610P - Predicting benefit from FOLFOXIRI plus bevacizumab versus FOLFOX/FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer

Background

Individual patient outcomes may substantially differ from average treatment effects obtained in randomised controlled trials (RCT) due to patient heterogeneity. We aimed to predict which patients with metastatic colorectal cancer (mCRC) will benefit from first-line FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab.

Methods

Data from 639 patients (434 deaths) included in the phase III TRIBE2 RCT were used for developing a Cox regression model based on prespecified clinical, molecular, and laboratory variables for predicting 2-year mortality. Data from 232 patients (199 deaths) included in the phase II CHARTA RCT were used for external validation and heterogeneity in treatment effects analysis. Missing data was handled by multiple imputation. The C-index and calibration plots were used for performance assessment. C-for-benefit was calculated to assess evidence for treatment heterogeneity. The hazard ratio and absolute risk reduction were plotted as a function of the predicted mortality risk to explore treatment heterogeneity.

Results

In TRIBE2, the C-index was 0.68 (95%CI 0.65 – 0.71). At external validation, the C-index was 0.70 (95%CI 0.64 – 0.75), and the calibration plot indicated slight underestimation of mortality in high-risk patients. The c-for-benefit was 0.56 (95%CI 0.47 – 0.65). On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.16). On the absolute scale, the risk reduction in the lowest risk to highest risk quarter was 18% (95%CI 0 – 37%), 24% (95%CI 2 – 45%), -4% (95%CI -3 – 18%) and 0% (95%CI -16 – 16%), respectively.

Conclusions

Although our data suggest that patients with a low mortality risk have greater benefit of intensified treatment on an absolute scale, the predictions lack sufficient certainty to be used in clinical practice for individualised decision making. Larger samples are required to draw final conclusions on whether benefit from FOLFOXIRI could be predicted in patients with mCRC.

Clinical trial identification

NCT02339116, NCT01321957.

Editorial acknowledgement

Legal entity responsible for the study

J. J. Kwakman.

Funding

Has not received any funding.

Disclosure

C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Amgen, Pierre Fabre, Nordic Pharma; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono; Financial Interests, Institutional, Coordinating PI: Roche, Bayer, Servier, Merck. H.J.E. Schmoll: Financial Interests, Other, Travel, accommodations, and expenses: Roche; Financial Interests, Research Funding: Roche; Financial Interests, , Advisory Board: Roche. D. Rossini: Financial Interests, Speaker’s Bureau: MSD. M. Koopman: Financial Interests, Institutional, Advisory Board, advisory board and speaker: Pierre Fabre; Financial Interests, Institutional, Advisory Board: MSD, Bayer; Financial Interests, Institutional, Advisory Board, Advisory Board, speaker: Servier; Financial Interests, Institutional, Invited Speaker: Merck, Bristol Myers Squibb; Financial Interests, Institutional, Trial Chair: Servier; Financial Interests, Institutional, Research Grant: Servier, Roche, Bayer, Bristol Myers Squibb, Merck, Personal Genomics Diagnostics, Sirtex, Pierre Fabre; Financial Interests, Institutional, Funding: Pierre Fabre, Amgen, Nordic Pharma, Novartis, Merck, Servier, Bristol Myers Squibb; Non-Financial Interests, Leadership Role, vice-chair of DCCG: Dutch Colorectal Cancer Group; Non-Financial Interests, Advisory Role, Member of KWF scientific board: KWF; Non-Financial Interests, Other, ESMO faculty member for the Gastro-Intestinal Tumours – colorectal cancer: ESMO; Non-Financial Interests, Advisory Role, expert member of committee “regie op registers dure geneesmiddelen” ZINNL: ZiNNL; Non-Financial Interests, Advisory Role, CRC expert on Kanker.nl platform for answering online CRC questions of CRC (non) patients: Patient respresentative organisation (Kanker.nl); Non-Financial Interests, Leadership Role, chair of RWD & DH working group: ESMO; Other, PI of the Dutch Prospective Colorectal Cancer Cohort study: PLCRC project. C.J.A. Punt: Financial Interests, Institutional, Advisory Board: Nordic Group BV. All other authors have declared no conflicts of interest.