Cetuximab and Irinotecan With or Without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial

Marla Lipsyc-Sharf, Fang-Shu Ou, Matthew B Yurgelun, Douglas A Rubinson, Deborah Schrag, Shaker R Dakhil, Philip J Stella, Douglas J Weckstein, Donald B Wender, Meredith Faggen, Tyler J Zemla, Erica N Heying, Samantha R Schuetz, Stephanie Noble, Jeffrey A Meyerhardt, Tanios Bekaii-Saab, Charles S Fuchs, Kimmie Ng, Marla Lipsyc-Sharf, Fang-Shu Ou, Matthew B Yurgelun, Douglas A Rubinson, Deborah Schrag, Shaker R Dakhil, Philip J Stella, Douglas J Weckstein, Donald B Wender, Meredith Faggen, Tyler J Zemla, Erica N Heying, Samantha R Schuetz, Stephanie Noble, Jeffrey A Meyerhardt, Tanios Bekaii-Saab, Charles S Fuchs, Kimmie Ng

Abstract

Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes.

Patients and methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs).

Results: The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46).

Conclusion: In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted.Clinical Trial Registration: NCT02292758.

Keywords: bevacizumab; cetuximab; colorectal neoplasm; irinotecan.

© The Author(s) 2022. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
CONSORT Diagram: Patient flow through BOND-3 trial of cetuximab and irinotecan with or without bevacizumab.
Figure 2.
Figure 2.
Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival by treatment group. Abbreviations: CBI, cetuximab, bevacizumab, and irinotecan; CI, cetuximab and irinotecan.

References

    1. Siegel RL, Miller KD, Goding Sauer A, et al. . Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.
    1. Tejpar S, Stintzing S, Ciardiello F, et al. . Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194-201.
    1. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V.. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70:87-98.
    1. Brulé SY, Jonker DJ, Karapetis CS, et al. . Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405-1414.
    1. Cunningham D, Humblet Y, Siena S, et al. . Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.
    1. Saltz LB, Lenz HJ, Kindler HL, et al. . Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;25(29):4557-4561.
    1. Tol J, Koopman M, Cats A, et al. . Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-572.
    1. Hecht JR, Mitchell E, Chidiac T, et al. . A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672-680.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
    1. National Cancer I. Common terminology criteria for adverse events: (CTCAE). 2010.
    1. Pocock SJ, Simon R.. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103-115.
    1. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50(3):163-170.
    1. Kaplan E. L. PM. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282): 457-481.
    1. Cox DR. Regression models and life-tables. Journal of the Royal Statistical Society Series B (Methodological). 1972;34(2):187-220.
    1. Mann HB, Whitney DR.. On a test of whether one of two random variables is stochastically larger than the other. Ann Math Statist. 1947;18(1):50-60. doi:10.1214/aoms/1177730491
    1. Cochran WG. The χ2 test of goodness of fit. Ann Math Statist. 1952;3:315-345.
    1. Fisher RA. On the interpretation of χ2 from contingency tables, and the calculation of P. Journal of the Royal Statistical Society. 1922;85(1):87-94. doi:10.2307/2340521
    1. Bennouna J, Sastre J, Arnold D, et al. ; ML18147 Study Investigators . Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29-37.
    1. Hochster HS, Catalano PJ, O’Dwyer PJ, et al. . Randomized trial of irinotecan and cetuximab (IC) versus irinotecan, cetuximab and ramucirumab (ICR) as 2nd line therapy of advanced colorectal cancer (CRC) following oxaliplatin and bevacizumb based therapy: Result of E7208. J Clin Oncol. 2018;36(15_suppl):3504-3504. doi:10.1200/JCO.2018.36.15_suppl.3504
    1. André T, Vernerey D, Im SA, et al. . Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020;31(2):246-256.
    1. Taieb J, Tabernero J, Mini E, et al. ; PETACC-8 Study Investigators . Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(8):862-873.
    1. Pretzsch E, Bösch F, Neumann J, et al. . Mechanisms of metastasis in colorectal cancer and metastatic organotropism: hematogenous versus peritoneal spread. J Oncol. 2019;2019:7407190.
    1. Almog N. Molecular mechanisms underlying tumor dormancy. Cancer Lett. 2010;294(2):139-146.
    1. Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ.. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 2002;8(5):994-1003.
    1. Ciardiello F, Bianco R, Damiano V, et al. . Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res. 2000;6(9):3739-3747.
    1. Tonra JR, Deevi DS, Corcoran E, et al. . Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res. 2006;12(7 Pt 1):2197-2207.
    1. Shaheen RM, Ahmad SA, Liu W, et al. . Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001;85(4):584-589.
    1. Venook AP. Right-sided vs left-sided colorectal cancer. Clin Adv Hematol Oncol. 2017;15(1):22-24.
    1. Lièvre A, Bachet JB, Boige V, et al. . KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374-379.

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