The growing understanding of cancer biology has demanded that the design of cancer clinical trials evolve as well to optimize translation of the findings in a timely, but safe way for patients. One example of this is the “basket trial” design mentioned numerous times throughout the ASCO 2014 meeting. This novel study design attempts to match patients with a rare mutation, regardless of tumor histology, to a drug expected to work through the mutated pathway.
This is in comparison to a genotyping study where patients all have the same type of tumor and are directed to treatment based on their mutations. For example, in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, all patients had pretreated non-small cell lung cancer and were assessed for mutations/copy number amplification in EGFR, mutations in KRAS or BRAF, overexpression of VEGF and/or VEGFR-2 , and retinoid X receptor (RXR) or cyclin D1 overexpression. Based on the mutation findings, patients were then assigned to treatment with erlotinib, vandetinib, erlotinib plus bexarotene, or sorafenib. Adaptive randomization was used to ensure more patients were assigned to the more effective therapies. One challenge of this design is the need for collaboration with several different pharmaceutical companies that may be providing the agents, which can increase the amount of time to complete the trial, risking the clinical relevance of the findings at completion. Additionally, some mutations may be extremely rare in a specific disease, decreasing the power to interpret statistical findings.
In contrast to tumor type, the mutation is the similarity across the arms in the basket trial and the design is ideal for mutations seen across many types of cancer, but only in small numbers. Though randomized clinical trials are the preferred gold standard for FDA approval, the design is often not feasible in a timely manner for rare mutations and patients with rapidly advancing malignancies. The basket trial design allows for testing a specific hypothesis of a biologic pathway and its response to a particular drug. Though only a small number of patients are usually enrolled on each arm, if a response signal is seen, the trial can be expanded to enrich for a certain tumor type or a separate phase II trial can be designed with the pilot data generated. Additionally, sub-baskets could be added for a particular tumor type in which the findings of a specific single nucleotide polymorphism (SNP) appear to predict response rather than the family of mutations as a whole (i.e., BRAF V600K instead of just BRAF). Alternatively, arms may be deleted if a lack of preliminary response is seen, allowing for hypothesis generating research to investigate a different driver pathway for that particular type of tumor.
An example of a large basket trial currently enrolling is the NCI Molecular Analysis for Therapy Choice (MATCH) trial in which more than 200 actionable mutations/amplifications /translocations are assessed in pretreated solid tumors and lymphomas of varying histology; patients are then matched to investigational drugs directed at the mutation of interest. The objective of the trial is to assess whether the response rate and/or 4-month progression- free survival is improved following treatment with agents chosen based on the presence of specific mutations in patient tumors. Currently, the trial has 20 treatment arms looking at targeted therapy directed toward mutations, such as BRAF, GNAQ, GNA11, MET, NF1, and many others. More than 40 pharmaceutical companies have collaborated to supply targeted agents.
As our understanding of molecular drivers of oncogenesis evolves and tumor sequencing becomes more available and cost-effective, treatment options based on these results are in growing demand. Novel trial designs, such as the basket trial and genotyping trials, are needed to keep pace with the science being translated into the clinic.