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Ohio State's 2014 ASCO Review Colorectal Cancer Update Presentation by Dr. Axel Grothey

Ohio State's 2014 ASCO Review Colorectal Cancer Update Presentation by Dr. Axel Grothey


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  • 1. Axel Grothey Professor of Oncology Mayo Clinic, Rochester Updates on Colorectal Cancer from ASCO 2014
  • 2. Highlights on CRC from ASCO 2014 • Rectal cancer • Confirming current clinical practice: • Neoadjuvant therapy with FP + radiation • Adjuvant therapy like colon cancer • Adjuvant colon cancer • Impact of MSI-H on treatment selection • Advanced colorectal cancer • Maintenance therapy for mCRC • Extended RAS testing before EGFR mAbs • H2H comparison BEV vs cetuximab in first-line • Paving the future of clinical practice • Molecular classification of mCRC
  • 3. Rectal Cancer
  • 4. Background: Postop.- vs. Preop. Chemoradiotherapy : CAO/ARO/AIO-94 Arm I: 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks OP 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 120h-infusion 120h-infusion RT: 50.4 Gy Arm II: 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d 120h-infusion 120h-infusion i.v.-bolus RT: 50.4 + 5.4 Gy Boost 5-FU 5-FU 5-FU 5-FU 500 mg/m2/d i.v.bolus OP Sauer et al., N Engl J Med 2004; 351:1731-40
  • 5. Background (2): CAO/ARO/AIO-94: 10y Update • Can local control be improved further? -- neoadjuvant • More effective systemic therapy needed! – (neo-)adjuvant Sauer R. et al., J Clin Oncol 2012; 30:1926-33
  • 6. NSABP-R04 Phase III 2x2 Design Comparison N patients pCR (%) G3/4 diarrhea (%) 5-FU 777 17.8 Cape 779 20.7 (p=0.14) Oxali - 636 17.8 6.9 Oxali + 640 19.5 (p=0.42) 16.5 (p<0.001) Chemotherapy: 5FU CVI 225mg/m2 5d/week Capecitabine 825 mg/m 2 PO BID (weekends off) +/- Oxaliplatin 50 mg/m 2 /week X 5 Radiation: 4600cGy + 540-1080cGy O’Connell et al., JCO 2014
  • 7. Oxaliplatin in Neoadjuvant Radio- Chemotherapy for Rectal Cancer Author N Chemo RT Grade 3- 4 toxicity Pathological CR rate Aschele (STAR) 379 5-FU 225 mg/m2/d 50.4 Gy in 28 fractions 8% 16% 368 5-FU 225 mg/m2/d Oxaliplatin 60 mg/m2/w x 6 50.4 Gy in 28 fractions 24% 16% Gerard (ACCORD) 295 Capecitabine 800 mg/m2 bid 45 Gy in 25 fractions 11% 14% 292 Capecitabine 800 mg/m2 bid 5 of 7 d Oxaliplatin 50 mg/m2/w 50 Gy in 25 fractions 25% 19% Aschele, JCO 2011; Gerard, JCO 2010.
  • 8. 2 additional studies evaluating oxaliplatin in the perioperative setting • Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer (PETACC6): Disease-free survival results at interim analysis. • H-J. Schmoll et al. ASCO 2014 • Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer: Results of the CAO/ARO/AIO-04 randomized phase III trial • C. Rödel et al. ASCO 2014
  • 9. Stage II&III Rectal Cancer Treated with Pre-op Fluoropyrimidines + RT +/- Oxaliplatin Study # Pts ChemoRT Regimen ypCR Rate (%) ACCORD 12 (JCO 2010) 291 Cape+RT 14 293 Cape + Oxali 50mg/m2 wkly+RT 19 (p=0.09) STAR-01 (JCO 2011) 379 FU CI+RT 16 368 FU CI + Oxali 60mg/m2 wkly+RT 16 (p=NS) NSABP R-04 (JCO 2014) 636 FU/Cape+RT 18 640 FU/Cape + Oxali 50mg/m2 wkly+RT 20 (p=0.42) PETACC-6 (ASCO 2014) 547 Cape+RT 12 547 Cape + Oxali 50mg/m2 wkly+RT 14 (p=0.27) CAO/ARO/AIO-04 (ASCO 2014) 615 FU CI+RT 13 596 FU CI + Oxali 50mg/m2 wkly+RT 17 (p=0.04)* * Unplanned exploratory analysis
  • 10. ADORE study schema Preop FP with radiation  TME  ypStage II (ypT3-4N0) ypStage III (ypTanyN1-2) Adjuvant FOLFOX Every 2 weeks x 8 cycles n = 149 Adjuvant 5-FU/LV Days 1-5 q 4 weeks x 4 cycles n = 146 Primary Endpoint: 3-year DFS Secondary Endpoints: AEs Patterns of failure OS QOL 1:1 Kim et al., ASCO 2014
  • 11. DFS Summary STUDY REGIMEN # pts % LN+ 3 yr DFS HR ADORE “Mayo” 321 62 (yp N+) 63 mFOLFOX6 72 0.63 p=0.03 AIO-04 5-FU 1265 72 (clinical) 71 FOLFOX6 76 0.79 p=0.03 PETACC-6 Cap 1094 71 (clinical) 75 CAPOX 74 1.04 p=0.78 NSABP C-07 5-FU 2407 71 72 FLOX 76 0.80 p=0.003 MOSAIC 5-FU 2246 60 73 FOLFOX4 78 0.77 p=0.002
  • 12. Conclusions from the rectal cancer studies • Adjuvant therapy in rectal cancer should be guided by same principles as in colon cancer • Adjuvant oxaliplatin-based therapy is superior to FP alone in stage III (assessed before neo-adjuvant therapy!) • Supported by similarities in biology between colon and rectal cancer in TCGA • Oxaliplatin does not provide benefit as radiation sensitizer in the neoadjuvant setting • ypCR rates not increased in 4/5 studies  Validates current clinical practice
  • 13. The future of rectal cancer management?
  • 14. Total Neoadjuvant Therapy (TNT) ChemoRT SurgeryChemotherapy Novel Radiosensitization Strategies Novel Targeted Therapies For High-risk Patients Courtesy of T. George, PI, presented by C. Allegra, ASCO 2014
  • 15. FOLFOX x 8TME5FUCMT FOLFOX x 6TME “Selective Arm” Response ≥20% “Standard Arm” Ongoing Intergroup Trial N0148 Response <20% RANDOMIZE1:1 5FUCMT TME FOLFOX x 2 FOLFOX x 6
  • 16. Adjuvant Colon Cancer: Microsatellite instability
  • 17. dMMR results in MSI • ~15% of colorectal cancers develop via dMMR pathway • Microsatellite Instability (MSI) by PCR is a way to assess MMR status • IHC (MLH1, MSH2, MSH6, PMS2) allows testing for dMMR and identifies affected gene • dMMR (tested by IHC) 97% concordant with MSI-H by PCR1 • dMMR cells presumed to be less sensitive to 5-FU 1Lindor et al, JCO 2002
  • 18. Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: An AGEO multicenter study David Tougeron MD, PhD • Retrospective study evaluating the chemosensitivity of MSI-H tumors • 433 pts from 2000-2011 stage II or III
  • 19. Tougeron et al., ASCO 2014
  • 20. Tougeron et al., ASCO 2014
  • 21. Decision Algorithm in Adjuvant Therapy Resected Colon Ca Stage II Stage III FOLFOX XELOX High-Risk dMMR No therapy! 5-FU/LV or Capecitabine * * *pts not considered candidates for oxaliplatin T4 and/or <12 LNs Low-Risk Intermed. Risk yes yes no no ?Marker signature? Grothey, Oncology 2010
  • 22. Advanced Colorectal Cancer: Maintenance Therapy
  • 23. Studies on Maintenance Therapy in BEV Era OX FP BV AIO-KRK-0207 CAIRO-3 MACRO
  • 24. AIO 0207: Treatment algorithms FP* + Bev any FP* +/- Bev +/- Ox Bev no treatment Induction: 24 wks Maintenance: non-PD Re-Induction *FP= any fluoropyrimidine in a standard protocol (e.g. mFOLFOX6, FOLFOX4, Cape/Ox, LV5FU2; Cape 2x1000) Bev used in standard doses (5mg/kg q 2 wks or 7.5mg/kg q 3wks arm A; 7.5 mg/kg 3q 3 wks arm B) R 1stprogression 2ndprogression PFS1 TFS Stratification Adjuvant tx. CR/PR vs. SD ECOG PS CEA @ baseline FP* + Bev + Oxaliplatin with CR/PR/SD Arnold et al., ASCO 2014 N=473
  • 25. AIO 0207: Treatment algorithms FP* + Bev Bev no treatment Maintenance: non-PD No Re-Induction R 1stprogression PFS1 other drugs(s) / 2nd line or no further treatment TFS Induction: 24 wks Stratification Adjuvant tx. CR/PR vs. SD ECOG PS CEA @ baseline *FP= any fluoropyrimidine in a standard protocol (e.g. mFOLFOX6, FOLFOX4, Cape/Ox, LV5FU2; Cape 2x1000) Bev used in standard doses (5mg/kg q 2 wks or 7.5mg/kg q 3wks arm A; 7.5 mg/kg 3q 3 wks arm B) FP* + Bev + Oxaliplatin with CR/PR/SD Arnold et al., ASCO 2014 N=473
  • 26. PFS1 from start of maintenance 0 4 8 12 16 20 24 28 32 36 0.0 0.2 0.4 0.6 0.8 1.0 Med. PFS1 all patients from rand.: 4.6 months Ratewithoutevent FP/Bev: n=141, 116 events, median = 6.2 months Bev: n=153, 135 events, median = 4.8 months No therapy: n=153, 145 events, median = 3.6 months 382 6 10 14 18 22 26 30 34 B vs A: HR=1.21; 95% CI: 0.95-1.56; log rank p=0.13 C vs A: HR=2.06; 95% CI: 1.60-2.66; log rank p<0.001 C vs B: HR=1.57; 95% CI: 1.24-1.99; log rank p<0.001 Log rank test: p<0.0001 Time (months) Arnold et al., ASCO 2014
  • 27. TFS: All arms Time (months) 0.0 0.2 0.4 0.6 0.8 1.0 Ratewithoutevent FP/Bev: n=141, 115 events, median = 6.8 months Bev: n=153, 129 events, median = 6.5 months No therapy: n=153, 138 events, median = 6.1 months 0 4 8 12 16 20 24 28 32 36 382 6 10 14 18 22 26 30 34 Log rank test: p=0.099 Median TFS all patients: 6.5 months (from randomization) Arnold et al., ASCO 2014
  • 28. No tx. Bev FP/Bev Median TFS Median PFS1 Re-induction No re-induction 45% 43% 21% Re-induction rates and PFS1/TFS 2 4 6 months Arnold et al., ASCO 2014
  • 29. Issues with this trial 1. The point of maintenance therapy is to minimize adverse effects in the palliative setting • Don’t need to push 12 cycles of FOLFOX upfront!
  • 30. Issues with this trial 1. The point of maintenance therapy is to minimize adverse effects in the palliative setting • Don’t need to push 12 cycles of FOLFOX upfront! 2. Plenty of evidence BEV alone is not as effective as FP + BEV as a maintenance strategy (SAKK ASCO 2014, E3200)
  • 31. Issues with this trial 1. The point of maintenance therapy is to minimize adverse effects in the palliative setting • Don’t need to push 12 cycles of FOLFOX upfront! 2. Plenty of evidence BEV alone is not as effective as FP + BEV as a maintenance strategy (SAKK ASCO 2014, E3200) 3. OS is affected by differences in subsequent therapy • PFS is a better measure of the activity of the regimen
  • 32. CAIRO-3 XELOX+Bev x6 CTX-BEV CTX-BEV R PD1 PFS1 Mos MT CFI HR P PFS1 8.5 4.1 0.43 <0.0001 PFS2 11.7 8.5 0.67 <0.0001 TT2PD 13.9 11.1 0.68 <0.0001 OS 21.6 18.1 0.89 0.22 MT: LD-Cape (625 mg/m2 BID daily) + BEV (7.5 mg/KG every 3 wks) MT CFI N=558 Koopman, M et al. ASCO GI 2014 PD2 PFS2 TT2PD PFS2: time from R until PD upon re-introduction of XELOX-B TT2PD: time from R until PD upon any treatment after PFS1 XELOX+Bev x6
  • 33. Median PFS1 Observation 4.1 m Maintenance 8.5 m Stratified HR 0.43 [95%CI: 0.36-0.52] p value < 0.0001 CAIRO-3 : PFS1 Koopman, M et al. ASCO GI 2014 Induction treatment of 6x cycles BEV + XELOX prior to randomisation not included (4-5 months) PFS1estimate 1.0 0.8 0.6 0.4 0.2 0 279 84 18 10 7 6 5 Time (months) No. at risk: 278 173 96 53 36 18 10 4.1 8.5 0 6 12 18 24 30 36
  • 34. Maintenance trials: combined analysis CAIRO3 cape/bev –0.84397007 0.09065533 27.4% 0.43 [0.36, 0.51] AIO 0207 FP/bev –0.71334989 0.12971368 24.1% 0.49 [0.38, 0.63] AIO bev –0.4462871 0.12595133 24.5% 0.64 [0.50, 0.82] SAKK4106 bev –0.28768207 0.13114787 24.0% 0.75 [0.58, 0.97] Total (95% CI) 100.0% 0.56 [0.43, 0.72] Heterogeneity: Tau2 = 0.05; Chi2 = 14.92, df = 3 (P = 0.002); I2=80% Test for overall effect: Z = 4.42 (P < 0.00001) PFS Favours active tx. Favours no tx. Study or subgroup Log [Hazard ratio] SE Weight Hazard ratio IV, random, 95% CI Hazard ratio IV, random, 95% CI 0.1 0.2 0.5 1 2 5 10 CAIRO3 cape/bev –0.11653382 0.10111254 47.1% 0.89 [0.73, 1.09] AIO 0207 FP/bev –0.01005034 0.16961535 16.8% 0.99 [0.71, 1.38] AIO bev –0.12783337 0.1705144 16.6% 0.88 [0.63, 1.23] SAKK4106 bev –0.18632958 0.15712878 19.5% 0.83 [0.61, 1.13] Total (95% CI) 100.0% 0.89 [0.78, 1.02] Heterogeneity: Tau2 = 0.00; Chi2 = 0.59, df = 3 (P = 0.90); I2=0% Test for overall effect: Z = 1.64 (P = 0.10) OS Favours active tx. Favours no tx. Study or subgroup Log [Hazard ratio] SE Weight Hazard ratio IV, random, 95% CI Hazard ratio IV, random, 95% CI 0.5 0.7 1 1.5 2 Arnold et al., ASCO 2014
  • 35. Conclusions on maintenance therapy • Remember the point is to minimize toxicity • OPTIMOX is mandatory when oxaliplatin is used first-line! • Maintenance therapy consistently improves PFS • These maintenance strategy trials were not designed to evaluate OS • Drawbacks of maintenance therapy • Impact on the patient • Financial burden for the system
  • 36. Advanced Colorectal Cancer: Extended RAS Mutation Analyses and Treatment Outcome
  • 37. mAbs Target Tumor Cell-Bound EGFR Extracellular Intracellular Ligand EGF-R PI3K Akt Raf MEK MAPK Cell Motility MetastasisAngiogenesis Proliferation Cell survival DNA PTEN Ras
  • 38. mAbs Target Tumor Cell-Bound EGFR Extracellular Intracellular Ligand EGF-R PI3K Akt Raf MEK MAPK Cell Motility MetastasisAngiogenesis Proliferation Cell survival DNA Ras PTEN
  • 39. PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status “Final Analysis” Median (mos) (95% CI) Panitumumab + FOLFOX4 10.0 (9.3 – 11.4) FOLFOX4 8.6 (7.5 – 9.5) HR = 0.80 (95% CI: 0.67 – 0.95) Log-rank p-value = 0.01 Median (mos) (95% CI) Panitumumab + FOLFOX4 7.4 (6.9 – 8.1) FOLFOX4 9.2 (8.1 – 9.9) HR = 1.27 (95% CI: 1.04 – 1.55) Log-rank p-value = 0.02 WT KRAS MT KRAS ProportionEvent-Free 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Months 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% ProportionEvent-Free Months 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Douillard et al., JCO 2011
  • 40. Mutations beyond KRAS codon 12/13 NT4%3% 6%4%40% EXON 1 EXON 2 EXON 3 EXON 4 EXON 2 EXON 3 EXON 4 KRAS NRAS 12 13 12 13 61 146 59 61 117 146 EXON 1 EXON 15EXON 11BRAF 600 NT 8% 117 NT=not tested 17% additional mutations in KRAS and NRAS ! Douillard et al., NEJM 2013
  • 41. Douillard et al., NEJM 2013 Hazard Ratios for RAS subgroups Potential detriment May 23, 2014: FDA approval for p-mab in combination with FOLFOX as 1st line therapy for KRAS wt CRC
  • 42. CRYSTAL: Effect of RAS mutation status on treatment outcomes Ciardiello, et al. ASCO 2014. Abstract 3506 RAS WT* (all tested loci) New RAS MT* RAS MT‡ (any tested locus) Cetux + FOLFIRI (n=178) FOLFIRI (n=189) Cetux + FOLFIRI (n=32) FOLFIRI (n=31) Cetux + FOLFIRI (n=246) FOLFIRI (n=214) Median OS, mos 28.4 20.2 18.2 20.7 16.4 17.7 HR (95% CI); p-value§ 0.69 (0.54–0.88); 0.0024 1.22 (0.69–2.16); 0.50 1.05 (0.86–1.28); 0.64 Median PFS, mos 11.4 8.4 7.2 6.9 7.4 7.5 HR (95% CI); p-value§ 0.56 (0.41–0.76); 0.0002 0.81 (0.39–1.67); 0.56 1.10 (0.85–1.42); 0.47 ORR, % 66.3 38.6 34.4 35.5 31.7 36.0 OR (95% CI); p-value¶ 3.11 (2.03–4.78); <0.0001 1.02 (0.33–3.15); 0.97 0.85 (0.58–1.25); 0.40 *RAS evaluable population, N=430; ‡Subset of CRYSTAL KRAS evaluable population, N=1063; §Cochran-Mantel-Haenszel; ¶log-rank
  • 43. OPUS Phase II Study 1. Bokemeyer, et al. Ann Oncol 2011 2. Bokemeyer, et al. ASCO 2014. Abstract 3505 R Previously untreated mCRC (ITT n=338; RAS evaluable population n=118) FOLFOX4 Cetuximab + FOLFOX4 • Primary endpoint: ORR • Secondary endpoints included: resection rate, OS, PFS and safety • Tumour genomic DNA was available from 85% (152/179) of the KRAS-WT intent-to-treat (ITT) population. Additional RAS mutations (KRAS exons 3 and 4; NRAS exons 2, 3, and 4) were detected using BEAMing technology.2
  • 44. OPUS: Effect of RAS mutations on treatment outcomes Bokemeyer, et al. ASCO 2014. Abstract 3505 RAS WT (all tested loci) New RAS MT RAS MT (any tested locus) Cetux + FOLFOX4 (n=38) FOLFOX4 (n=49) Cetux + FOLFOX4 (n=15) FOLFOX4 (n=16) Cetux + FOLFOX4 (n=92) FOLFOX4 (n=75) Median OS, mo 19.8 17.8 18.4 17.8 13.5 17.8 HR (95% CI); p-value 0.94 (0.56–1.56); p=0.80 1.09 (0.44–2.68); p=0.86 1.29 (0.91–1.84); p=0.157 Median PFS, mo 12.0 5.8 7.5 7.4 5.6 7.8 HR (95% CI); p-value 0.53 (0.27–1.04); p=0.062 0.77 (0.28–2.08); p=0.60 1.54 (1.04–2.29); p=0.031 ORR, % 57.9 28.6 53.3 43.8 37.0 50.7 OR (95% CI); p-value 3.33 (1.36–8.17); p=0.008 1.50 (0.35–6.53); p=0.60 0.58 (0.31–1.08); p=0.087
  • 45. Conclusions • Extended RAS testing should be performed on all mCRC patients to determine eligibility for treatment with EGFR inhibitors • Identifies who will benefit • Prevent potential survival detriment (in particular if combined with oxaliplatin)
  • 46. Side-note: BRAF mutant mCRC
  • 47. BRAF Mutations in CRC • BRAF is primary effector of KRAS signaling • BRAF mutations: • Occur most frequently in exon 15 (V600E) • Found in 4%-14% of patients with CRC • Mutually exclusive with KRAS mutations Raf MEK Erk P P P P Tumor cell proliferation and survival EGF Tumor Cell Ras Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.
  • 48. PETACC-3: Survival after relapse according to BRAF mutation status Roth, A. D. et al. JCO 2010 BRAF mut BRAF wildtype Tejpar et al, ASCO 2010 Median OS: BRAF mut: 7.49 m BRAF wt: 25.2 m (p = 1.9e-11)
  • 49. TRIBE: study design • TRIBE is a phase III, randomised, multicentre, open-label study of 1L BEV + FOLFOXIRI or FOLFIRI followed by BEV + FP until PD • Primary endpoint: PFS • Secondary endpoints: ORR, secondary R0 resection rate, OS, safety, biomarker evaluation • This was a retrospective analysis of impact of early tumour shrinkage (ETS) and deepness of response (DoR) on survival Previously untreated, unresectable mCRC (n=508) Bevacizumab + FOLFIRI* Bevacizumab + FOLFOXIRI* R BEV + 5-FU/LV BEV + 5-FU/LV PD PD Induction Maintenance *Up to 12 cycles Cremolini, et al. ASCO GI 2014. Abstract 521
  • 50. TRIBE: RAS MT, BRAF MT and all WT subgroup analyses Loupakis, et al. ASCO 2014. Abstract 3519 Bevacizumab + FOLFIRI Bevacizumab + FOLFOXIRI HR (95% CI) Median PFS, months Median OS, months Median PFS, months Median OS, months PFS OS All WT (n=129) 11.3 34.4 13.3 41.7 0.77 (0.52–1.12) 0.84 (0.51–1.38) RAS MT (n=218) 9.5 23.1 12.0 28.6 0.82 (0.62–1.09) 0.86 (0.61–1.23) BRAF MT (n=28) 5.5 10.8 7.5 19.1 0.56 (0.20–1.14) 0.55 (0.24–1.23)
  • 51. Head-to-Head Comparison Phase III: Cetuximab vs Bevacizumab First-Line
  • 52. mab: 40 mg m i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w Bevacizumab: 5 mg/kg i.v. 30-90min q 2w /0i FIRE-3 Phase III study design Cetux 2 FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v. 30-90min q 2w mCRC 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 Cetuximab: 400 mg/m2 i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w • Primary objective: Overall response rate (ORR) (inv assessed) • Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) • 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5% FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h) Heinemann et al., ASCO 2013
  • 53. FIRE-3 ORR Primary Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Odds ratio p Assessable for response (N= 526) 72.2 66.2 – 77.6 63.1 57.1 – 68.9 1.52 1.05-2.19 0.017 1.18 0.85-1.64 0.183 p = Fisher´s exact test (one-sided) ORR % 95%-CI % 95%-CI ITT population 62.0 56.2 – 67.5 58.0 52.1 – 63.7 (N= 592) Heinemann et al., ASCO 2013
  • 54. FIRE-3 PFS 0.75 1.0 0.50 0.25 Probabilityofsurvival Events n/N (%) Median (months) 10.0 95% CI ―FOLFIRI + Cetuximab 250/297 (84.2%) 8.8 – 10.8 ― FOLFIRI + Bevacizumab 242/295 (82.0%) HR 1.06 (95% CI 0.88 – 1.26) 10.3 9.8 – 11.3 Log-rank p= 0.547 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 100 99 19 15 10 6 5 4 3 at risk 295 Heinemann et al., ASCO 2013
  • 55. FIRE-3 Overall survival Events n/N (%) Median (months) 28.7 95% CI ― FOLFIRI + Cetuximab 158/297 (53.2%) 24.0 – 36.6 ― FOLFIRI + Bevacizumab 185/295 (62.7%) HR 0.77 (95% CI: 0.62 – 0.96) 25.0 22.7 – 27.6 Log-rank p= 0.017 0.75 1.0 0.50 0.25 Probabilityofsurvival 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 218 214 111 111 60 47 29 18 9 2at risk 295 PFS Split of curves Heinemann et al., ASCO 2013
  • 56. Potential reasons for OS difference with same PFS • Imbalance in post-progression therapy • First-line therapy affects sensitivity of cancer cells to subsequent treatments • Early clonal selection • Is there an optimal sequence of treatment options? • First-line therapy is highly effective in a subpopulation of CRC with long-lasting treatment benefit
  • 57. FIRE-3 Update: Tested Mutations 0% 4.3% 4.9% KRAS wt exon 2 subset EXON 1 EXON 2 EXON 3 EXON 4 EXON 2 EXON 3 EXON 4 KRAS NRAS 12 13 12 13 61 146 59 61 117 146 wt 3.8% 2% EXON 1 EXON 15EXON 11BRAF 600 0% 10% 15% additional RAS mutations!
  • 58. Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 91/171 (53.2%) 33.1 24.5 – 39.4 ― FOLFIRI + Bevacizumab 110/171 (64.3%) 25.6 22.7 – 28.6 HR 0.70 (95% CI: 0.53 – 0.92) p (log-rank)= 0.011 FIRE-3 ESMO/ECCO Update Overall survival All-RAS* wild-type 0.0 12 24 36 48 60 72 months since start of treatment 171 171 No. at risk 128 127 71 68 39 26 20 9 6 1 0.75 1.0 0.50 0.25 0.0 Probabilityofsurvival RAS* wild-type: KRAS 61/146; NRAS Exon2, NRAS Exon3 Median Δ = 7.5 months Heinemann et al., ECC 2013
  • 59. CALGB/SWOG 80405: Phase III trial of FOLFIRI or FOLFOX with Bevacizumab or Cetuximab for patients w/ KRAS wild type untreated metastatic adenocarcinoma of the colon or rectum A Venook, D Niedzwiecki, HJ Lenz, F Innocenti, M Mahoney, B O’Neil, J Shaw, B Polite, H Hochster, R Goldberg, R Mayer, R Schilsky, M Bertagnolli, C Blanke for the ALLIANCE and SWOG
  • 60. CALGB/SWOG 80405: FINAL DESIGN N = 1140 1° Endpoint: Overall Survival Chemo + Cetuximab Chemo + Bevacizumab mCRC 1st-line KRAS wild type (codons 12,13) STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT FOLFIRI or FOLFOX MD choice Venook et al., ASCO 2014
  • 61. CHEMO + BEV N=559 (%) CHEMO + CETUX N=578 (%) TOTAL N=1137 (%) Age median (range) 59 (21-85) 59 (20-89) 59 (20-89) Male 348 (62.3) 349 (60.4) 697 (61.3) Primary in place 157 (28) 154 (27) 311 (28) Palliative Intent 465 (86.4) 458 (82.5) 923 (84.4) FOLFOX / FOLFIRI (%) 73 /27 74 / 26 73 / 27 CALGB/SWOG 80405: Patient Characteristics Venook et al., ASCO 2014
  • 62. CALGB/SWOG 80405: Progression-Free Survival (Investigator Determined) Arm N (Events) PFS (m) Median 95% CI Chemo + Bev 559 (498) 10.8 9.7-11.4 Chemo + Cetux 578 (499) 10.4 9.6-11.3 P=0.55 HR 1.04 (0.91 -1.17) Venook et al., ASCO 2014
  • 63. CALGB/SWOG 80405: Overall Survival Arm N (Events) OS (m) Median 95% CI Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 P=0.34 HR 0.925 (0.78-1.09) Venook et al., ASCO 2014
  • 64. CALGB/SWOG 80405: Overall Survival FOLFIRI Treated Arm N(Events) OS (m) Median 95% CI FOLFIRI + Bev 150 (81) 33.4 27.3-41.3 FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2 P=0.28 HR 1.2 (0.9-1.6) Venook et al., ASCO 2014
  • 65. CALGB/SWOG 80405: Overall Survival FOLFOX Treated Arm N (Events) OS (m) Median 95% CI FOLFOX + Cetux 426 (277) 30.1 26.6-34.8 FOLFOX + Bev 409 (290) 26.9 24.7–30.0 P=0.09 HR 0.9 (0.7-1.0) Venook et al., ASCO 2014
  • 66. Conclusions EGFR mAbs • Cetuximab and panitumumab are interchangeable (see ASPECCT trial results ECC 2013) • Further molecular refinement of patient population beyond KRAS codon 12/13 essential • To avoid detrimental effect of therapy • To enrich patient population with better benefit/side-effect margin • FIRE-3 and 80405 generated somewhat contradictory results • All-RAS analysis of 80405 pending (ESMO)
  • 67. Does 80405 definitively answer the cetuximab vs bevacizumab 1st line question? • Not yet… • Awaiting: • Response rates • All-RAS analysis • Information on subsequent lines of therapy • Information on duration of therapy
  • 68. Considerations for First-line Therapy • Two competing approaches: • Chemo + EGFR mAb • Supported by FIRE-3, PRIME, 80405 • Longest time on therapy • Beware of toxicities • Chemo + BEV with prolonged duration of VEGF inhibition • Supported by CAIRO-3, TML, 80405 • More limited subjective toxicities
  • 69. Optimized Treatment Strategy mCRC, palliative setting, PS 0-1 Unresectable Liver and Retroperitoneal LN Metastases Molecular testing PD1 PD2 PD3 PD4 VEGFi + CT doublet Regorafenib BSC Bevacizumab + CT doublet VEGFi + CT doublet EGFR inhibitor +/- irinotecan Regorafenib BSC Bevacizumab + CT doublet Bevacizumab + CT doublet Regorafenib BSC EGFR inhibitor + CT doublet Any RAS mut (55%) All RAS wt (40%) BRAF mut (5%) Regorafenib BSC Bevacizumab + FOLFOXIRI EGFR inhibitor + /- chemotherapy Sridharan et al., Oncology 2014
  • 70. J Clin Oncol, 1992 CALGB/SWOG 80405 Colorectal Cancer: 20 Years after meta-analysis 1992 Venook et al., ASCO 2014
  • 71. The future of CRC: Focus on Molecular Biology
  • 72. Garraway LA, JCO 2013 Common cancers are becoming a collection of rare diseases
  • 73. MD Anderson Molecular Analysis: Primary Tumor vs Metastases • 115 mCRC patients with resection or biopsy of primary tumor and metastatic lesion • Clinical variables • Intervening chemotherapy administration (61% of patients) • Synchronous resections (33%) • Location of metastases and primary tumor • Surgical specimen or biopsy (22%) Kopetz et al., ASCO 2014
  • 74. Low Concordance Between Primary and Metastases for PIK3CA and Minor Genes TP53 KRAS APC NRAS BRAF PIK3CA SMAD4 Minor 82% 89% 53%* OR 6.8 P<0.001 85% 71% 83% 83% 64%* OR 4.4, P=0.008 Kopetz et al., ASCO 2014
  • 75. Synchronous vs Metachronous Metachronous resection is associated with: 3.4 fold higher odds of discordance (95% CI 1.5 to 7.8, P<0.001) Numberofmutations 10% 27% Kopetz et al., ASCO 2014
  • 76. Dienstmann et al., ASCO 2014 Colorectal cancer subtyping consortium (CRCSC)
  • 77. CMS1 13% Females, older age, right colon, MSI, hypermutation, BRAF mut, immune activation Better RFS, intermediate OS, worse SaR CMS2 35% Left colon, epithelial, MSS, high CIN, TP53 mut, WNT/MYC pathway activation Intermediate RFS, better OS, better SaR CMS3 11% Epithelial, CIN/MSI, KRAS mut, MYC ampl, IGFBP2 overexpression Intermediate RFS, OS and SaR CMS4 20% Younger age, stage III/IV, mesenchymal, CIN/MSI, TGFβ/VEGF activation, NOTCH3 overexpression Worse RFS, worse OS Intermediate SaR Unclassified 21% Mixed subtype with variable epithelial- mesenchymal activation? Intermediate RFS, OS and SaR CRCSC – Results Summary Dienstmann et al., ASCO 2014
  • 78. Progression on First-line Treatment of Metastatic Colorectal Cancer Analysis of metastatic tumor specimen Marker Defined Sub-Groups (potential options) RAS BRAF PIK3CA PTEN AKT Both RAS and PI3K Not RAS Not PI3K Targeted therapy Control arm*R Targeted therapy Control arm*R Targeted therapy Control arm*R Targeted therapy Control arm*R Targeted therapy Control arm*R *Standard chemotherapy-containing regimen Consent patient to screen Consent patient to sub-study ASSIGN: CURRENT DESIGN Intergroup Proposal: Second-line trial