Final results from PAVES, a phase 3, randomized, double-blind, placebo-controlled trial of pegfilgrastim in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab for locally advanced or metastatic colorectal cancer (LA/mCRC) (NCT00911170)

Background: The incremental infection risk of adding bevacizumab to chemotherapy (ctx) and pegfilgrastim's role in reducing this risk are not well understood. PAVES evaluated efficacy of pegfilgrastim in reducing febrile neutropenia (FN) in pts with LA/mCRC receiving first-line FOLFOX + bevacizumab or FOLFIRI + bevacizumab. PAVES met its primary endpoint; pegfilgrastim significantly reduced grade 3/4 FN incidence in the first 4 treatment (tx) cycles (placebo: 5.7% [95%CI: 3.7–8.3], pegfilgrastim: 2.4% [1.1–4.3], odds ratio [OR] 0.41, P=0.014). Secondary endpoints prospectively assessed effect of pegfilgrastim on tumor-related outcomes. Here we present final results for objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) from PAVES.

Material and Methods: Tx-naïve pts ≥18yrs with LA/mCRC measurable per RECIST 1.1 were randomly assigned 1:1 to placebo or 6mg pegfilgrastim (Neulasta^®) ∼24 h after ctx + bevacizumab. The study-tx period included 4 Q2W cycles, but pts could continue on assigned tx until progression. Pts who remained on study after the tx period were followed at regular intervals for up to 60 months (mo), and data on tumor and survival status were collected during the follow-up. The Cochran-Mantel-Haenszel test was used to test differences between tx groups for ORR and the Cox proportional hazard model was used to estimate hazard ratios (HRs) for OS and PFS.

Results: 845 pts were randomized (Nov 2009 to Jan 2012); 422 to pegfilgrastim, 423 to placebo. Median age was 61yrs. 512 (61%) pts were male; 819 (97%) had metastatic disease; 574 (68%) had colon cancer; 414 (49%) received FOLFOX; 431 (51%) received FOLFIRI. 774 (92%) pts completed 4 cycles of ctx + bevacizumab. By Mar 2, 2015 (database lock), median follow-up was 21.4 mo (21.5, pegfilgrastim; 21.4, placebo). See table for ORR, PFS, and OS results. Subgroup analyses of outcomes by ctx received (FOLFOX vs FOLFIRI) are ongoing.

Conclusions: PAVES is the largest randomized trial that has prospectively evaluated effect of pegfilgrastim on treatment outcomes. No significant differences in ORR, PFS, and OS were observed between the pegfilgrastim and placebo arms, suggesting that pegfilgrastim does not negatively impact tumor response or survival in this pt population.

^aMeasurable disease. ^bNot adjusted for randomization stratification factors. ^cAdjusted for randomization stratification factors.

Conflict of interest: Ownership: Phuong Khanh Morrow (Amgen), Maureen Reiner (Amgen), Zandra Klippel (Amgen). Other Substantive Relationships: Adina Croitoru (lecture fee and research support, Amgen). Lynn Khosrowshahi (contractor to Amgen).