The lancet oncology
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The lancet oncology · Oct 2024
ReviewInterchangeability of immune checkpoint inhibitors: an urgent need for action.
Prevailing uncertainties regarding the therapeutic interchangeability of PD-1 and PD-L1 inhibitors affect both clinical decision making and health-care budgeting. This Personal View presents a comprehensive assessment of the fragmented regulatory landscape of PD-1 and PD-L1 inhibitors, highlighting the complex dynamics of market competition, pricing, and the effect on health-care budgets. ⋯ To address these challenges, research that will inform us of the extent of interchangeability of PD-1 and PD-L1 inhibitors is needed. We recommend head-to-head randomised controlled trials, standardised study designs for indirect comparisons, trials with monotherapy groups, post-approval trials funded from private or public sources, and adoption of a near-equivalence framework in both conducting and evaluating trials.
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The lancet oncology · Oct 2024
ReviewBest practices and novel approaches for the preclinical development of drug-radiotherapy combinations for cancer treatment.
Drug-radiation combination therapy is a practical approach to improving clinical outcomes for many tumours. Unfortunately, most clinical combination studies combine drugs with radiotherapy empirically and do not exploit mechanistic synergy in cell death and the interconnectivity of molecular pathways of tumours or rationale for selecting the dose, fractionation, and schedule, which can result in suboptimal efficacy and exacerbation of toxic effects. However, opportunities exist to generate compelling preclinical evidence for combination therapies from fit-for-purpose translational studies for simulating the intended clinical study use scenarios with standardised preclinical assays and algorithms to evaluate complex molecular interactions and analysis of synergy before clinical research. Here, we analyse and discuss the core issues in the translation of preclinical data to enhance the relevance of preclinical assays, in vitro clonogenic survival along with apoptosis, in vivo tumour regression and growth delay assays, and toxicology of organs at risk without creating barriers to innovation and provide a synopsis of emerging areas in preclinical radiobiology.
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Opportunities to decrease the toxicity and cost of approved treatment regimens with lower dose, less frequent, or shorter duration alternative regimens have been limited by the perception that alternatives must be non-inferior to approved regimens. Non-inferiority trials are large and expensive to do, because they must show statistically that the alternative and approved therapies differ in a single outcome, by a margin far smaller than that required to demonstrate superiority. Non-inferiority's flaws are manifest: it ignores variability expected to occur with repeated evaluation of the approved therapy, fails to recognise that a trial of similar design will be labelled as superiority or non-inferiority depending on whether it is done prior to or after initial registration of the approved treatment, and relegates endpoints such as toxicity and cost. ⋯ This situation is the tyranny of the non-inferiority trial: its statistics perpetuate less cost-effective regimens, which are not patient-centred, even when less intensive therapies confer survival benefits nearly identical to those of the standard, by placing a disproportionately large burden of proof on the alternative. This approach is illogical. We propose that the designation of trials as superiority or non-inferiority be abandoned, and that randomised, controlled trials should henceforth be described simply as "comparative".
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The lancet oncology · Oct 2024
Meta AnalysisEfficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.
The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. ⋯ None.
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The lancet oncology · Oct 2024
ReviewChallenges and opportunities for early phase clinical trials of novel drug-radiotherapy combinations: recommendations from NRG Oncology, the American Society for Radiation Oncology (ASTRO), the American College of Radiology (ACR), the Sarah Cannon Research Institute, and the American College of Radiation Oncology (ACRO).
NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.