肿瘤学试验中的联合治疗剂量优化

Table of contentsIntroductionThe growing role of combination therapies inoncologyDose optimization: The shift away from maximum tolerated doseTrial design, feasibility, and execution considerationsData analysis: Modeling and simulation for decision-makingConclusionReferences 1236101112 Combination therapies represent the future of oncology innovation, offeringclinicians with regimens that have the potential to enhance efficacy, delayresistance and improve patients’ responses and outcomes. Yet, determining doseoptimization for such regimens is among the field’s most complex challenges andrequires rigorous operational and statistical planning and execution. This whitepaper reviews the design, operational, and analytic challenges that sponsorsmust consider when designing effective and efficient combination dose-findingtrials. Sponsors who partner with clinical research organizations like IQVIA canleverage their experience in this setting to realize precision and efficiencies toadvance combination therapies aligned with global regulatory expectations.Introduction iqvia.com | 1 standard of care or another novel investigational drugcomprised one third of the 292 FDA drug approvals forsolid tumors from 2011 to 2023.These approved combinations received indicationsas first-line treatments nearly twice as often asmonotherapies. They were also more than twice as likelyas single drugs to use overall survival (OS) as a primaryendpoint in pivotal studies.3Despite their increased availability, many combinationshave yet to differentiate significantly from monotherapiesin patient responses and survival and may increasetreatment-related toxicities.To solve for improved patient responses and survivaland superior safety profiles, pharmaceutical andbiotech sponsors registered more than 1,750 clinicaltrials examining combination therapies as of early April2025.4By promoting earlier regulatory engagement,Project FrontRunner also incentivizes the design andinitiation of combination studies in earlier treatmentlines, potentially speeding up the development of moreeffective multi-drug therapies.5Figure 1. Comparison of approval pathway and scenario between single-agent vs. combination cancer therapyDrug classCytotoxic chemotherapy (N=12)Immunotherapy (N=107)42 (42.4%)Combination 2 | Combination Therapy Dose Optimization in Oncology TrialsThe growing role ofcombination therapiesinoncologyThe combination of drugs is now central to modernoncology clinical practice, where the heterogeneity ofpatients’ tumors necessitates multifaceted therapeuticstrategies. Figure 1 shows immunotherapies (IO),molecularly targeted small molecules, biologics, andcytotoxic chemotherapies are increasingly used togetherto overcome treatment resistance and enhance thedurability of patient response.One of the most recent oncology regimens to receiveU.S. Food and Drug Administration (FDA) approvalcombined the novel targeted agent inavolisib with thetargeted drugs palbociclib and fulvestrant for adultswith a genetically defined form of locally advanced ormetastatic breast cancer following its recurrence on orafter prior therapy.1,2Approvals for combination therapies have risen steadily,particularly for common cancers.3Oncology regimenscombining an experimental medicine to the existingindications from 2011 to 2023.3Hormonal (N=14)30 (30.3%)Small moleculartargeted agents(N=116)Biologic agents (N=37) 4 (4.0%)4 (4.0%)19 (19.2%)(N=99) iqvia.com | 3for a range of doses in early phase trials to justify doseselection for registration trials.9,10This change, whileadding time and resources to protocol design planning,is expected to bring about efficiencies in trial execution.The optimization step should yield greater safety andtolerability for patients and an overall superior treatmentregimen. IQIVIA suggests sponsors begin designs usingdata- and model-informed scenario planning, which theFDA encourages. With the right study design and deliverystrategies, the impact of the additional time required fordose optimization can be minimized.For sponsors to align with the FDA’s Project Optimus,it is critical they recognize and plan how to address thechallenges of optimizing doses for multi-therapeuticregimens in early phase trials. Partnering with a clinicalresearch organization (CRO) with deep experience inoncology and novel drug platforms can help sponsorsdetermine a strategic approach to support identifyingclinically effective doses that meet regulatory standardsfor the best patient outcomes.Sponsors have differed in their approaches to doseoptimization of investigational combination regimens,depending on the agents’ mechanism of action, efficacyand safety while considering the variability of patientpopulations and the biology of their cancers andtreatment responses.8,9These strategies include usingcomparative arms or biomarker data, but all begin with arigorous evaluation of the study drugs’ characteristics.9,10Study drug characteristics pivotal todoseoptimizationPlann