The development of novel drug-radiotherapy combinations faces unique challenges in early-phase clinical trials, distinct from those encountered in traditional drug-only trials. A collaborative effort by 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) has identified key hurdles and proposed recommendations to streamline the evaluation of these promising therapies. The findings, published in in The Lancet Oncology, come at a time when advancements in both radiation delivery and the breadth of available drugs are creating an opportune moment for exploration of these combinations.
Unique Challenges in Combination Trials
Unlike drug-drug combination trials, integrating radiotherapy introduces complexities related to treatment schedules, target volume delineation, and the assessment of combined toxicity. The inherent delays between radiation treatment and potential clinical response, often weeks or months, pose a significant challenge for early-phase trials designed to quickly assess efficacy. Traditional dose-escalation schemes used in drug development may not be directly applicable when radiotherapy is involved, requiring innovative trial designs.
The report highlights the difficulty in attributing observed effects to either the drug, the radiation, or the synergistic interaction between the two. Standard endpoints used in oncology trials may not adequately capture the benefits of combined modalities, necessitating the development of novel biomarkers and imaging techniques to accurately assess response. The logistical coordination required to deliver both systemic therapy and radiation therapy concurrently or sequentially adds another layer of complexity.
Recommendations for Optimized Trial Designs
The collaborative group advocates for several strategies to mitigate these barriers and improve the success rate of early-phase drug-radiotherapy trials. One key recommendation is the adoption of adaptive trial designs, which allow for modifications to the treatment plan based on accumulating data. This flexibility can optimize dose escalation, identify responsive patient populations, and reduce the number of patients exposed to ineffective regimens.
The researchers also emphasize the importance of robust biomarker strategies. Identifying predictive biomarkers that correlate with response to the combination therapy can help stratify patients and enrich clinical trials with individuals most likely to benefit. This targeted approach can increase the efficiency of drug development and reduce the risk of false-negative results.
Specific clinical trial designs are suggested to facilitate efficient evaluation. These include randomized phase II trials with biomarker-driven stratification, and Simon two-stage designs that allow for early termination if the combination therapy demonstrates insufficient activity. The use of innovative imaging techniques, such as functional MRI and PET scans, is also encouraged to provide more sensitive and accurate assessments of treatment response.
Addressing Toxicity Concerns
Managing toxicity is a critical consideration in drug-radiotherapy combinations. The report stresses the need for careful dose selection and monitoring of adverse events. Proactive strategies to mitigate toxicity, such as supportive care interventions and dose modifications, are essential to ensure patient safety and maintain treatment adherence.
The researchers acknowledge that the assessment of late toxicity, which may not become apparent for months or years after treatment, presents a particular challenge. Long-term follow-up studies are crucial to fully characterize the safety profile of these combinations and identify potential long-term complications.
The Broader Context of Combination Therapies
The push for innovative trial designs reflects a growing recognition of the potential benefits of combining radiotherapy with systemic therapies. Radiotherapy, beyond its role as a local treatment modality, is increasingly understood to have systemic effects, including immune stimulation and modulation of the tumor microenvironment. Combining radiotherapy with drugs that enhance these effects, such as immunotherapies or targeted agents, may lead to synergistic improvements in treatment outcomes.
The recommendations from NRG Oncology and its collaborating organizations are timely, given the rapid pace of innovation in both radiation oncology and systemic therapy. As new drugs and radiation techniques become available, the need for efficient and effective clinical trial designs will only become more pressing. The adoption of these recommendations could accelerate the development of novel drug-radiotherapy combinations and ultimately improve the lives of cancer patients.
The interdisciplinary group assembled by NRG Oncology’s Developmental Therapeutics and Radiation Therapy Subcommittee underscores the importance of collaboration in addressing the challenges of combination therapy development. Bringing together experts from radiation oncology, medical oncology, radiology, and biostatistics is essential to design trials that are scientifically rigorous, clinically relevant, and patient-centered.
