Denis L Jardim1, Denis L Fontes Jardim1, Maria Schwaederle2, Caimiao Wei2, J Jack Lee2, David S Hong2, Alexander M Eggermont2, Richard L Schilsky2, John Mendelsohn2, Vladimir Lazar2, Razelle Kurzrock1. 1. Department of Clinical Medicine, Hemocentro da Unicamp, University of Campinas, Sao Paulo, Brazil (DLFJ); Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo, Brazil (DLFJ); Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA (MS, RK); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX (CW, JJL); Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX (DSH); Department of Functional Genomics, Institut Gustave Roussy, University Paris-Sud, Villejuif, France (AME, VL); Worldwide Innovative Network in Personalized Cancer Medicine, Villejuif, France (AME, RLS, JM, VL, RK); American Society of Clinical Oncology, Alexandria, VA (RLS); The University of Texas MD Anderson Cancer Center, Houston, TX (JM). rkurzrock@ucsd.edu jardimde@gmail.com. 2. Department of Clinical Medicine, Hemocentro da Unicamp, University of Campinas, Sao Paulo, Brazil (DLFJ); Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo, Brazil (DLFJ); Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA (MS, RK); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX (CW, JJL); Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX (DSH); Department of Functional Genomics, Institut Gustave Roussy, University Paris-Sud, Villejuif, France (AME, VL); Worldwide Innovative Network in Personalized Cancer Medicine, Villejuif, France (AME, RLS, JM, VL, RK); American Society of Clinical Oncology, Alexandria, VA (RLS); The University of Texas MD Anderson Cancer Center, Houston, TX (JM).
Abstract
BACKGROUND: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale. METHODS: Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents. All statistical tests were two-sided. RESULTS: Fifty-eight drugs were included (leading to 57 randomized [32% personalized] and 55 nonrandomized trials [47% personalized], n = 38 104 patients). Trials adopting a personalized strategy more often included targeted (100% vs 65%, P < .001), oral (68% vs 35%, P = .001), and single agents (89% vs 71%, P = .04) and more frequently permitted crossover to experimental treatment (67% vs 28%, P = .009). In randomized registration trials (using a random-effects meta-analysis), personalized therapy arms were associated with higher relative response rate ratios (RRRs, compared with their corresponding control arms) (RRRs = 3.82, 95% confidence interval [CI] = 2.51 to 5.82, vs RRRs = 2.08, 95% CI = 1.76 to 2.47, adjusted P = .03), longer PFS (hazard ratio [HR] = 0.41, 95% CI = 0.33 to 0.51, vs HR = 0.59, 95% CI = 0.53 to 0.65, adjusted P < .001) and a non-statistically significantly longer OS (HR = 0.71, 95% CI = 0.61 to 0.83, vs HR = 0.81, 95% CI = 0.77 to 0.85, adjusted P = .07) compared with nonpersonalized trials. Analysis of experimental arms in all 112 registration trials (randomized and nonrandomized) demonstrated that personalized therapy was associated with higher response rate (48%, 95% CI = 42% to 55%, vs 23%, 95% CI = 20% to 27%, P < .001) and longer PFS (median = 8.3, interquartile range [IQR] = 5 vs 5.5 months, IQR = 5, adjusted P = .002) and OS (median = 19.3, IQR = 17 vs 13.5 months, IQR = 8, Adjusted P = .04). A personalized strategy was an independent predictor of better RR, PFS, and OS, as demonstrated by multilinear regression analysis. Treatment-related mortality rate was similar for personalized and nonpersonalized trials. CONCLUSIONS: A biomarker-based approach was safe and associated with improved efficacy outcomes in FDA-approved anticancer agents.
BACKGROUND: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale. METHODS: Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents. All statistical tests were two-sided. RESULTS: Fifty-eight drugs were included (leading to 57 randomized [32% personalized] and 55 nonrandomized trials [47% personalized], n = 38 104 patients). Trials adopting a personalized strategy more often included targeted (100% vs 65%, P < .001), oral (68% vs 35%, P = .001), and single agents (89% vs 71%, P = .04) and more frequently permitted crossover to experimental treatment (67% vs 28%, P = .009). In randomized registration trials (using a random-effects meta-analysis), personalized therapy arms were associated with higher relative response rate ratios (RRRs, compared with their corresponding control arms) (RRRs = 3.82, 95% confidence interval [CI] = 2.51 to 5.82, vs RRRs = 2.08, 95% CI = 1.76 to 2.47, adjusted P = .03), longer PFS (hazard ratio [HR] = 0.41, 95% CI = 0.33 to 0.51, vs HR = 0.59, 95% CI = 0.53 to 0.65, adjusted P < .001) and a non-statistically significantly longer OS (HR = 0.71, 95% CI = 0.61 to 0.83, vs HR = 0.81, 95% CI = 0.77 to 0.85, adjusted P = .07) compared with nonpersonalized trials. Analysis of experimental arms in all 112 registration trials (randomized and nonrandomized) demonstrated that personalized therapy was associated with higher response rate (48%, 95% CI = 42% to 55%, vs 23%, 95% CI = 20% to 27%, P < .001) and longer PFS (median = 8.3, interquartile range [IQR] = 5 vs 5.5 months, IQR = 5, adjusted P = .002) and OS (median = 19.3, IQR = 17 vs 13.5 months, IQR = 8, Adjusted P = .04). A personalized strategy was an independent predictor of better RR, PFS, and OS, as demonstrated by multilinear regression analysis. Treatment-related mortality rate was similar for personalized and nonpersonalized trials. CONCLUSIONS: A biomarker-based approach was safe and associated with improved efficacy outcomes in FDA-approved anticancer agents.
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