Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms a meta-Analysis

IMPORTANCE The impact of a biomarker-based (personalized) cancer treatment strategy in the setting of phase 1 clinical trials was analyzed. OBJECTIVE To compare patient outcomes in phase 1 studies that used a biomarker selection strategy with those that did not. DATA SOURCES PubMed search of phase 1 cancer drug trials (January 1, 2011, through December 31, 2013). STUDY SELECTION Studies included trials that evaluated single agents, and reported efficacy end points (at least response rate [RR]). DATA EXTRACTION AND SYNTHESIS Datawere extracted independently by 2 investigators. MAIN OUTCOMES AND MEASURES Response rate and progression-free survival (PFS)were compared for arms that used a personalized strategy (biomarker selection) vs those that did not. Overall survival was not analyzed owing to insufficient data. RESULTS A total of 346 studies published in the designated 3-year time period were included in the analysis. Multivariable analysis (meta-regression and weighted multiple regression models) demonstrated that the personalized approach independently correlated with a significantly higher median RR (30.6%[95%CI, 25.0%-36.9%] vs 4.9% [95%CI, 4.2%-5.7%]; P < .001) and a longer median PFS (5.7 [95%CI, 2.6-13.8] vs 2.95 [95%CI, 2.3-3.7] months; P < .001). Targeted therapy arms that used a biomarker-based selection strategy (n = 57 trials) were associated with statistically improved RR compared with targeted therapy arms (n = 177 arms) that did not (31.1%[95%CI, 25.4%-37.4%] vs 5.1% [95%CI, 4.3%-6.0%]; P < .001). Nonpersonalized targeted arms had outcomes comparable with those that tested a cytotoxic agent (median RR, 5.1%[95%CI, 4.3%-6.0%] vs 4.7%[95%CI, 3.6%-6.2%]; P = .63; respectively; median PFS, 3.3 [95%CI, 2.6-4.0] months vs 2.5 [95%CI, 2.0-3.7] months; P = .22). Personalized arms using a "genomic (DNA) biomarker" had higher median RR than those using a "protein biomarker" (42.0%[95%CI, 33.7%-50.9%] vs 22.4% [95%CI, 15.6%-30.9%]; P = .001). The median treatment-related mortality was not statistically different for arms that used a personalized strategy vs not (1.89% [95%CI, 1.36%-2.61%] vs 2.27%[95%CI, 1.97%-2.62%]; P = .31). CONCLUSIONS AND RELEVANCE In this meta-Analysis, most phase 1 trials of targeted agents did not use a biomarker-based selection strategy. However, use of a biomarker-based approach was associated with significantly improved outcomes (RR and PFS). Response rates were significantly higher with genomic vs protein biomarkers. Studies that used targeted agents without a biomarker had negligible response rates.