B. Chibaudel

Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study

BACKGROUNDnThe purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab).nnnPATIENTS AND METHODSnKRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.nnnRESULTSnSixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation.nnnCONCLUSIONnPanitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. CLINICALTRIALS.nnnGOV IDENTIFIERnNCT00655499.BACKGROUNDnThe purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab).nnnPATIENTS AND METHODSnKRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.nnnRESULTSnSixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation.nnnCONCLUSIONnPanitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499.

FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study

BACKGROUNDnAlkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study.nnnPATIENTS AND METHODSnPreviously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level <or=3 ULN versus 3-5 ULN.nnnRESULTSnAmong the 620 patients in OPTIMOX1 study, 63 had ALP 3-5 ULN; 33 in arm A and 30 in arm B. The response rate in these patients was 56% versus 59% in patients with ALP <or=3 ULN. Median progression-free survival and overall survival were, respectively, 6.4 and 11.5 months in patients with ALP 3-5 ULN and 9.0 and 21.1 months in patients with ALP <or=3 ULN. Thirty-three percent of the patients in the cohort experienced grade 3/4 toxicity.nnnCONCLUSIONnBoth FOLFOX regimens achieved high tumor response rates and offer good palliation in MCRC patients with a poor prognosis.

497OBEVACIZUMAB-ERLOTINIB AS MAINTENANCE THERAPY IN METASTATIC COLORECTAL CANCER. FINAL RESULTS OF THE GERCOR DREAM STUDY

ABSTRACT Aim: VEGF or EGFR targeted monoclonal antibodies with chemotherapy demonstrated clinical activity in metastatic colorectal cancer (mCRC). Yet, combining these monoclonal antibodies in mCRC achieved adverse outcomes. However, erlotinib (E), an EGFR tyrosine kinase inhibitor, combined with bevacizumab (B) as maintenance (m) therapy after B-based induction therapy (IT) improved progression-free survival (PFS) (Tournigand, ASCO 2012). We report here the final results of the DREAM study. Methods: DREAM is a phase III trial in patients with unresectable mCRC. Pts without progression or surgery after a B-based IT were randomised to B (7.5u2003mg/kg q3w) or B (same dose) plus E (150u2003mg/d) as maintenance therapy until progression after stratification by centre, baseline ECOG status, ALP, LDH, induction chemotherapy (XELOX2-B vs mFOLFOX7-B or FOLFIRI-B), KRAS status, age, number of metastatic sites and tumour response (RR). Primary endpoint was mPFS from randomisation. Secondary endpoints were overall survival (OS), PFS from registration (r), response according to KRAS status, adverse events, curative resection, chemotherapy-free interval (CFI), and HR-QoL. Results: Among 701 registered pts, 452 were randomised for maintenance (B, 228; BE, 224). Median follow-up was 50 months. B arm vs BE arm, medians were: mPFS 4.9 vs 5.9 months (HR 0.77, CI 0.62-0.94; p = 0.012), rPFS 9.3 vs 10.2 months (HR 0.76, 95%CI 0.63-0.93; p = 0.007), mOS 22.0 vs 25.0 months (HR 0.80, CI 0.63-0.98; p = 0.034), rOS 26.9 vs 30.5 months (HR 0.80, CI 0.64-0.99; p = 0.040). All subgroups, including KRAS, had a benefit in OS. RR from baseline maintenance were B vs BE arm: all patients 11.5% vs 22.5% (OR 0.45, CI 0.25-0.79; p = 0.003), KRAS WT 15.4% vs 24% (OR 0.58, CI 0.27-1.19; p = 0.133), KRAS mut 8.3% vs 19.7% (OR 0.37, CI 0.12-1.04; p = 0.041). Patients in the B arm vs BE arm experienced less grade 3/4 diarrhea (0.9% vs 9.3%) and skin rash (0% vs 21.4%). Median time on therapy was 110 days in arm BE. Conclusions: Combination of erlotinib and bevacizumab as maintenance therapy significantly prolonged PFS and OS in patients with unresectable mCRC. The combination of anti-VEGF mab and EGFR tyrosine kinase inhibitor is active, even in mutated KRAS patients. Disclosure: B. Chibaudel: Roche, Sanofi; C. Tournigand: Roche, Sanofi; F. Bonnetain: Roche, Nestle, Merck; T. Andre: Roche; A. De Gramont: Roche, Sanofi. All other authors have declared no conflicts of interest.

3 Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial

BACKGROUNDnPerioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative.nnnPATIENTS AND METHODSnIn this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fongs prognostic score. The primary end point was 2-year disease-free survival (DFS).nnnRESULTSnA total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI.nnnCONCLUSIONSnFOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing.nnnCLINICAL TRIALS NUMBERnNCT00268398.

A need to simplify informed consent documents in cancer clinical trials. A position paper of the ARCAD Group

Background In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents. Methods The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research. Results A simplified form of informed consent with the leading part of 1200–1800 words containing all of the key information necessary to meet ethical and regulatory requirements and ‘relevant supportive information appendix’ of 2000–3000 words is provided. Conclusions This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content.Background In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents. Methods The Aide et Recherche en Cancerologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research. Results A simplified form of informed consent with the leading part of 1200–1800 words containing all of the key information necessary to meet ethical and regulatory requirements and ‘relevant supportive information appendix’ of 2000–3000 words is provided. Conclusions This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content.

Chemotherapy in Patients with Initially Unresectable Liver Metastasis of Colorectal Cancer

Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of death from cancer in Western countries [1]. Colorectal cancer incidence is also rising in other parts of the world, especially in Asia. Death from colorectal cancer has slightly reduced over the past 30 years, partly own to the advance of treatment modalities.

1581PMOUSE-DREAM: VEGF INHIBITION IS ACCOMPANIED BY EGFR ACTIVATION IN COLORECTAL CANCER MODELS INDEPENDENT OF KRAS STATUS PROVIDING A RATIONAL FOR COMBINATIONS OF BEVACIZUMAB AND ERLOTINIB IN THE POSITIVE GERCOR PHASE III DREAM TRIAL

ABSTRACT Aim: We have recently shown that EGFR- and VEGF(R)- targeted small molecules showed synergistic activity in colorectal cancer (CRC) models refractory to combinations of monoclonal antibodies independent of KRAS status. We here wished to determine the activity of bevacizumab in combination with erlotinib and to elucidate the molecular basis for the activity of the combination. Methods: Three human CRC xenograft models, SW48 (KRAS wt, bevacizumab sensitive), HT-29 (KRAS wt, bevacizumab resistant) and SW620 (KRAS mutant, bevacizumab sensitive) were established in nude mice. Animals were treated with bevacizumab and erlotinib, alone and in combination, and the influence on tumor growth, and the presence of activated EGFR was determined. The influence of erlotinib on the viability of CRC cells and EGFR ligand expression was established under normoxia, hypoxia and hypoxia/reoxygenation. Results: Combinations of bevacizumab and erlotinib were significantly more active than bevacizumab alone for all three xenograft models. Quantitative IHC analysis showed that bevacizumab activated EGFR in the tumor cells as well as in the tumor-associated endothelial cells which was attenuated by erlotinib. Erlotinib was more cytotoxic toward CRC cells under hypoxia and hypoxia/reoxygenation than under normoxia and was able to down-regulate the EGFR ligands TGF-alpha and amphiregulin under all experimental conditions. Conclusions: We here show that combinations of bevacizumab and erlotinib are significantly more active than bevacizumab alone in CRC models with different KRAS status and bevacizumab sensitivity. These findings provided the rational basis for the positive GERCOR phase III DREAM trial. Disclosure: A.K. Larsen: This research was financed in part by Roche; A. Savina: Employed by Roche; B. Chibaudel: Associated with the related DREAM clinical study sponsored by Roche; C. Tournigand: Associated with the related DREAM clinical study sponsored by Roche; T. Andre: Associated with the related DREAM clinical study sponsored by Roche; A. De Gramont: Associated with the related DREAM clinical study sponsored by Roche. All other authors have declared no conflicts of interest.

720PSECOND LINE THERAPY WITH SUNITINIB AS SINGLE AGENT IN PATIENTS WITH ADVANCED INTRAHEPATIC CHOLANGIOCARCINOMA (UPDATE ON SUN-CK PHASE II TRIAL)

ABSTRACT Aim: Beyond platinum-based first line chemotherapy for advanced cholangiocarcinoma (CK), second line 5FU-based treatments yield median progression-free survival (PFS) of Methods: This multicenter phase 2 study enrolled pts with locally advanced intrahepatic CK failing prior first-line platinum-based chemotherapy, ECOG PS 0-1, and adequate liver function with bilirubin 6.3 months (primary objective) other endpoints being PFS, response (RECIST 1.1 & Choi criteria), safety, pharmacokinetics (PK), and pharmacodynamic (PD) biomarkers (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopontin). Results: Among 51 pts yet enrolled in this ongoing trial, 34 are currently evaluable for safety and efficacy. Median age was 62 years (range 36–80), 19 females/15 males were included, and ECOG PS was 0/1 in 23/11 pts. With a median follow-up of 15.4 months and a median duration of treatment of 3.8 months, the median OS was 9.6 months [95%CI: 5.8-13.1], exceeding the primary objective. Five pts (15%) had partial responses and 24 stable diseases (71%) by RECIST (disease control rate 85%) with 10 pts having disease control > 6 months (range 6-14 months). Among 12 evaluable patients for Choi criteria, 11 (92%) had objective responses. Median PFS was 5.2 months. Frequently reported adverse events were grade (Gr) 1-2 asthenia (80% of pts), mucositis (80%), diarrhea (60%), and hand-foot syndrome (43%). Gr 3/4 asymptomatic hematological toxicity occurred in 24% of patients (neutropenia 8 pts, thrombocytopenia 7 pt), Gr 3 hypertension was observed in 7 pts, and Gr 3 asthenia in 4 pts. PK & PD data will be updated at the meeting. Conclusions: Sunitinib (continuous daily dose of 37.5u2003mg) is well tolerated and shows promising activity with 9.6 months OS in second line therapy in pts with intrahepatic advanced CK. Disclosure: J. Seitz: Honoraria Support from: Merck Serono, Novartis, Amgen, Sanofi-Aventis, Pfizer, Amgen SAS, Bayer-Schering-Pharma, Lilly; L. Fartoux: Honoraria Support from: Bayer and Bristol Myer Squibb; D. Malka: Grant Support from: Amgen, Roche, Merck Serono, Sanofi-Aventis Honoraria Support from: Merck Serono, Ipsen, Celgene, Novartis, Amgen, Roche, Sanofi-Aventis, Imclone, Teva, Keocyt, Boehringer-Ingelheim; M. Bouattour: Honoraria Support from: Bayer; E. Raymond: Honoraria Support from: Bayer, Pfizer, Novartis; S. Faivre: Honoraria Support from: Bayer, Pfizer, Novartis; All other authors have declared no conflicts of interest.