title: Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses.
abstract: BACKGROUND
  Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents.
  
  
  RESULTS
  Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 vs. 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 vs. 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 vs. 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p < 0.001), vomiting (OR = 0.86 vs. 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs. 3.88, p < 0.001) and neuropathy (OR = 0.64 vs. 1.60, p < 0.001).
  
  
  CONCLUSIONS
  Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity.
authors.affiliation: Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocana
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Josee-Lyne
authors.initials: JL
authors.lastname: Ethier
authors.affiliation: Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Díez-González
authors.affiliation: Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: Verónica
authors.initials: V
authors.lastname: Corrales-Sánchez
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Amirrtha
authors.initials: A
authors.lastname: Srikanthan
authors.affiliation: Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, Switzerland.
authors.forename: María J
authors.initials: MJ
authors.lastname: Gascón-Escribano
authors.affiliation: Department of Medical Oncology and Hematology, CancerCare Manitoba and University of Manitoba, Winnipeg, Canada.
authors.forename: Arnoud J
authors.initials: AJ
authors.lastname: Templeton
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vera-Badillo
authors.affiliation: Centro de Investigación del Cáncer CIC-CSIC, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Seruga
authors.forename: Saroj
authors.initials: S
authors.lastname: Niraula
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D017277:Drug Approval; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D009422:Nervous System Diseases / Q000139:chemically induced; D057285:Precision Medicine / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D012871:Skin Diseases / Q000139:chemically induced; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents
keywords: cancer drugs; companion diagnostics; efficacy; trial design