Cancer Res Treat.  2017 Jul;49(3):834-845. 10.4143/crt.2016.249.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis

• Cremolini
• Antoniotti C
• Pietrantonio F
• Berenato R
• Tampellini M
• Baratelli
• Salvatore
• Marmorino
• Borelli B
• Nichetti F
• Bironzo P
• Sonetto C
• Di Bartolomeo M
• de Braud F
• Loupakis F
• Falcone A
• Di Maio M

• KMID: 2388329
• DOI: http://doi.org/10.4143/crt.2016.249

Abstract

PURPOSE
The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC).
MATERIALS AND METHODS
A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R²).
RESULTS
Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R²=0.539, p < 0.001) and poor correlation (R=0.169, R²=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident.
CONCLUSION
Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Keyword

Colorectal neoplasms; Biomarkers; Molecular targeted therapy

MeSH Terms

Arm
Biomarkers*
Colorectal Neoplasms*
Disease-Free Survival
Humans
Molecular Targeted Therapy
Translating
Biomarkers

Figure

• 

  Fig. 1. Outline of the search flow diagram. Selection process for randomized controlled trials included in the analysis. ASCO, American Society of Clinical Oncology; ESMO, European Society of Medical Oncology; ECCO, European Cancer Organization; GI, gastrointestinal; EGFR, epidermal growth factor receptor.

• 

  Fig. 2. Median progression free survival (PFS) and post-progression survival (PPS) in all comparisons with available information (n=24) [11-25],27-30.

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  Fig. 3. Correlation between overall survival (OS) and progression- free survival (PFS). (A) Correlation between hazard ratios in all comparisons with available information (n=21). (B) Correlation between hazard ratios in all comparisons with available information pertaining to antiangiogenic drugs (n=13). (C) Correlation between hazard ratios in all comparisons with available information with other drugs (n=8).

• 

  Fig. 4. Correlation between objective response rate and overall survival (OS). (A) Correlation between relative risks and hazard ratios in all comparisons with available information (n=20). (B) Correlation between relative risks and hazard ratios in all comparisons with available information with anti-angiogenic drugs (n=12). (C) Correlation between relative risks and hazard ratios in all comparisons with available information with other drugs (n=8).

Reference

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