Is neutropenia a prognostic or a predictive factor for second line metastatic colorectal cancer (mCRC) patients (Pts)? Exploratory analysis from RAISE, a randomized, double-blind, phase III study of ramucirumab (RAM) + FOLFIRI vs placebo (PBO) + FOLFIRI

Background

In the RAISE study, RAM + FOLFIRI improved the outcomes of pts with previously treated mCRC as compared to pts treated with PBO + FOLFIRI with an increase in adverse events. Notably, neutropenia occurred at a higher frequency in pts receiving RAM + FOLFIRI and often led to dose modifications or discontinuations. We conducted an exploratory analysis to determine whether the incidence of neutropenia affected outcomes in the RAISE pt population.

Methods

In the RAISE study, pts were randomized 1:1 to receive 8 mg/kg IV RAM + FOLFIRI or PBO + FOLFIRI every 2 weeks. Pts from both treatment arms were included in the analysis if they developed any-grade neutropenia after the initiation of study treatment. Overall survival (OS) was analyzed using the Kaplan-Meier method and a Cox proportional hazards model.

Results

The frequency of any-grade neutropenia was 59% (311/529) in RAM pts (grade ≥3; 38%) vs 46% (241/528) in PBO pts (grade ≥3; 23%). Dose modifications of one or more study drugs were required in most pts with neutropenia (RAM: 81% [253/311]; PBO: 80% [193/241]). Pts with any-grade neutropenia treated with RAM had a median OS (mOS) of 16.1 vs 12.6 months for those on PBO (HR = 0.79; 95% CI, 0.64, 0.96). Pts who did not experience neutropenia had a mOS of 10.7 months in both arms (HR = 1.05; 0.86, 1.28). Among pts who had at least one neutropenic event, 83% developed the event within 2 months of starting treatment. Similar efficacy was seen among pts with grade ≥1, ≥2, or ≥3 neutropenia.

Conclusions

Neutropenia may be a prognostic or predictive factor for pts with mCRC. Pts from the RAISE study with any-grade neutropenia in both treatment arms seemed to have longer survival compared to those who did not experience neutropenia; however, mOS for pts with neutropenia in the RAM arm was higher than that in the PBO arm. These results suggest that the treatment effect of RAM in neutropenic pts with mCRC is unlikely to be compromised despite lower chemotherapy dose intensity. Additional analyses are underway to elucidate the meaning and the biological mechanism of the effect of RAM in neutropenic pts.

Clinical trial identification

ClinicalTrials.gov NCT01183780

Legal entity responsible for the study

Eli Lilly and Company

Funding

Eli Lilly and Company

Disclosure

T.-E. Ciuleanu: Consultant/ Advisory board Eli Lilly, Roche, Merck, Amgen. G. Bodoky: I was attending an advisory board of Lilly. NO financial interest in products or processes involved in this research. This includes stock ownership, corporate-sponsored research, or other substantive relationships. R. Garcia-Carbonero: Scientific advise to Roche, Merck, Sanofi, Amgen, Bayer, Lilly. P. García Alfonso: Advisory role: Roche, Merck, Amgen, Bayer, Sanofi, Celgene, Lilly. Speaker: Roche, Merck, Amgen, Lilly. E. Van Cutsem: Research Grant from Lilly: Consultant: Lilly. D. Mytelka, O. Lipkovich, D. Ferry, A. Sashegyi, F. Nasroulah: Employee and shareholder of Eli Lilly and Company. J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda, Taiho. All other authors have declared no conflicts of interest.