china abstracts （结肠直肠癌）课件

1 BOA Colorectal Cancer BOA Colorectal Cancer Abstracts 2010Abstracts 2010 Daniel G. Haller, M.D.Daniel G. Haller, M.D. Nanjing ChinaNanjing China July 4, 2010July 4, 2010 2 Molecular and clinical determinants of Molecular and clinical determinants of survival following relapse after curative survival following relapse after curative treatment of stage II-III colon cancer. Results treatment of stage II-III colon cancer. Results of the translational study of the translational study on the PETACC 3 trial on the PETACC 3 trial A. D. Roth, D. Klingbiel, P. Yan, R. Fiocca, M. A. D. Roth, D. Klingbiel, P. Yan, R. Fiocca, M. Delorenzi, R. Labianca, D. Cunningham, E. Van Delorenzi, R. Labianca, D. Cunningham, E. Van Cutsem, F. BosmanCutsem, F. Bosman , , S. TejparS. Tejpar 3 RationaleRationale Our previous results showed that stage II and III Our previous results showed that stage II and III colon cancers harbor different biomarker colon cancers harbor different biomarker alteration frequencies with different prognostic alteration frequencies with different prognostic effects according to disease stage (ASCO proc. effects according to disease stage (ASCO proc. 2009, 27 abstr. #4002)2009, 27 abstr. #4002) There is a lack of data regarding biomarkers There is a lack of data regarding biomarkers prognostic for disease behavior prognostic for disease behavior after relapseafter relapse Early observations suggest that Early observations suggest that marker sets marker sets prognostic for the risk of relapse might be prognostic for the risk of relapse might be different from those prognostic for survival after different from those prognostic for survival after relapse (SAR)relapse (SAR) 4 ObjectivesObjectives To look for clinical and molecular markers To look for clinical and molecular markers prognostic for survival after relapse (SAR).prognostic for survival after relapse (SAR). To assess their respective and relative To assess their respective and relative prognostic relevance in the relapsing prognostic relevance in the relapsing patient population using SAR as endpoint.patient population using SAR as endpoint. To assess possible differences between To assess possible differences between markers prognostic for risk of relapse and markers prognostic for risk of relapse and markers prognostic for SAR.markers prognostic for SAR. 5 Stratification: Stage II vs. III Center RANDOMIZATION Day 1Day 2 FA 200 mg/m2 5-FU bolus 400 mg/m2 5-FU CI 600 mg/m2 Day 1Day 2 Irinotecan 180 mg/m2 LV/5-FU2 LV/5-FU2 as above F IF Repeat q2w for 12 cycles PETACC-3: Study DesignPETACC-3: Study Design CI = continuous infusion. Van Cutsem et al., 2005.; JCO 2009 6 PETACC-3: DFS Not Significantly PETACC-3: DFS Not Significantly Improved With FOLFIRI in Stage IIIImproved With FOLFIRI in Stage III 1.0 0.9 0.8 0.7 0.6 0.5 0 Estimated Probability (%) 036912 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) FOLFIRI 1,04463.3 5-FU/LV 1,05060.3 HR = 0.89 (95% CI: 0.771.11) p = .091 3-Year DFS (%)n Van Cutsem et al., 2005; JCO 2009 7 PETACC3 trial: Patient DistributionPETACC3 trial: Patient Distribution Total Accrual: NO suitable material for biomarkers With suitable material for biomarkers # relapsing# relapsing Patients treated 8 Relapsing Patients Relapsing Patients CharacteristicsCharacteristics VariablesFull set (n=990) % (.95 CI) Marker set (n=392) % (.95 CI) Early relapse 56457% (53.8- 60.1) 22156.4% (51.3- 61.3) Age 1 pathologically confirmed 1 pathologically confirmed lymph node identifiedlymph node identified Age Age 18 years 18 years Acceptable liver and kidney Acceptable liver and kidney functionfunction Standard hematologic parametersStandard hematologic parameters 30 Eligibility for N0147Eligibility for N0147 ExclusionExclusion Evidence of metastatic diseaseEvidence of metastatic disease En bloc resection for locally En bloc resection for locally advanced disease allowedadvanced disease allowed Prior chemotherapy or radiation for Prior chemotherapy or radiation for colon cancercolon cancer Prior or concurrent malignancies Prior or concurrent malignancies within 5 yearswithin 5 years Clinically significant peripheral Clinically significant peripheral neuropathyneuropathy 31 Final Study PopulationFinal Study Population 1864 randomized to A (FOLFOX) 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab)or D (FOLFOX + cetuximab) Trial halted on findings of planned Trial halted on findings of planned interim analysis for futilityinterim analysis for futility 90% of planned accrual90% of planned accrual Median follow-up 23 monthsMedian follow-up 23 months 32 Patient Patient CharacteristicsCharacteristics FOLFOXFOLFOX (N=909)(N=909) FOLFOX+CmabFOLFOX+Cmab (N=955)(N=955) Age (years)Age (years) Median (Range) Median (Range) 14% 70+ years of age14% 70+ years of age 58 (19 - 84)58 (19 - 84)58 (25 - 86)58 (25 - 86) GenderGender Female Female Male Male 46%46% 54%54% 48%48% 52%52% RaceRace Caucasian Caucasian African American African American Other Other 87%87% 5%5% 8%8% 86%86% 6%6% 8%8% 33 Tumor CharacteristicTumor Characteristic FOLFOXFOLFOX (N=909)(N=909) FOLFOX+CmabFOLFOX+Cmab (N=955)(N=955) Bowel ObstructionBowel Obstruction Yes Yes No No 15%15% 85%85% 16%16% 84%84% Bowel PerforationBowel Perforation Yes Yes No No 5%5% 95%95% 5%5% 95%95% HistologyHistology High High Low Low 27%27% 73%73% 27%27% 73%73% Lymph Node InvolvementLymph Node Involvement 1 - 3 1 - 3 3 3 56%56% 44%44% 57%57% 43%43% T StageT Stage T1 or T2 T1 or T2 T3T3 T4 T4 13%13% 76%76% 11%11% 16%16% 72%72% 11%11% 34 Outcomes for K-ras WT Outcomes for K-ras WT PatientsPatients 35 Disease-Free Survival (N=1847)Disease-Free Survival (N=1847) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=902N=902 75.8%75.8% (72.1%-79.6%)(72.1%-79.6%) 1.21.2 (0.96-1.5)(0.96-1.5) 0.220.22 FOLFOX + FOLFOX + CmabCmab N=945N=945 72.3%72.3% (68.5%-76.4%)(68.5%-76.4%) 36 Disease-Free SurvivalDisease-Free Survival Age 70 (N=258)70 (N=258) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-valueP-value FOLFOXFOLFOX N=112N=112 80.9%80.9% (73.0%-89.8%)(73.0%-89.8%) 1.791.79 (1.01-3.18)(1.01-3.18) 0.030.03 FOLFOX + FOLFOX + CmabCmab N=146N=146 66.1%66.1% (56.8%-77.0%)(56.8%-77.0%) 38 Forest Plot for DFSForest Plot for DFS Favors FOLFOX Favors FOLFOX alonealone 39 Overall Survival (N=1847)Overall Survival (N=1847) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-valueP-value FOLFOXFOLFOX N=902N=902 87.8%87.8% (84.7%-90.9%)(84.7%-90.9%) 1.31.3 (0.96-1.8)(0.96-1.8) 0.130.13 FOLFOX + FOLFOX + CmabCmab N=945N=945 83.9%83.9% (80.3%-87.6%)(80.3%-87.6%) 40 Toxicity Grade 3-4Toxicity Grade 3-4 Arm AArm AArm DArm D NeutropeniaNeutropenia10%10%13%13% Febrile NeutropeniaFebrile Neutropenia1%1%3%3% HypersensitivityHypersensitivity2%2%6%6% Rash/AcneRash/Acne0%0%19%19% NauseaNausea3%3%4%4% DiarrheaDiarrhea9%9%15%15% Peripheral Peripheral NeuropathyNeuropathy 4%4%5%5% OverallOverall51%51%71%71% 41 Reasons for DiscontinuationReasons for Discontinuation ReasonReasonArm AArm A 7070 (N=108)(N=108) Arm DArm D 7070 (N=143)(N=143) CompletionCompletion77.9%77.9%78.9%78.9%77.8%77.8%70.2%70.2%67.0%67.0%51.1%51.1% RefusalRefusal6.7%6.7%6.7%6.7%4.6%4.6%11.7%11.7%8.7%8.7%13.3%13.3% AEAE9.3%9.3%7.4%7.4%13.0%13.0%9.1%9.1%18.1%18.1%21.0%21.0% OtherOther6.1%6.1%7.0%7.0%4.6%4.6%9.0%9.0%6.2%6.2%14.6%14.6% 42 ConclusionsConclusions No benefit to adding cetuximab in No benefit to adding cetuximab in patients with resected stage 3 Kpatients with resected stage 3 K -ras WT expressing colon cancer-ras WT expressing colon cancer Potential explanationsPotential explanations Decreased tolerance with cetuximabDecreased tolerance with cetuximab Differences in dose intensityDifferences in dose intensity Interaction with age: Interaction with age: Worse outcomes in older patients Worse outcomes in older patients receiving cetuximabreceiving cetuximab Lessened ability to complete therapyLessened ability to complete therapy 43 ConclusionsConclusions MechanisticMechanistic Cetuximab may have a different Cetuximab may have a different form of activity on micrometastatic form of activity on micrometastatic disease compared to that disease compared to that observed in stage 4 diseaseobserved in stage 4 disease Differences in biology of earlier Differences in biology of earlier stage diseasestage disease Current focus of correlative Current focus of correlative studiesstudies 44 Adjuvant mFOLFOX6 +/- cetuximab Adjuvant mFOLFOX6 +/- cetuximab in patients in patients with K-ras mutantwith K-ras mutant resected stage III colon cancerresected stage III colon cancer Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven AlbertsGill, Morton Kahlenberg, Suresh Nair, Steven Alberts * Coordinating group Cooperative Group Trial N0147 NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG 45 Treatment Assignment,Treatment Assignment, by K-ras Statusby K-ras Status FOLFOXFOLFOX +Cmab Total K-ras WT9099551864 K-ras Mut 374343717 Total128312982581 46 DFS: FOLFOX +/- Cmab by DFS: FOLFOX +/- Cmab by K-ras status K-ras status K-Ras WTK-Ras WTK-Ras MutK-Ras Mut ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=374N=374 67.2%67.2% (61.4-73.5%)(61.4-73.5%) 1.21.2 (0.9-1.6)(0.9-1.6) 0.130.13 FOLFOX FOLFOX + Cmab+ Cmab N=343N=343 64.2%64.2% (58.7-70.2%)(58.7-70.2%) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=902N=902 75.8%75.8% (72.1-79.6%)(72.1-79.6%) 1.21.2 (0.96-(0.96- 1.5)1.5) 0.220.22 FOLFOX FOLFOX + Cmab+ Cmab N=945N=945 72.3%72.3% (68.5-76.4%)(68.5-76.4%) 47 DFS: FOLFOX +/- Cmab by DFS: FOLFOX +/- Cmab by K-ras status K-ras status K-Ras WTK-Ras WTK-Ras MutK-Ras Mut ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=374N=374 67.2%67.2% (61.4-73.5%)(61.4-73.5%) 1.21.2 (0.9-1.6)(0.9-1.6) 0.130.13 FOLFOX FOLFOX + Cmab+ Cmab N=343N=343 64.2%64.2% (58.7-70.2%)(58.7-70.2%) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=902N=902 75.8%75.8% (72.1-79.6%)(72.1-79.6%) 1.21.2 (0.96-(0.96- 1.5)1.5) 0.220.22 FOLFOX FOLFOX + Cmab+ Cmab N=945N=945 72.3%72.3% (68.5-76.4%)(68.5-76.4%) 48 K-Ras WTK-Ras WTK-Ras MutK-Ras Mut ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=374N=374 88.0%88.0% (83.8%-92.5%)(83.8%-92.5%) 1.51.5 (0.9-2.3)(0.9-2.3) 0.120.12 FOLFOX FOLFOX + Cmab+ Cmab N=343N=343 80.4%80.4% (74.8%-86.4%)(74.8%-86.4%) ArmArm3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue FOLFOXFOLFOX N=902N=902 87.8%87.8% (84.7%-90.9%)(84.7%-90.9%) 1.31.3 (0.96-(0.96- 1.8)1.8) 0.130.13 FOLFOX FOLFOX + Cmab+ Cmab N=945N=945 83.9%83.9% (80.3%-87.6%)(80.3%-87.6%) OS: FOLFOX +/- Cmab by OS: FOLFOX +/- Cmab by K-ras status K-ras status 49 Duration of TherapyDuration of Therapy K-Ras WT CycleCycleFOLFOXFOLFOX (N=871)(N=871) FOLFOX+FOLFOX+ CmabCmab (N=925)(N=925) P-valueP-value 6 6 89%89%79%79% 80% dose 80% dose intensity for all drugsintensity for all drugs Consider only patients aged 80%) 80%) K-ras MutK-ras Mut ArmArmOxaliplatinOxaliplatin5-FU5-FUCetuximabCetuximab FOLFOX FOLFOX (N=300)(N=300) 66%66%84%84%N/AN/A FOLFOX + CmabFOLFOX + Cmab (N=278)(N=278) 60%60%73%73%59%59% P-valueP-value010.001 ArmArmOxaliplatinOxaliplatin5-FU5-FUCetuximabCetuximab FOLFOXFOLFOX (N=276)(N=276) 44%44%78%78%N/AN/A FOLFOX + CmabFOLFOX + Cmab (N=238)(N=238) 41%41%63%63%53%53% P-valueP-value0.480.480.00020.0002 Cycle 6 Cycle 10 52 % Grade 3+ Adverse Events% Grade 3+ Adverse Events K-Ras WTK-Ras WT K-Ras MutK-Ras Mut Adverse EventAdverse EventFOLFOXFOLFOX (N=883)(N=883) FOLFOX + CFOLFOX + C (N=919)(N=919) ParesthesiasParesthesias 9 9 7 7 N-penia (Gr 4+)N-penia (Gr 4+)10101111 DiarrheaDiarrhea 8 8 1515 NauseaNausea 3 3 4 4 ThrombosisThrombosis 3 3 3 3 HypokalemiaHypokalemia 3 3 8 8 FatigueFatigue 3 3 6 6 HypersensitivityHypersensitivity 2 2 6 6 VomitingVomiting 3 3 3 3 RashRash0.10.1 8 8 MucositisMucositis 2 2 7 7 Adverse EventAdverse EventFOLFOXFOLFOX (N=364)(N=364) FOLFOX + CFOLFOX + C (N=339)(N=339) ParesthesiasParesthesias1313 9 9 N-penia (Gr 4+)N-penia (Gr 4+)12121313 DiarrheaDiarrhea 8 8 1515 NauseaNausea 2 2 6 6 ThrombosisThrombosis 3 3 5 5 HypokalemiaHypokalemia 3 3 5 5 FatigueFatigue 3 3 4 4 HypersensitivityHypersensitivity 3 3 6 6 VomitingVomiting 3 3 5 5 RashRash 0 0 9 9 MucositisMucositis 3 3 7 7 AEs did not differ by KRAS status 53 Is K-ras prognostic in FOLFOX Is K-ras prognostic in FOLFOX treated patients?treated patients? K-ras K-ras StatusStatus 3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue WTWT N=902N=902 75.8%75.8% (72.1-79.6%)(72.1-79.6%) 0.70.7 (0.5-0.9)(0.5-0.9) 0.040.04 MutMut N=374N=374 67.2%67.2% (61.4-73.5%)(61.4-73.5%) 54 Is K-ras prognostic in Is K-ras prognostic in FOLFOX+Cmab treated patients?FOLFOX+Cmab treated patients? K-ras K-ras StatusStatus 3 Year Rates 3 Year Rates (95% CI)(95% CI) HR HR (95% CI)(95% CI) P-P- valuevalue WTWT N=945N=945 72.3%72.3% (68.5-76.4%)(68.5-76.4%) 0.70.7 (0.5-0.9)(0.5-0.9) 0.0040.004 MutMut N=343N=343 64.2%64.2% (58.7-70.2%)(58.7-70.2%) 55 Why did patients with K-ras Mut Why did patients with K-ras Mut treated with Cetuximab do worse?treated with Cetuximab do worse? While they had lower drug While they had lower drug exposure, we dont believe that is exposure, we dont believe that is the key reason based on the the key reason based on the idealized patient analysisidealized patient analysis We believe that the explanation is We believe that the explanation is related to tumor biologyrelated to tumor biology Hypothesis: Cetuximab treatment Hypothesis: Cetuximab treatment of K-ras mutated tumors drives of K-ras mutated tumors drives chemotherapy resistance chemotherapy resistance 56 Aiming at the Wrong Aiming at the Wrong Target?Target? Discussion of Abstracts Discussion of Abstracts CRA3507 (Alberts) and 3508 (Goldberg)CRA3507 (Alberts) and 3508 (Goldberg) Louis M. Weiner, MDLouis M. Weiner, MD Lombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center Georgetown University Medical CenterGeorgetown University Medical Center 57 This Should Have Worked!This Should Have Worked! EGFR How did we miss the target? 58 The EGFR Signaling Network is Vast and ComplicatedThe EGFR Signaling Network is Vast and Complicated 59 Possible Explanations and ImplicationsPossible Explanations and Implications 1.Antibody Dependent Cellular Cytotoxicity (ADCC): not relevant 2.EGFR Signaling is complicated Robust EGFR resistance networks 3.EGFR is not a relevant target in colon cancer micro metastasis 60 Right Target, Wrong Setting?Right Target, Wrong Setting? Epithelial-Mesenchymal Transition (EMT)Epithelial-Mesenchymal Transition (EMT) Adapted from Kalluri & Weinberg, J Clin Invest 119: 1420-8, 2009 EGFRSyndecan E-cadherinMUC1 CytokeratinDesmoplakin ZO-1a1 (IV) collagen Laminin-1miR200 family Entactin FTS binding protein FAPSnail FSP-1Slug N-cadherinSIP1 Vimentina-SMA FibronectinTwist b-cateninGoosecoid Ob-cadherinLEF-1 Syndecan-1FOXC2 miR10bmiR21 61 Relative Sensitivity to CetuximabRelative Sensitivity to Cetuximab HighLowHigh “EMT status may be a broadly applicable indicator of sensitivity to EGFR inhibitors.” (Barr et al, Clin Exp Metastasis (2008) 25:685693) Primary Tumor Metastasis Established Metastasis EGFR 62 Summary and ImplicationsSummary and Implications Cetuximab therapy does Cetuximab therapy does notnot prevent prevent metastasis following resection of Stage III metastasis following resection of Stage III colon cancer colon cancer Likely to be true for panitumumab and other anti-Likely to be true for panitumumab and other anti- EGFR antibodiesEGFR antibodies EGFR-directed monoclonal antibodies EGFR-directed monoclonal antibodies should should notnot be used in Stage III colon cancer- be used in Stage III colon cancer- directed adjuvant therapy regimensdirected adjuvant therapy regimens Numerous genes contribute to resistance to Numerous genes contribute to resistance to EGFR antagonismEGFR antagonism May underlie resistance to cetuximabMay underlie resistance to cetuximab Combination signaling inhibitor strategies are Combination signaling inhibitor strategies are neededneeded 63 Summary and ImplicationsSummary and Implications Cetuximab therapy does Cetuximab therapy does notnot prevent prevent metastasis following resection of Stage III metastasis following resection of Stage III colon cancer colon cancer Likely to be true for panitum