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Novel treatment strategies in metastatic colorectal cancer patients with KRAS wildtype tumors

Novel treatment strategies in metastatic colorectal cancer patients with KRAS wildtype tumors. Prof.dr. Cornelis Punt Dept. of Medical Oncology Radboud University Nijmegen Medical Center Nijmegen, The Netherlands. Current standard in 1 st line metastatic colorectal cancer.

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Novel treatment strategies in metastatic colorectal cancer patients with KRAS wildtype tumors

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  1. Novel treatment strategies in metastatic colorectal cancer patients with KRAS wildtype tumors Prof.dr. Cornelis Punt Dept. of Medical Oncology Radboud University Nijmegen Medical Center Nijmegen, The Netherlands

  2. Current standard in 1st line metastatic colorectal cancer • Chemotherapy + bevacizumab Questions: • does the choice of chemotherapy matter? • how long should bevacizumab be continued?

  3. Bevacizumab in 1st-line advanced CRC: significant benefit in 4 studies with different chemotherapy regimens * Statistically significant 1Hurwitz et al. NEJM 2004 2Kabbinavar et al. JCO 2005 3Saltz et al. JCO 2008 4Tebbutt et al. ECCO/ESMO 2009

  4. Progression Free Survival Median PFS C: 5.7 months CB: 8.5 months CBM: 8.4 months Hazard ratios C vs CB: 0.63, p<0.001 C vs CBM: 0.59, p<0.001 Capecitabine + Bevacizumab + Mitomycin C 1.0 0.8 Capecitabine + Bevacizumab 0.6 Capecitabine Proportion not progressed 0.4 Tebbutt et al. ECCO/ESMO 2009 0.2 0.0 24 0 6 12 18 Months from randomisation Number at Risk: C: 156 67 22 4 CB: 157 106 38 15 5 CBM: 158 104 40 20 6

  5. KRAS in EGFR signal transduction cetuximab panitumumab

  6. KRAS wildtype metastatic colorectal cancer: options in 1st line treatment • Chemotherapy + bevacizumab • Chemotherapy + anti-EGFR (cetuximab/panitumumab) Questions: • is there a preference? • does the choice of chemotherapy matter?

  7. Published/presented studies in 2009 with anti-EGFR antibodies * prospectiveevaluation of results in patientswithKRAS wildtype

  8. CRYSTAL: FOLFIRI with or without cetuximab in 1st-line treatment of metastatic CRC Van Cutsem et al. NEJM&ECCO/ESMO 2009

  9. CRYSTAL study Adding cetuximab to FOLFIRI in 1st-line • results in a significant benefit in median PFS, and in a larger absolute benefit in median OS in patients with KRAS wildtype • has no detrimental effect in patients with KRAS mutation • Effect of salvage treatments on median OS?

  10. OPUS: FOLFOX with or without cetuximab in 1st-line treatment of metastatic CRC Bokemeyer et al. J ClinOncol 2009 and ECCO/ESMO 2009

  11. OPUS study Adding cetuximab to FOLFOX in 1st-line • results in a significant benefit in median PFS in patients with KRAS wildtype • has a detrimental effect in patients with KRAS mutation • Randomized phase II study with limited number of patients

  12. COIN: FOLFOX/XELOX with or without cetuximab in 1st-line treatment of metastatic CRC Maughan et al. ECCO/ESMO 2009

  13. COIN study Adding cetuximab to FOLFOX or CAPOX in 1st-line • does not result in any benefit in patients with KRAS wildtype • has no detrimental effect in patients with KRAS mutation • Cetuximab significantly increased non-haematological toxicity, grade 3 diarrhea FOLFOX 20% vs 11%, p=0.005; CAPOX 26% vs 15%, p<0.001 • Capecitabine dose was reduced during trial (1000 mg/m2 to 850 mg/m2 bid) • In patients with KRAS wildtype treated with cetuximab: non-significant advantage for FOLFOX compared to CAPOX • Patients in cetuximab arm received significantly less 2nd line treatment (overall 56% vs 62% p=0.014; KRAS WT 54% vs 65%, p=0.006) • Cross-over of anti-EGFR therapy in only 6%

  14. PRIME: FOLFOX with or without panitumumab in 1st-line treatment of metastatic CRC Douillard et al. ECCO/ESMO 2009

  15. PRIME study Adding panitumumab to FOLFOX in 1st-line • results in a significant benefit in median PFS in patients with KRAS wildtype • has a detrimental effect in patients with KRAS mutation • Longer follow-up is required • Cross-over of anti-EGFR agents in 10% of KRAS wildtype patients

  16. CAIRO2 Progression-free survival Arm A (without cetuximab) 10.7 months (9.7-12.3) Arm B (with cetuximab) 9.4 months (8.4-10.5) Hazard ratio for progression 1.21, p 0.018 Randomization, n = 755 Capecitabine Oxaliplatin Bevacizumab Capecitabine Oxaliplatin Bevacizumab Cetuximab CB CBC Tol et al. NEJM 2009 CB group CBC group

  17. CAIRO2 study: CAPOX plus bevacizumab withor without cetuximab in 1st-line treatment of metastatic CRC Tol et al. NEJM 2009

  18. CAIRO2 study Adding cetuximab to CAPOX plus bevacizumab in 1st-line • has no benefit in patients with KRAS wildtype • results in a significant decrease in median PFS and OS in patients with KRAS mutation • Significantly lower incidence of hypertension in cetuximab-arm: negative interaction between cetuximab and bevacizumab?

  19. PACCE: chemotherapy plus bevacizumab with or without panitumumab in 1st-line treatment of metastatic CRC Ox-CT = oxaliplatin-based chemotherapy Ir-CT = irinotecan-based chemotherapy, NE = not estimable Hecht et al. J ClinOncol 2009

  20. PACCE: chemotherapy plus bevacizumab with or without panitumumab in 1st-line treatment of metastatic CRC Ox-CT = oxaliplatin-based chemotherapy Ir-CT = irinotecan-based chemotherapy Hecht et al. J ClinOncol 2009

  21. PACCE study Adding panitumumab to oxaliplatin- or irinotecan-based chemotherapy plus bevacizumab in 1st-line • results in a decreased median PFS in patients with KRAS wildtype • results in a decreased median OS in oxaliplatin-treated patients with KRAS wildtype • Addition of panitumumab increased toxicity • Cohort of irinotecan-treated patients was relatively small, with safety as primary endpoint

  22. 181: FOLFIRI with or without panitumumab in 2nd-line treatment of metastatic CRC Peeters et al. ECCO/ESMO 2009

  23. 181 study Adding panitumumab to FOLFIRI in 2nd-line • results in a significant benefit in median PFS in patients with KRAS wildtype • has no detrimental effect in patients with KRAS mutation • Cross-over of anti-EGFR agents in control arm in 31% of patients

  24. Absolute benefits/hazard ratios of anti-EGFR plus chemotherapy in KRAS wildtype metastatic CRC * statistically significant

  25. Absolute benefits/hazard ratios of anti-EGFR plus chemotherapy in KRAS mutated metastatic CRC * statistically significant

  26. Chemotherapy + anti-EGFR antibodiesconclusions Benefit of anti-EGFR antibodies is limited to patients with KRAS wild-type tumors Detrimental effect of anti-EGFR antibodies in KRAS mutant tumors is only observed with oxaliplatin-based schedules Combination of bevacizumab with cetuximab/panitumumab should not be used Punt & Tol, Nature RevClinOncol 2009

  27. Chemotherapy + anti-EGFR antibodiesquestions Is this better than bevacizumab in 1st line in patients with KRAS wildtype tumors? Cross study comparisons do not suggest an outright superiority for anti-EGFR over bevacizumab

  28. Absolute benefits of bevacizumab plus chemotherapy in metastatic CRC * statistically significant

  29. Bevacizumab or cetuximab? CALGB study 80405 R First-line metastatic colorectal cancer + bevacizumab FOLFOX or FOLFIRI + cetuximab + bevacizumab+cetuximab Currently ongoing only in patients with KRAS wildtype tumors

  30. Chemotherapy + anti-EGFR antibodiesquestions 2) Is there a preferencebetweenirinotecan and oxaliplatin in patientswithKRAS wildtype tumors? Cross-studycomparisons do notsuggestanoutrightpreference, only few prospective data available

  31. Choice of chemotherapy in combination with cetuximab: randomized phase II study FOLFOX vs FOLFIRI ASCO 2009 Koza #4055

  32. Choice of chemotherapy in combination with cetuximab: randomized phase II study FOLFOX vs FOLFIRI * statistically significant versus KRAS mutant group ASCO 2009 Koza #4055

  33. Chemotherapy + anti-EGFR antibodiesquestions 3) Is there a preference for anti-EGFR therapy in KRAS wildtype patients with potentially resectable metastases? Cross-study comparisons show higher response rates for anti-EGFR therapy compared to bevacizumab. Whether this results in a higher proportion of patients that become resectable, and whether this subsequently results in an improved outcome has never been demonstrated in a prospective trial

  34. Chemotherapy + anti-EGFR antibodiesquestions 4) Is there a preference for capecitabine over 5FU in combination with oxaliplatin? Pooled analysis of randomized trials does not show a relevant difference between FOLFOX and CAPOX1 In 2 phase III studies with targeted therapy, the results with FOLFOX are slightly better than with CAPOX. Any benefit of FOLFOX, if at all, should be balanced against the use of infusional devices and more frequent patient visits 1Arkenau et al. J ClinOncol 2008

  35. Chemotherapy + anti-EGFR antibodiesquestions 5) Do patients with KRAS wildtype andBRAF mutated tumors benefit at all from systemic treatment? BRAF mutation is a negative prognostic marker, results of CAIRO2 study in control arm (CAPOX+bevacizumab): Tol et al. NEJM 2009

  36. CAIRO2: Progression-free survival -BRAF and KRAS- Cetuximab group No cetuximab group BRAF and KRAS wild type KRAS mutated BRAF mutated BRAF: HR 2.2 (1.3-3.8) KRAS: HR 1.05 (0.8-1.4) BRAF: HR 2.1 (1.6-3.2) KRAS: HR 1.5 (1.1-2.0) Tol et al. NEJM & ECCO/ESMO 2009

  37. Chemotherapy + anti-EGFR antibodiesquestions 6) Are there other markers that may predict the efficacy of anti-EGFR therapy within the group of KRAS wildtype patients? Several candidate markers (EGFR FISH, PIK3CA, PTEN, EGFR ligands, FcγR polymorphisms, etc), but to date none of them have shown results that may be used in the clinic

  38. First-line treatment options for chemotherapyin metastatic colorectal cancer - potentially resectable mets - relief of symptoms - salvage treatment unlikely - all other patients (majority)1 sequential - or combination chemotherapy combination chemotherapy • Choice between irinotecan and oxaliplatin should be made on an individual basis • Capecitabine may replace 5FU as monotherapy or in combination schedules 1CAIRO study: Koopman et al. Lancet 2007 FOCUS study: Seymour et al. Lancet 2007

  39. Choice of targeted drug in patients with KRAS wildtype tumors • In first-line, the results with anti-EGFR antibodies do not appear superior to bevacizumab • Absolute benefit of anti-EGFR antibodies appears to increase in late-line treatment, while this appears to decrease with bevacizumab • Bevacizumab is better tolerated than anti-EGFR agents in most patients • Current data suggest a preference for bevacizumab in first-line, and a role for cetuximab/panitumumab in salvage treatments

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