Original StudyMOMENTUM: A Phase I Trial Investigating 2 Schedules of Capecitabine With Aflibercept in Patients With Gastrointestinal and Breast Cancer
Introduction
Neo-angiogenesis is a hallmark of cancer, providing the basis for tumor growth, invasion, and metastatic dissemination.1 Over the past 2 decades, a number of agents targeting pro-angiogenic pathways have been developed and ultimately approved for use in many tumor types, either as monotherapy or in combination with other therapies.2 These drugs have generally been shown to be well-tolerated. Although cardiovascular toxicity is potentially concerning, severe or fatal events occur in a minority of patients.3, 4, 5, 6 Furthermore, no significant overlap exists between the toxicity profile of anti-angiogenic and cytotoxic drugs, and the risk of the former enhancing side effects that are primarily caused by the latter is limited overall.
As a result of their unique mechanism of action and manageable safety profile, anti-angiogenics have largely expanded therapeutic options in cancer treatment.2 In many disease settings, including gastrointestinal cancers, adding these drugs to standard chemotherapy has led to better outcomes.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Furthermore, these agents have represented ideal companion drugs to test in combination with de-intensified chemotherapy regimens whenever contraindications exist to the use of standard chemotherapy combination treatments. One of the best examples of this was the AVEX trial, which set a new standard of care by randomizing treatment-naive patients with metastatic colorectal cancer aged ≥ 70 years and deemed not suitable for doublet chemotherapy between capecitabine alone or in combination with bevacizumab, an anti-vascular endothelial growth factor (VEGF)-A monoclonal antibody.20 In this study, the addition of bevacizumab to single-agent chemotherapy was associated with outcome results that are comparable overall to historical data of doublet chemotherapy regimens, without substantially increasing toxicity.
Aflibercept is a recombinant fusion protein that exerts anti-angiogenic activity by binding VEGF-A, VEGF-B, and placental growth factor with high affinity.21 In a randomized phase III trial (VELOUR) including patients with metastatic colorectal cancer who had previously been treated with oxaliplatin-based chemotherapy, combining aflibercept with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) significantly improved objective response rate (19.8% vs. 11.1%; P = .0001), median progression-free survival (PFS) (6.9 vs. 4.7 months; hazard ratio [HR], 0.76; P < .0001), and median overall survival (OS) (13.5 vs. 12.1 months; HR, 0.82; P = .0032) as compared with FOLFIRI alone.9 As a result, both the European Medicines Agency and the United States Food and Drug Administration approved this agent for use in metastatic colorectal cancer in combination with second-line FOLFIRI chemotherapy. Despite these results and the preclinical evidence suggesting enhancement of the anti-tumor activity of anti-angiogenic drugs by capecitabine,22, 23, 24, 25, 26 data on the combination of this oral fluoropyrimidine with aflibercept are limited.27,28 Furthermore, aflibercept has never been investigated in the clinical setting of breast cancer.
Based on these premises, we conducted MOMENTUM, a phase I clinical trial evaluating the safety and tolerability of 2 schedules of capecitabine in combination with aflibercept in patients with chemorefractory gastrointestinal and breast cancers.
Section snippets
Patient Selection
Eligibility was restricted to patients aged ≥ 18 years with histologically confirmed, unresectable, locally advanced or metastatic gastrointestinal (ie, colorectal, gastric, esophageal, pancreatic, biliary) or breast cancer that were refractory to standard therapy. Patients had to have an Eastern Cooperative Oncology Group performance status of ≤ 1, normal bone marrow and organ function, and a life expectancy of > 12 weeks. The main exclusion criteria included administration of chemotherapy,
Patient Characteristics
Between September 2013 and October 2016, 38 eligible patients were enrolled in the study (17 in arm A and 21 in arm B). Of these, 5 were not evaluable for DLT owing to non–toxicity-related missed doses or early discontinuation of capecitabine (n = 4) and early death (n = 1), which was considered to be secondary to tumor progression. Baseline characteristics of the 33 eligible patients who were assessable for DLTs are reported in Table 1. The median age was 54 years (range, 31-74 years) in arm A
Discussion
In this study, we have shown that combining aflibercept with capecitabine is feasible and associated with a manageable safety profile. By using a 2-arm trial design, we established the RP2Ds for 2 administration schedules of this combination treatment, including a continuous (1350 mg/m2) and a 2-weeks-on/1-week-off (2500 mg/m2) dosing of capecitabine. Encouraging signals of anti-tumor activity and overall efficacy were also observed for both schedules.
Further to the preliminary findings of
Conclusions
Combining aflibercept with the standard intermittent or a metronomic dosing schedule of capecitabine is feasible, associated with a manageable safety profile and no unexpected adverse events. Bearing in mind the small numbers, this combination treatment may have interesting anti-tumor activity.
Disclosure
This study was supported by Sanofi who provided aflibercept and a research grant. A. Deleporte reports travel grants from Amgen and Ipsen. M. Piccart-Gebhart reports board member (scientific board) for Oncolytics; consultant (honoraria) for AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, and Seattle Genetics; research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer
Acknowledgments
The authors thank all patients who participated in this study and their families.
References (42)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: a systematic review and meta-analysis
Cancer Treat Rev
(2017) - et al.
RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study
Lancet Oncol
(2015) - et al.
Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial
Lancet
(2013) - et al.
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesphageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Lancet
(2014) - et al.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial
Lancet Oncol
(2014) - et al.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial
Lancet
(2018) - et al.
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet Oncol
(2019) - et al.
Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial
Lancet Oncol
(2013) - et al.
Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts
Cancer Lett
(2008)
Anti-angiogenesis participates in antitumor effects of metronomic capecitabine on colon cancer
Cancer Lett
A phase I/II dose finding study evaluating the safety and tolerability of capecitabine and aflibercept in patients with unresectable metastatic colorectal cancer deemed unsuitable for doublet/triplet chemotherapy: results of the phase I study
Eur J Cancer
TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study
Lancet Oncol
TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial
Lancet Oncol
Trends and challenges in tumor anti-angiogenic therapies
Cells
Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: a meta-analysis of approximately 29,000 cancer patients
Eur J Prev Cardiol
Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis
JAMA
Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors
J Clin Oncol
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study
J Clin Oncol
Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen
J Clin Oncol
Cited by (0)
S.C. and A.D. contributed equally to this article as first authors.
F.S. and A.H. contributed equally to this article as senior authors.