Basket Trials and the Evolution of Clinical Trial Design in an Era of Genomic Medicine

Since the days of the ancient Greeks, the pathologic hallmarks of malignancy have been reflected in the language of oncology. Hippocrates was the first to use carcinoma—or crab—to describe the familiar invading sweep of tumor cells across tissue planes, and several hundred years later, Galen described the oncos—or swelling—of tumors from which the field of oncology takes its name. However, although the histopathology of malignancy has remained unchanged across several millennia, scientific advances of the modern era have begun to challenge earlier views of oncology, where patients were treated with an exclusive focus on the tissue of origin of a tumor. The translation of next-generation sequencing (NGS) into oncology practice has begun to demonstrate that although the primary site of origin of a tumor matters, so too does its genetic landscape. The significance of classifying tumors based on defining genetic alterations has been particularly relevant for thoracic oncology. The development of tyrosine kinase inhibitors for patients harboring mutations in the epidermal growth factor receptor (EGFR) has been one of the success stories of translational research endeavors and has spurred efforts to identify other driver mutations in lung cancer. National Comprehensive Cancer Network guidelines for non–smallcell lung cancer (NSCLC) now include genetic testing, and the list of potentially actionable mutations continues to grow. However, despite the tremendous promise of this new era of oncology, several challenges have emerged. First, a genetic classification and treatment strategy may not always follow the traditional boundaries of histopathology. Aberrant HER2 signaling is well established in breast cancer but is also an oncogenic driver in a small subset of lung cancers. Similarly, BRAF mutations are most often associated with melanoma but can be found in hairy cell leukemia, colon cancer, lung cancer, thyroid cancer, and brain tumors. Consequently, although we diagnose patients with lung cancer or breast cancer, the genetic makeup of a tumor may be just as important when considering treatment strategies. A lung tumor and a breast tumor with inappropriate activation of the same signaling pathways may share more molecular vulnerabilities with each other than with a lung or breast tumor lacking the same mutations. However, how are such patients to be identified and directed toward appropriate clinical trials? Even the most effective of targeted therapies fail to impress when evaluated in the wrong patient population, as illustrated by early trials with EGFR inhibitors in unselected patients. Furthermore, despite increasing recognition of the importance of genomic analysis in oncology practice, evaluating targeted therapies can present a formidable challenge when the mutations in question are rare and found across disease types. Some eminently targetable mutations may be so rare they are only discovered in the context of a negative trial. In recent reports, the mammalian target of rapamycin inhibitor everolimus caused extraordinary and durable efficacy for two specific patients, despite a lack of efficacy in bladder and thyroid cancers generally. These exceptional responders were retrospectively found to harbor specific mutations in mammalian target of rapamycin signaling pathways, which rendered them uniquely sensitive to everolimus. If other patients with similar mutations can be identified, everolimus may well be the treatment of choice irrespective of tissue diagnosis. As our ability to probe the genome of an individual tumor continues to expand, so too must strategies for clinical trial design. 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 five targeted therapies in patients grouped by molecular markers along with tumor histology. The five targeted therapies included erlotinib (EGFR mutations), the MEK inhibitor selumetinib (KRAS, HRAS, NRAS, and BRAF mutations), the AKT inhibitor MK2206 (PIK3CA, AKT1, and PTEN mutations), lapatinib (HER2 mutations), and sunitinib (KIT and PDGFRA mutations). 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. Of note, some trials also considered to have a basket design may start with the use of a targeted therapy in an unselected population followed by NGS in patients who respond to identify genetic biomarkers for subsequent prospective screening. Basket trials have generated an enormous amount of interest because JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 9 MARCH 2