Original Study
A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES)

These data were previously presented in part at the 2013 Gastrointestinal Cancers Symposium, the American Society of Clinical Oncology 2013 Annual Meeting, the 2013 European Cancer Congress, the 2013 MASCC/ISOO International Symposium on Supportive Care in Cancer, and the 2015 European Cancer Congress.
https://doi.org/10.1016/j.clcc.2016.08.008Get rights and content

Abstract

Background

Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]).

Patients and Methods

Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period.

Results

A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300).

Conclusion

Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

Introduction

Colorectal cancer (CRC) is the third most common cancer and fourth most common cause of neoplastic-related death worldwide.1 The current standard of care for advanced CRC is 5-fluorouracil (5-FU) plus leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), with or without bevacizumab.2

Neutropenia is a major toxicity associated with chemotherapy for advanced CRC.3, 4 Moderate or severe neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L) increases the risk of serious infections5, 6 and, combined with fever (febrile neutropenia [FN]), can lead to hospitalization and treatment with antibiotics, as well as chemotherapy dose delays, dose reductions, and/or treatment discontinuation.6, 7 These complications can adversely affect patient outcomes.8, 9

Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) that has been shown to reduce the incidence of FN in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy.10, 11 The clinical guidelines from the European Organization for Research and Treatment of Cancer (EORTC),12 the American Society of Oncology (ASCO),13 and the National Comprehensive Cancer Network (NCCN)14 recommend primary prophylaxis with G-CSF when a patient's overall FN risk is > 20%. G-CSF support has also been used to maintain high relative dose intensity (RDI) of the myelosuppressive chemotherapy. A high RDI with a threshold of 85% has been identified as an independent factor for improving outcomes in different cancers, including breast cancer, lymphoma,15 and CRC.16, 17

FN incidence has been reported to increase with regimens containing bevacizumab,18, 19 but the efficacy and short- and long-term safety of pegfilgrastim for patients with CRC receiving chemotherapy and bevacizumab is unknown. We conducted a randomized, placebo-controlled, phase III trial (Pegfilgrastim and Anti-VEGF Evaluation Study [PAVES]) to evaluate the effect of pegfilgrastim on the incidence of grade 3/4 FN during the first 4 treatment cycles in patients with locally advanced or metastatic CRC receiving bevacizumab combined with first-line FOLFOX or FOLFIRI. We present the final results of the primary and secondary neutropenia-related endpoints evaluated during the study treatment period and the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS), evaluated at the end of the long-term follow-up (LTFU) period.

Section snippets

Eligibility

Treatment-naive patients aged ≥18 years with confirmed, measurable (modified Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1), locally advanced or metastatic adenocarcinoma of the colon or rectum were enrolled. Patients were required to have the following: Eastern Cooperative Oncology Group performance status of 0 to 2, ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, bilirubin ≤ 1.5 times the upper limit of normal (ULN), creatinine ≤ 1.5 times the ULN, and adequate organ

Patients and Treatments

From November 2009 to January 2012, 847 patients were enrolled at 114 sites in 17 countries and randomized (424 to placebo and 423 to pegfilgrastim; Figure 1). The baseline demographic data and clinical characteristics were similar between the 2 arms (Table 1). Almost all patients (97%) had metastatic disease; 414 (49%) received FOLFOX plus bevacizumab and 431 (51%) received FOLFIRI plus bevacizumab.

The primary analysis included 783 patients who completed 4 treatment cycles and was performed on

Discussion

PAVES is the largest prospective, randomized study to evaluate pegfilgrastim's effect on FN incidence and survival outcomes in patients with locally advanced or metastatic CRC receiving FOLFOX/bevacizumab or FOLFIRI/bevacizumab. PAVES met its primary endpoint: pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles by 57.9%. However, this reduction was less than the targeted reduction of 66.7%, in part because of the lower-than-expected incidence of

Conclusion

Pegfilgrastim prophylaxis appeared safe and effective in reducing the incidence of FN in patients with locally advanced or metastatic CRC receiving chemotherapy and bevacizumab. A limitation of the present study was capturing the incidence of FN only for 4 cycles, which limited our ability to discern the FN risk for patients who were receiving therapy for longer periods. The lack of significant differences in ORR, OS, and PFS between the pegfilgrastim and placebo arms suggests that

Disclosures

Z. Klippel, M. Reiner, and P.K. Morrow are employees and stockholders of Amgen Inc. S. Whittaker is a stockholder of Amgen Inc. S. Whittaker and M.R. Choi were employees and stockholders of Amgen Inc at the time of the study. T. Pinter participated in an advisory board and/or was a consultant to Pfizer, Novartis, and Roche. A. Cesas received research funding from Amgen Inc. A. Croitoru received research funding and was a consultant to Amgen Inc. The remaining authors declare that they have no

Acknowledgments

This work was supported by Amgen Inc. Kathryn Boorer of Amgen Inc and Martha Mutomba (on behalf of Amgen Inc) provided writing assistance. The authors thank Esteban Abella, a former employee of Amgen Inc, and May Mo of Amgen Inc for their involvement in the study design and analysis and interpretation of data. The authors also thank Florian Vogl of Amgen Inc for useful discussions.

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    • J. Novotny is currently at Sunderby Hospital, Luleä, Sweden.

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