1. D. P. Modest 1, R. P. Laubender 2, L. Fischer von Weikersthal 3, U. Vehling-Kaiser 4, M. Stauch 5, H. Hass 6, H. F. Dietzfelbinger 7, D. V. Oruzio 8, S. Klein 9, K. Zellmann 10, T. Decker 11, M. Schulze 12, W. Abenhardt 13, G. Puchtler 14, H. W. Kappauf 15, J. Mittermueller 16, C. Haberl 17, S. Stintzing 1, U. R. Mansmann 2, V. Heinemann 1 ; 1 Department of Hematology and Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, LMU Munich; 2 Institute for Medical Informatics, Biometry and Epidemiology, University of Munich; 3 Department of Oncology, Gesundheitszentrum St. Marien GmbH, Amberg; 4 Practice for Medical Oncology, Landshut; 5 Outpatient Department, Kronach; 6 Marienhospital, Stuttgart; 7 Privatklinik Schindlbeck, Herrsching; 8 Medical Department II, Klinikum Augsburg, Augsburg; 9 Department of Internal Medicine IV, Klinikum Bayreuth, Bayreuth; 10 Schlossbergklinik, Oberstaufen; 11 Onkologie Ravensburg, Muenster; 12 Oncological Practice, Zittau; 13 Oncological Practice, Elisenhof, Munich; 14 Kliniken der Stadt und des Landkreises Rosenheim GmbH, Rosenheim; 15 Oncological Practice, Medicenter, Starnberg; 16 Oncological Practice, Germering; 17 Klinikum St. Elisabeth, Straubing, Germany. Purpose This study investigated the impact of early tumor-shrinkage (ETS) on progression-free- (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial. ETS was previously shown to be a predictor of treatment response to cetuximab. The present analysis, for the first time, evaluates the correlation of ETS with outcome parameters in patients undergoing capecitabine-based therapy. It also aims to correlate the predictive value of ETS and cetuximab-induced skin toxicity. Patients and methods: The AIO KRK0104 trial was performed as a randomised study comparing capecitabine/oxaliplatin (CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab in the first-line treatment of mCRC. 121 patients were available for evaluation of ETS at 6 weeks. ETS was defined as a relative change of ≥20% in the sum of the longest diameters of target lesions compared to baseline. Results: Tumors of sixty-three patients (71% KRAS wild-type (wt), 100% skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs 4.7 months, p<0.001, hazard ratio: 0.37) and OS (31.6 vs 15.8 months, p=0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in patients with KRAS mutant mCRC. ETS occurred more frequently with CAPOX- vs CAPIRI-based therapy (p=0.05). There was a highly significant correlation between the occurrence of ETS and cetuximab-related skin toxicity of any grade (I-III) (p=0.002). ETS occurred more frequently in patients with liver metastasis (p=0.09), metastatic involvement of <2 organs (p=0.09), KRAS wild-type tumors (p=0.06) and no previous adjuvant chemotherapy (p=0.06). Conclusion: In patients with KRAS wild-type mCRC receiving capecitabine-and cetuximab-based 1st-line therapy ETS correlates with prolonged PFS and OS. ETS also correlates with cetuximab-induced skin toxicity. Both parameters may therefore serve as post-randomisation surrogate markers of favourable outcome for cetuximab-based treatment. Early tumor shrinkage in patients with metastatic colorectal cancer receiving 1st-line treatment with cetuximab combined with either CAPIRI or CAPOX- an analysis of the AIO KRK 0104 trial Study Design Patient Characteristics According to ETS #3588 Treatment Parameters According to ETS Conclusions Design of Investigation From 2004-2006, 185 patients were recruited into the trial, of which 146 patients were evaluable for tumor response and KRAS status. 121 patients were evaluable for ETS-evaluation (drop-outs due to: early progression/death in ten patients and in 15 patients due to withdrawal of informed consent, adverse events within the first weeks of therapy or protocol violations concerning response evaluation) Early tumor shrinkage (ETS): tumor shrinkage >20% No early tumor shrinkage (no ETS): tumor shrinkage <20% 1.In patients with KRAS wild-type mCRC receiving capecitabine- and cetuximab-based 1st-line therapy ETS correlates with prolonged PFS and OS. 2.ETS correlates with cetuximab-induced skin toxicity. 3.ETS and skin toxicity may serve as post-randomisation surrogate markers of favourable outcome during cetuximab- based treatment. Parameters Early tumor shrinkage No early tumor shrinkage p-value No of patients No% % 63525848 Age, years Median6360 0.20 Range32-7538-77 Sex Female19301933 0.85 Male44703967 Karnofsky PS 100264223 40 0.69 9023381628 8010161526 703535 Not reported11 Primary tumor site Colon42673764 0.33 Rectum19302136 Colon + Rectum2300 Prior adjuvant therapy Chemotherapy71115260.06 Radiotherapy6106 1.0 Disease site Liver599448830.09 Liver only metastasis304819330.14 Lung213322380.70 Peritoneum586100.76 Other213331530.03 >1 disease sites111718310.09 Treatment-arm CAPIRI28443764 0.05 CAPOX35562136 KRAS Wild-type45713153 0.06 Mutant18292747 Cetuximab related skin toxicity of any grade Skin toxicity (Grade 1-4)631005086 0.002 No skin toxicity (Grade 0)00814 Table Legend: Characteristics of patients, percentages based on non-missing data. P-values: Chi- square-test/Fisher´s exact test, except age: independent samples: Mann Whitney U test. Parameter Early tumor shrinkage All patients No early tumor shrinkage All patients Early tumor shrinkage KRAS WT No early tumor shrinkage KRAS WT Number of patients63584531 ORR-Recist V. 1.0 (%)84248219 Median PFS (months) 95% CI Log rank HR (95%CI) 8.6 7.4-9.8 5.1 4.3-6.0 8.9 7.1-10.6 4.7 4.0-5.5 <0.001 0.50 (0.34-0.73) <0.001 0.37 (0.23-0.60) Median OS (months) 95% CI Log rank HR (95%CI) 28.7 22.6-34.7 17.0 8.9-25.1 31.6 26.6-35.5 15.8 8.5-23.1 0.023 0.63 (0.43-0.94) 0.005 0.48 (0.29-0.82) Table Legend: ORR: overall response rate; HR: hazard ratio; CI: confidence interval; PFS: progression-free survival; OS: overall survival. Patients with KRAS wt mCRC Patients with KRAS Mutant mCRC Metastatic colorectal cancer R CAPOX+ Cetuximab CAPIRI+Cetuximab CAPIRI + Cetuximab (*) Capecitabine 800 mg/m² oral BID day 1-14, q 3wks Irinotecan 200 mg/m² iv, 30 minday 1, q 3wks Cetuximabinitial dose 400 mg/m² iv, 120 min, then 250 mg/m² iv,60 min, wkly CAPOX + Cetuximab Capecitabine 1,000 mg/m² oral BID day 1-14, q 3wks Oxaliplatin 130mg/m² iv, 120 minday 1, q 3wks Cetuximabinitial dose 400 mg/m² iv, 120 min, then 250 mg/m² iv,60 min, wkly * 20% dose reduction for patients > 65 years in the XELIRI + Cetuximab arm. early tumor shrinkage: 8.9 months no early tumor shrinkage:4.7 months logrank p = <0.001 HR = 0.37 (0.23-0.60) PFS OS PFS OS early tumor shrinkage: 31.6 months no early tumor shrinkage:15.8 months logrank p = 0.005 HR = 0.48 (0.29-0.82) early tumor shrinkage: 7.5 months no early tumor shrinkage:5.8 months logrank p = 0.73 HR = 0.90 (0.49-1.67) early tumor shrinkage: 19.7 months no early tumor shrinkage:28.7 months logrank p = 0.81 HR = 1.09 (0.57-2.05)