Association of Biomarker-Based Treatment Strategies With Response Rates and Progression-Free Survival in Refractory Malignant Neoplasms: A Meta-analysis.
OBJECTIVE
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.


METHODS
PubMed search of phase 1 cancer drug trials (January 1, 2011, through December 31, 2013).


METHODS
Studies included trials that evaluated single agents, and reported efficacy end points (at least response rate [RR]).


METHODS
Data were extracted independently by 2 investigators.


METHODS
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
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.
Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California, San Diego.
Maria
M
Schwaederle
Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California, San Diego.
Melissa
M
Zhao
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston.
J Jack
JJ
Lee
Worldwide Innovative Network for Personalized Cancer Therapy, Villejuif, France.
Vladimir
V
Lazar
Avera Cancer Institute, Sioux Falls, South Dakota.
Brian
B
Leyland-Jones
Worldwide Innovative Network for Personalized Cancer Therapy, Villejuif, France5American Society of Clinical Oncology, Alexandria, Virginia.
Richard L
RL
Schilsky
Worldwide Innovative Network for Personalized Cancer Therapy, Villejuif, France6Khalifa Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston.
John
J
Mendelsohn
Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California, San Diego3Worldwide Innovative Network for Personalized Cancer Therapy, Villejuif, France.
Razelle
R
Kurzrock
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017321:Clinical Trials, Phase I as Topic; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor