Cediranib With mFOLFOX6 Versus Bevacizumab With mFOLFOX6 As First-Line Treatment for Patients With Advanced Colorectal Cancer: A Double-Blind, Randomized Phase III Study (HORIZON III)

2012 ◽  
Vol 30 (29) ◽  
pp. 3588-3595 ◽  
Author(s):  
Hans-Joachim Schmoll ◽  
David Cunningham ◽  
Alberto Sobrero ◽  
Christos S. Karapetis ◽  
Philippe Rougier ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Significant Difference ◽  
Patient Reported ◽  
First Line Treatment

Purpose To compare the efficacy of cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab (anti–VEGF-A monoclonal antibody) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer (mCRC). Patients and Methods HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6 [oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 intravenously followed by fluorouracil 400 mg/m2 intravenously on day 1 and then continuous infusion of 2,400 mg/m2 over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to compare progression-free survival (PFS). Results In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P = .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common adverse events with more than 5% incidence in the cediranib arm included diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12 cycles). Patient-reported outcomes (PROs) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients (P < .001). Conclusion Cediranib activity, in terms of PFS and OS, was comparable to that of bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS noninferiority was not met. The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab. Investigation of oral TKIs in CRC continues.

Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study

2012 ◽  
Vol 30 (15) ◽  
pp. 1755-1762 ◽  
Author(s):  
Kjell Magne Tveit ◽  
Tormod Guren ◽  
Bengt Glimelius ◽  
Per Pfeiffer ◽  
Halfdan Sorbye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
First Line Treatment

Purpose The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. Patients and Methods Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. Results Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. Conclusion Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer

2007 ◽  
Vol 25 (33) ◽  
pp. 5225-5232 ◽  
Author(s):  
Josep Tabernero ◽  
Eric Van Cutsem ◽  
Eduardo Díaz-Rubio ◽  
Andrés Cervantes ◽  
Yves Humblet ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Study ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Curative Intent ◽  
First Line Treatment

PurposeThis phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC).Patients and MethodsThe activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m2during week 1, then 250 mg/m2weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m2on day 1; leucovorin 200 mg/m2on days 1 and 2, followed by fluorouracil 400 mg/m2bolus then 600 mg/m2intravenous infusion during 22 hours on days 1 and 2).ResultsThe preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.ConclusionCetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

scholarly journals Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group

2017 ◽  
Vol 28 (6) ◽  
pp. 1288-1293 ◽  
Author(s):  
J.J.M. Kwakman ◽  
L.H.J. Simkens ◽  
J.M. van Rooijen ◽  
A.J. van de Wouw ◽  
A.J. ten Tije ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Phase Iii Trial ◽  
Cancer Group ◽  
First Line Treatment

Safety analysis of the randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 86-86
Author(s):  
Takanori Watanabe ◽  
Akihito Tsuji ◽  
Manabu Shiozawa ◽  
Hirofumi Ota ◽  
Hironaga Satake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Safety Analysis ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Randomized Phase Ii ◽  
First Line Treatment ◽  
Triplet Regimen

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

Sign in / Sign up

Export Citation Format

Share Document