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Basket Trials and the Evolution of Clinical Trial Design
In an Era of Genomic Medicine
An article published in the Journal of Clinical Oncology (JCO), presents the results of the CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) trial. (See Figure 1.)
This trial used a basket trial methodology and may be a harbinger of new approaches to studying and treating lung and other thoracic cancers.
“In the article accompanying this editorial, Lopez-Chavez et al present the results of the CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) trial, a so-called basket trial seeking to identify molecular biomarkers in advanced NSCLC, small-cell lung cancer, and thymic malignancies and to simultaneously evaluate 5 targeted therapies in patients grouped by molecular markers along with tumor histology. An attempt was made to evaluate each treatment in all three histologic subtypes, for a total of 15 study arms.
“Basket trials are a new and evolving form of clinical trial design and are predicated on the hypothesis that the presence of a molecular marker predicts response to a targeted therapy independent of tumor histology. In the study reported by Lopez-Chavez et al, the targeted therapies and actionable mutations were identified prospectively, with patients assigned in a nonrandomized way to a specific treatment arm. The intention of this design is to conduct several independent and parallel phase II trials."
Squamous Non–small Cell Lung Cancer as a Distinct Clinical Entity
This study also published in the JCO discusses the concept of treating squamous non-small cell lung cancer as a distinct clinical entity.
“Traditionally, the treatment of lung cancer has been based on histologic type [non–small cell lung cancer (NSCLC) or small cell lung cancer], performance status, and stage of disease. However, more recently, treatment decisions are being made based on molecular and histologic characteristics of the tumor. Specifically, the subclassification of NSCLC as squamous or nonsquamous is important in the context of newer treatments because clinical data have demonstrated differences in the tolerability and activity of these agents.
“Although progress continues to be made in the treatment of nonsquamous NSCLC, a significant unmet need exists for patients with squamous NSCLC. For both targeted and chemotherapeutic agents, the majority of regulatory approvals and updates to clinical practice guidelines for advanced NSCLC have focused on nonsquamous disease.
“In addition, because of safety concerns, patients with squamous NSCLC have been excluded from a number of clinical trials of investigational agents, particularly those targeting angiogenesis. This review discusses the importance of histology for treatment selection in NSCLC and summarizes recently completed and ongoing trials of investigational agents in squamous NSCLC. In addition, exciting developments in next-generation sequencing of squamous NSCLC have highlighted differences between squamous and nonsquamous disease and revealed potential new therapeutic targets.
“Advances in the molecular genetics of squamous NSCLC and implications for therapy will also be reviewed. Although progress in squamous NSCLC has faced limitations, momentum is building toward the identification of more effective treatments for this patient population.”
Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer
This study reports favorable results with the use of radiation therapy in the treatment of oligometastatic non-small cell lung cancer.
“Interest has been increasing in the treatment of non-small cell lung cancer (NSCLC) patients with limited or oligometastatic disease. Surgery has historically been used to remove non-small cell lung cancer metastases, but recent developments including advanced radiotherapy planning and delivery techniques, often called stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR), has been associated with high rates of treated metastasis control. Therefore, given common comorbid disease, often precluding surgery, an increasing number of oligometastatic NSCLC patients are receiving radiation for ablation of all disease.
“Early results have reported favorable survival for some, with improved median survival, and approximately 25 % alive long term. Patients with fewer metastases, those treated to all known cancerous sites, and longer disease-free intervals tend to have better outcomes. While promising, better clinical criteria are needed to optimize patient selection.
“The biologic underpinnings of the oligometastatic state are beginning to be demonstrated with specific microRNAs being associated with limited or no progression both in human samples and murine models. Clinical trials are ongoing to improve the techniques used to deliver radiotherapy for NSCLC oligometastases. Ideally, randomized studies will need to be conducted to demonstrate the utility of these treatments suggested by the uncontrolled studies to date. In lieu of these, data presented here may help guide clinicians as to appropriate patient selection.
