemo-light” (+/- biologics) (OPTIMOX1, CONcePT) • Conventional chemotherapeutics, continuation of biologics (DREAM)

  7. Definition of “Chemo-Holiday” • Stop can occur: • After pre-defined number of cycles • When “best response” is achieved • When long-lasting SD has been documented • When toxicity threshold is reached • Restart/re-intensify therapy: • After pre-defined interval (OPTIMOX1, CONcePT) • When “relevant” tumor progression noted (OPTIMOX2)

  8. 9.3 mos 5.8 mos N9741: FOLFOX4 - TTP and TTF 1 0 0 9 0 TTP TTF 8 0 7 0 63% of pts stopped FOLFOX for otherreasons than PD % Event-free 6 0 5 0 4 0 3 0 2 0 1 0 0 0 6 12 18 24 Time (mos) Green et al., GI ASCO 2005

  9. mFOLFOX7 mFOLFOX7 sLV5-FU2 OPTIMOX-2 N = 202 mFOLFOX7 mFOLFOX7 CFI OPTIMOX Studies FOLFOX4 until TF OPTIMOX-1 N = 620 FOLFOX7 FOLFOX7 sLV5-FU2 Tournigand et al, JCO 2006 Maindrault-Goebel et al, ASCO 2007 Abstract #4013

  10. FOLFOX4 R 6xFOLFOX7- 12x sLV5-FU2 - 6xFOLFOX7 620 pts Cum. Oxali 780 1,560 Stop and Go Concept - OPTIMOX1 (%) FOLFOX4FOLFOX7 RR 58.5 58.3 PFS 9.0 8.7 DDC 9.0 10.6 OS 19.3 21.2 G3/4 NTox17.913.3 Primary endpoint Tournigand et al., JCO 2006

  11. OPTIMOX2 - 5-FU/LV Maintenance vs Chemo-Free Intervals Maindrault-Goebel et al, ASCO 2007 Abstract #4013

  12. Maintenance 1 . 0 36 weeks P = 0.08 0 . 8 29 weeks CFI 0 . 6 0 . 4 0 . 2 0 . 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 OPTIMOX2: Progression-free Survival weeks Maindrault-Goebel et al, ASCO 2007 Abstract #4013

  13. Maintenance 1 . 0 26 months 0 . 8 P = 0.0549 19 months CFI 0 . 6 0 . 4 0 . 2 0 . 0 0 1 0 2 0 3 0 4 0 5 0 OPTIMOX2: Overall Survival Lesson from OPTIMOX2: Don’t stop treatment before progression! months Maindrault-Goebel et al, ASCO 2007 Abstract #4013

  14. Take-home Messages OPTIMOX2 • A strategy with complete chemotherapy-free intervals (CFI) leads to inferior outcome compared to an induction-maintenance-reintroduction approach • If PFS is the primary endpoint of your trial, do not stop treatment before progression (see NO16966) • DDC is NOT an appropriate endpoint in CRC  In advanced CRC, the default treatment strategy should be “treatment to progression”

  15. Recommendation for Case 3 • In palliative situation, goal of therapy is to extend duration and maintain the quality of life as long as possible • Do not “waste” potentially active agents unnecessarily (no irinotecan here!) • Maintenance therapy should be default position • Infusional 5-FU/LV + BEV or capecitabine + BEV should be considered • No role so far for BEV single agent as maintenance therapy

  16. Case 4: First-line Colorectal Cancer • 52-year-old healthy restaurant owner presents with increasing pain on bowel movement and complains of several weeks of diarrhea and weight loss of 10 pounds • Finally cannot move bowels and begins to vomit • CT scan shows 12 cm mass in the LLQ with multiple liver nodules and an elevated CEA level of 60 ng/mL • GI evaluation with colonoscopy shows a nearly obstructing sigmoid mass – cannot pass scope – biopsy shows adenocarcinoma

  17. Case 4: First-line Colorectal Cancer • Undergoes sigmoid colon resection with primary anastomosis and a wedge biopsy of the left lobe of the liver • Pathology reveals a mucinous adenocarcinoma of the sigmoid colon metastatic to lymph nodes and liver • Now referred for consideration of chemotherapy

  18. Case 4: First-line Colorectal Cancer • Which chemotherapy would you recommend? • 5-FU/LV or capecitabine • FOLFOX • CAPOX (XELOX) • FOLFIRI • IROX • FOLFOXIRI

  19. Case 4: First-line Colorectal Cancer • Which targeted agent would you add? • None • Bevacizumab • Cetuximab • Panitumumab • Bevacizumab + cetuximab • Bevacizumab + panitumumab

  20. Case 4: First-line Colorectal Cancer • Which targeted agent would you add? • None • Bevacizumab • Cetuximab • Panitumumab • Bevacizumab + cetuximab • Bevacizumab + panitumumab • Recommended approach • FOLFOX + bevacizumab or FOLFIRI + bevacizumab

  21. Pertinent Issues for Case 4 • Palliative situation with unresectable, scattered liver metastases • Symptomatic primary (obstruction) → resection of primary warranted • What is optimal chemotherapy? • And should a biologic be added upfront?

  22. New Agents Have Significantly Improved Treatment and Patient Outcomes More regimens provide more options formultiple lines of therapy to extend survival * FOLFIRI † FOLFOX ‡ IFL, FOLFIRI, FOLFOX, and 5-FU/LV Modified from Venook A. Oncologist. 2005.

  23. NCCTG/Intergroup Trial N9741 RANDOMI ZAT ION IFL: Irinotecan + 5-FU/LV FOLFOX4: Oxaliplatin + 5-FU/LV 795 patients IROX: Irinotecan + oxaliplatin Goldberg et al., JCO 2004

  24. NCCTG/Intergroup Trial N9741Efficacy Goldberg et al., JCO 2004

  25. 2nd line:62% 2nd line:74% Tournigand Trial (N = 220) FOLFOXFOLFIRI FOLFIRIFOLFOX (1st line 2nd line) (1st line 2nd line) N pts111 69 109 81 • RR54%4% 56% 15% • Resection of • Hepatic Metastases21%9% • PFS (mos)8.12.58.54.2 • Median OS (mos)20.6 21.5 Tournigand et al., JCO 2004

  26. Multivariate analysis: Effect on OS P First-line doublet 0.69 All 3 drugs 0.005 Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5,768 Patients 22 21 20 19 18 17 16 15 14 13 12 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5-FU2 FOLFOXIRI CAIRO Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) 2007 OS (mos)=13.2 + (% 3 drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005

  27. EGFR Biologic Agents in Colorectal Cancer Monoclonal Antibodies Fab Fc Murine Ab “momab” Chimeric Mouse-HumanAb “ximab” Humanized Ab “zumab” Human Ab “mumab” (17-1A) Cetuximab Matuzumab Bevacizumab Panitumumab VEGF

  28. Cetuximab as Salvage Therapy for CRC *P <0.05

  29. CRYSTAL Study (First-line) FOLFIRI + Cetuximab N = 599 EGFR-expressingmetastatic CRC PFS R FOLFIRI Stratified by: • Regions • ECOG PS N = 599 • Primary Endpoint: PFS (independent review) • Secondary Endpoints: RR, DCR, OS, Safety, QoL • Sample Size: 1,217 patients randomized, ITT: 1,198 pts Van Cutsem et al., ASCO 2007 Abstract #4000

  30. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Subjects at risk FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1 Cetuximab + FOLFIRI 599 499 392 298 196 103 58 29 12 5 1 CRYSTAL Trial: Primary Endpoint PFS ITT Population Independent Review 1.0 Cetuximab + FOLFIRI, N = 599 FOLFIRI, N = 599 HR = 0.851; 95% CI = [0.726-0.998] Stratified log-rank P-value = 0.0479 8.9 mo PFS estimate 1-year PFS rate 23% vs 34% 8.0 mo Progression-free survival time (months) Van Cutsem et al., ASCO 2007 Abstract #4000

  31. CRYSTAL Trial:Independent Assessment of Response P-value* = 0.0038 *Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate Van Cutsem et al., ASCO 2007 Abstract #4000

  32. 1.00 Skin reaction grade 3*, n=112 Skin reaction grade 2, n=243 0.75 Skin reaction grade 0 or 1, n=244 PFS estimate 0.50 11.3 mo 9.4 mo 5.4 mo 0.25 0.00 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Progression-free survival time (months) *There were no grade 4 skin reactions CRYSTAL Trial:Subgroup Analysis of PFS Time by On-study Skin Reactions: Cetuximab + FOLFIRI Van Cutsem et al., ASCO 2007 Abstract #4000

  33. KRAS Mutation Status Predictive of Response to Cetuximab? • 30 patients with CRC on cetuximab • PR: 11/30 patients (37%) • KRAS mutation in • 0/11 responders • 13/19 non-responders (68%) • P = 0.0003 • Increased EGFR gene copy number in 10% • significantly associated with response (P =0.04) 16.3 mo 6.9 mo Lievre et al., Cancer Res 2006

  34. Anti-VEGF antibodies (bevacizumab) Soluble VEGF receptors (VEGF-TRAP) Anti-VEGFR antibodies (IMC-1121b) P P P P P P P P Agents Targeting the VEGF Pathway VEGF VEGFR-1 VEGFR-2 Small-moleculeVEGFR inhibitors (Vatalanib, sunitinib, sorafenib) Endothelial cell

  35. Phase III Trial of Bevacizumab in MCRC: Efficacy Hurwitz et al., N Engl J Med 2004

  36. Phase III Trial of IFL ± Bevacizumab in mCRC: Survival 1.0 HR = 0.66, P = 0.00004 Median survival: 15.6 vs. 20.3 mo 0.8 0.6 Proportion surviving 0.4 Treatment Group 0.2 IFL + placebo IFL + bevacizumab 0 0 10 20 30 40 Duration of survival (mo) Hurwitz et al., N Engl J Med 2004

  37. mIFL + bevacizumab BICC-CPeriod 2: Overall Survival 1 0 . 9 0 . 8 0 . 7 Proportion of Patients Who Survived 0 . 6 0 . 5 0 . 4 0 . 3 FOLFIRI + bevacizumab 0 . 2 0 . 1 0 0 5 1 0 1 5 2 0 2 5 3 0 Survival Time (months) Fuchs et al., ASCO GI 2007

  38. BICC-C: Summary NR = not reached Fuchs et al., ASCO GI 2007

  39. XELOX vs FOLFOX ± Bevacizumab Roche NO16966 Study Design RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX N = 317 XELOX + placebo N = 350 XELOX + bevacizumab N = 350 FOLFOX4 N = 317 FOLFOX4 + placebo N = 351 FOLFOX4 + bevacizumab N = 350 Protocol amended to 2x2 placebo-controled design after bevacizumab phase III data1 became available (N = 1401) Initial 2-arm open-label study (N = 634) Cassidy et al., ESMO 2006 1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

  40. FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N = 1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumab N = 1017; 813 events PFS XELOX Non-inferiority: Primary Objective Met Based on ITT 1.0 0.8 0.6 0.4 0.2 0 HR = 1.04 [97.5% CI 0.93-1.16] Upper limit ≤ 1.23 (non-inferiority margin) PFS estimate 8.0 8.5 0 5 10 15 20 25 30 Months Cassidy et al., ESMO 2006

  41. FOLFOX+placebo/XELOX+placebo N = 701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N = 699; 513 events PFS Chemotherapy + Bevacizumab Superiority: Primary Objective Met 1.0 0.8 0.6 0.4 0.2 0 HR = 0.83 [97.5% CI 0.72–0.95] (ITT) P = 0.0023 PFS estimate 8.0 9.4 0 5 10 15 20 25 Months Cassidy et al., ESMO 2006

  42. 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months PFS Chemotherapy + Bevacizumab Superiority: XELOX and FOLFOX Subgroups PFS estimate 8.6 9.4 7.4 9.3 FOLFOX+placebo N = 351; 277 events FOLFOX+bevacizumab N = 349; 255 events XELOX+placebo N = 350; 270 events XELOX+bevacizumab N = 350; 258 events XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT) P = 0.0026 FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT) P = 0.1871 Cassidy et al., ESMO 2006

  43. NO16966 Response Rate Saltz et al., ASCO GI 2007

  44. Why Did BEV Not Increase PFS When Added to FOLFOX in NO16966? • No synergistic/additive effect with FOLFOX? • No, see E3200 (second-line) • Ceiling effect of first-line chemotherapy? • Perhaps… • Failure to OPTIMOXize? • Very likely!

  45. NO16966 Study Drug Exposure – Median Months of Treatment * Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo or bevacizumab alone but not oxaliplatin alone Saltz et al., ASCO GI 2007

  46. NO16966 PFS Subgroup Analyses:On-treatment Population XELOX Group FOLFOX Group 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Survival Survival 7.0 m 9.5 m 8.4 m 10.6 m 0 100 200 300 400 500 0 100 200 300 400 500 Study day Study day HR = 0.61 [97.5% CI 0.48–0.78] P ≤ .0001 HR = 0.65 [97.5% CI 0.50–0.84] P = .0002 XELOX + placebo XELOX + Bev FOLFOX4 + placebo FOLFOX4 + Bev VS. VS. Saltz et al., ASCO GI 2007

  47. - - - Rationale for Combining EGFR- and Angiogenesis- Inhibitors EGFR Inhibitors Angiogenesis Inhibitors • Tumor cell growth • Synthesis of angiogenic proteins • Response of endothelial cells to angiogenic proteins Targets Angiogenic proteins bFGF VEGF TGF- Endothelial cells Tumor Herbst et al., J Clin Oncol. 2005;23:2544.

  48. BOND-2 Trial - Efficacy (Historic Comparison with BOND-1) Saltz et al., ASCO 2005; Lenz et al., ASCO GI 2007

  49. Panitumumab 6 mg/kg Q2W Ox-CT Bevacizumab Ox-based CT (e.g., FOLFOX) N = 800 Inv choice S C R E E N I N G R A N D O M I Z E 1:1 Ox-CT Bevacizumab Panitumumab 6 mg/kg Q2W Iri-CT Bevacizumab Iri-based CT (e.g., FOLFIRI) N = 200 Inv choice 1:1 Iri-CT Bevacizumab PACCE Study Schema PACCE: Panitumumab Advanced Colorectal Cancer Evaluation Randomized, Open-Label, Controlled Phase 3b Trial Stratification Factors: ECOG score, prior adjuvant Tx, disease site,Ox doses/Iri regimen, number of metastatic organs Tumor assessments:Q12w until disease progression or intolerability Hecht et al., World GI Barcelona 2007

  50. Objective Response Rate By Cohort(Central Review) Oxaliplatin Irinotecan ITT set*Included missing and unreadable scans Hecht et al., World GI Barcelona 2007

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