Revisiting Risk and Benefit in Early Oncology Trials in the Era of Precision Medicine: A Systematic Review and Meta-Analysis of Phase I Trials of Targeted Single-Agent Anticancer Therapies

Abstract

PURPOSE Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

Risk and Benefit for Targeted Therapy Agents in Pediatric Phase II Trials in Oncology: A Systematic Review with a Meta-Analysis

“…We reduced it by performing subgroup analyses within cancer types (solid tumors and hematological malignancies) according to the number of drugs tested in a trial, study type, and the number of malignancies included in a study. Fourth, we did not explore whether cancer phase II clinical trials integrating biomarkers as eligibility criteria have higher response rates, as it was observed in single-agent targeted therapy, phase I studies [ 20 ]. However, this limitation may determine a possible direction for future research.…”

“…From each study, we extracted data related to: study characteristics (e.g., year of results publication, phase, funding, study status), patient characteristics (e.g., age, number of adverse events (AEs) and response rates of anticancer agents in phase I adults as well as pediatric clinical trials [16][17][18][19][20]; others focused on the risks and benefits of particular drugs [21,22] or interventions in specific cancer types [23,24]. Historically, targeted drugs are considered to have a better toxicity profile than chemotherapy agents [25,26].…”

“…The determination of whether risks and potential benefits of research interventions are acceptable requires ethical and clinical expertise and scientific knowledge and data [ 15 ]. Numerous studies have considered adverse events (AEs) and response rates of anticancer agents in phase I adults as well as pediatric clinical trials [ 16 – 20 ]; others focused on the risks and benefits of particular drugs [ 21 , 22 ] or interventions in specific cancer types [ 23 , 24 ]. Historically, targeted drugs are considered to have a better toxicity profile than chemotherapy agents [ 25 , 26 ].…”

Ethical Considerations for Phase I Trials in Oncology

“…67 Numerous meta-analyses of risk/benefit in phase I trials describe difficulties with interpreting adverse event reporting (eg, not defining denominators when serious adverse events are reported as percentages). 19 Suboptimal reporting might be regarded as unimportant, since many interventions tested in phase I are either abandoned or advanced into more rigorous evaluation. As noted, however, phase I dose expansion cohorts are increasingly being used to support regulatory approvals.…”

Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis

“…The safety and toxicity rates of anticancer agents in standard phase I-III clinical trials have already been estimated [26][27][28]. The recent analyses were focused on targeted therapies [29,30] which play an important role in precision medicine [31]; the performance of targeted therapies is enhanced when used in combination with cytotoxic drugs [32]. However, the only RCT in precision oncology was negative for survival [33].…”