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

Strzebońska, Karolina; Wasylewski, Mateusz; Zaborowska, Łucja; Polak, Maciej; Sługocka, Emilia; Straś, Jakub; Blukacz, Mateusz; Gyawali, Bishal; Waligóra, Marcin

doi:10.1007/s11523-021-00822-5

Cited by 6 publications

(1 citation statement)

References 42 publications

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“…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].…”

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confidence: 99%

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

Strzebońska

Blukacz

Wasylewski

et al. 2022

BMC Med

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Background Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy. Methods Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed. Results Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5–25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9–2.9), and the median OS was 7.1 months (95% CI 6.1–8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3–1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40–0.50). Conclusions Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

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Section: Introductionmentioning

confidence: 99%

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

Strzebońska

Blukacz

Wasylewski

et al. 2022

BMC Med

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

et al. 2021

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Background For research with human participants to be ethical, risk must be in a favorable balance with potential benefits. Little is known about the risk/benefit ratio for pediatric cancer phase II trials testing targeted therapies. Objective Our aim was to conduct a systematic review of preliminary efficacy and safety profiles of phase II targeted therapy clinical trials in pediatric oncology. Methods Our protocol was prospectively registered in PROSPERO (CRD42020146491). We searched EMBASE and Pub-Med for phase II pediatric cancer trials testing targeted agents. We included solid and hematological malignancy studies published between 1 January, 2015 and 27 February, 2020. We measured risk using drug-related grade 3 or higher adverse events, and benefit by response rates. When possible, data were meta-analyzed. All statistical tests were two-sided. Results We identified 34 clinical trials (1202 patients) that met our eligibility criteria. The pooled overall response rate was 24.4% (95% confidence interval [CI] 14.5-34.2) and was lower in solid tumors, 6.4% (95% CI 3.2-9.6), compared with hematological malignancies, 55.1% (95% CI 35.9-74.3); p < 0.001. The overall fatal drug-related (grade 5) adverse event rate was 1.6% (95% CI 0.6-2.5), and the average drug-related grade 3/4 adverse event rate per person was 0.66 (95% CI 0.55-0.78). Conclusions We provide an estimate for the risks and benefits of participation in pediatric phase II cancer trials. These data may be used as an empirical basis for informed communication about benefits and burdens in pediatric oncology research.

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Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

Lee

Yang

Gocho

et al. 2023

Nat Med

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Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.

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

Cited by 6 publications

References 42 publications

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

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

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

Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

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