The Evolution of Clinical Trials in Oncology: Defining Who Benefits from New Drugs Using Innovative Study Designs

The dawn of the modern era of randomized drug treatment trials (RCTs) in clinical medicine was ushered in by the seminal study of streptomycin versus placebo for the treatment of tuberculous meningitis reported in 1948 [1]. As drugs with apparent promise for treating cancer in humans emerged from cell culture and animal studies, the oncology community experimented with and subsequently embraced the notion of the RCT. Courageous advocates of the RCT in oncology such as Bernard Fisher and the clinical trial organization that he led, as well as the U.S. government, which funded these studies through the National Cancer Institute, challenged and ultimately contributed to changing the paradigm for testing cancer treatments in the U.S. [2]. Similar commitments of intellectual power and resources across the world led to international trials and global efforts to generate evidence of promise in preclinical model systems and translate those findings into improved patient outcomes. Advances in cancer treatment and the patients who have benefited as a consequence owe an enormous debt to the participants in and proponents of RCTs. The science of clinical trials in oncology evolved to include phase I dose-finding trials, phase II studies to establish efficacy in a single tumor type, phase III trials comparing standards of care with potential advances in care, and phase IV studies to extend safety and activity data in a post-marketing scenario. As a consequence, we can expect higher cure rates in locally confined cancers and in some metastatic cancers. Investigators have substantially extended median overall survival statistics for trial subjects and patients treated off of trials who have had advanced stages of malignant diseases. An example of this extension of median overall survival in the setting of advanced, incurable disease comes from patients treated on clinical trials for advanced colorectal cancer. In 50 years of clinical trials, median survivals have improved from 12 months in the 5Fluorouracil era of the 1980s to >30 months in the current era where targeted therapies are combined with chemotherapy strategies across multiple lines of treatment [3]. Efforts to improve clinical outcomes have spawned a new discipline of clinical trial design and led to synergistic intellectual partnerships between clinicians, translational scientists, statisticians, pharmaceutical companies, and regulatory authorities. At its best, this “concordance of interest” across the academic, clinical, industry, and regulatory stakeholders has revolutionized cancer care and benefited mankind. It has saved many lives and extended others, built careers, led to enormous and highly profitable pharmaceutical and medical device corporations, and consumed billions of health care dollars. As the statisticians and clinical trialists were designing and completing studies, the laboratory scientists were laboring in parallel to unravel the biology of cancer and understand how to exploit new discoveries for the benefit of those afflicted with these diseases. The Human Genome Project is one highprofile and expensive example of an investment whose huge implications for changing cancer treatment are just becoming clear. It has been said that genomics is making every type of cancer into a rare cancer. It is allowing us to change our thinking and complicating our practice of medicine. While adenocarcinomas look virtually alike under the microscope, the factors that drive their growth and the genomic targets that determine their vulnerabilities divide them into categories that can be exploited by drug developers and treating clinicians. This gives us the promise that the rather crude tools of chemotherapy drugs, with their narrow marginal differences between effects on tumor cells and rapidly dividing healthy cells, can be succeeded by more precise interventions that switch off the cellular defects that lead to cancer with a minimum of collateral damage to healthy tissues. In recent years, the Food and Drug Administration (FDA) in the U.S. has begun to recognize that data acquired from small trials in rare tumors or in biologically defined rare subtypes of common tumors can lead to startling evidence of efficacy that can provide an evidence base to permit rapid approval of new agents. Examples include findings of dramatic responses in BRAF mutated melanoma patients treated with vemurafinib and in patients with ALK 1mutated non-small cell lung cancers treated with crizotinib. The most extreme example of economical use of resources is the “N-of-1” trial, where a single patient is the sole unit of observation, and outcomes in such endeavors are