J.F. Seitz

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer

BACKGROUND Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m2 i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION The addition of sorafenib to gemcitabine does not improve PFS in APC patients.BACKGROUND Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION The addition of sorafenib to gemcitabine does not improve PFS in APC patients.

A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802)

BACKGROUND This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. PATIENTS AND METHODS A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). RESULTS Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. CONCLUSION Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

506PDINTERIM ANALYSIS OF PRODIGE 9, A RANDOMIZED PHASE III TRIAL COMPARING NO TREATMENT TO BEVACIZUMAB MAINTENANCE DURING CHEMOTHERAPY-FREE INTERVALS IN METASTATIC COLORECTAL CANCER

ABSTRACT Aim: The FOLFIRI + bevacizumab (bev) regimen is a standard 1st-line chemotherapy (CT) in metastatic colorectal cancer (mCRC). Several trials have evaluated chemotherapy-free intervals (CFI) with the aim of prevening patients (pts) from experiencing toxicities, with conflicting results. Methods: This study aimed to compare the tumour control duration (TCD) by a 1st-line CT followed by either bev maintenance (Arm A) or no treatment during CFI (Arm B). Both arms start with 12 cycles of induction CT of FOLFIRI + bev; then a CFI is made until progression. CT is reintroduced at progression, for a 8 further cycles; then a new CFI is put in place and so on. The TCD is defined by the time between randomization and strategy failure corresponding to tumour progression during a FOLFIRI + bev sequence. It was expected that bev maintenance will extend TCD from 10 to 14 months. We present the results of the planned interim analysis (IA) after 203 events were observed. Results: 494 pts were enrolled from March 2010 to July 2013. The IA was performed on the data of 490 pts (245 in both arms). The median age was 64.5 years; 218 (44%) pts had a non-resected primary tumour. During induction CT, 68% of the pts received the 12 planned cycles. At the time of analysis, 60% of the pts received only the 1st sequence of FOLFIRI + bev, and 29% received 2 sequences. The median TCD was 14.3 months in arm A and 13.4 months in arm B (HR = 0.98, p = 0.86). The estimated progression free survival (PFS) was 9.2 months [8.2; 9.7] in arm A and 8.0 months [7.7; 9.0] in arm B. The median overall survival was not met. Grade 3-4 toxicities were observed in 74% of the pts in arm A and 71% in arm B. No safety issue was detected based on the serious adverse events (SAE). Conclusions: The strategy evaluated in PRODIGE 9, to alternate CT sequences with or without bev maintenance during CFI, revealed an impressive TCD in both groups and longer than expected in arm B. The IA shows no significant improvement of TCD with bev maintenance therapy. A trend to a PFS improvement is observed in the bev maintenance arm that should be confirmed by the final analysis planned in 2015. No increase in toxicity was observed in the bev maintenance arm. This study validates the concept of a chemo re-introduction strategy with irinotecan-based regimen in first-line mCRC. Disclosure: T. Aparicio: Roche, Sanofi, Merck, Novartis; J. Bennouna: Roche; J. Taieb: Roche; O. Bouche: Roche; J. Phelip: 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 37.5 mg) 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.

Body mass index (BMI) as a prognostic and predictive factor in stage II/III colon cancer: An analysis of the ACCENT database.

e21126 Background: Obesity is an established risk factor for developing colon cancer. We determined the impact of body mass index (BMI) upon prognosis and treatment benefit using the Adjuvant Colon Cancer Endpoints (ACCENT) database. METHODS BMI (kg/m2) was categorized at baseline in patients (pts) with TNM stage II and III colon carcinomas (n= 23,315) enrolled in 20 randomized trials of 5-fluorouracil-based adjuvant therapy. Cox models were used to determine the association of BMI with time-to-recurrence (TTR), disease-free (DFS) and overall survival (OS). RESULTS Among colon cancer pts, 4194 (18%) were obese (BMI ≥30 kg/m2), 8347 (35.8%) overweight (BMI 25-29.9 kg/m2), 9062 (38.9%) normal weight (BMI 20-24.9 kg/m2), and 1712 (7.3%) underweight (BMI < 20 kg/m2). Obese vs normal weight pts were more likely to be younger (median age 60 vs 61 yr; p=0.0006), have distal tumors (57% vs 55%; p=0.0066), and be stage III vs II (68% vs 64%; p<0.0001). In univariate analyses, obese [HR 1.13 (1.06, 1.20), p=0.0003] and underweight [HR 1.12 (1.02, 1.23), p=0.0145] pts had poorer OS compared to normal weight pts. Analysis by gender demonstrated that underweight men [HR 1.26 (1.09, 1.47), p=0.0022], but not women (HR=1.09, p=0.13), had a worse OS vs normal weight pts. Similar results were found for DFS and OS; TTR was weaker among underweight pts. BMI category was not predictive of treatment benefit. CONCLUSIONS Obese and underweight colon cancer survivors have a statistically significant, but clinically modest, worse prognosis. Obesity does not predict chemotherapy benefit. Studies to determine if weight loss can attenuate the adverse prognostic impact of obesity are warranted. [Table: see text].