Kenneth Anderson, MD

MANY PATIENTS WITH CANCER are living long and fulfilling lives thanks to advances in treatments. Some cancer types have a number of therapeutic options that patients can choose when one treatment fails. These incredible successes, built upon decades of basic and clinical research, are worthy of celebration, but they pose increasing challenges for developing new therapies.

Clinical trials for cancer treatments have traditionally relied on measuring whether taking a new drug extends patients’ lives compared with the standard of care. This endpoint, called overall survival, is considered the gold standard for determining the safety and efficacy of a drug. However, because many new treatments are so successful, it may now take years to show a real difference in overall survival between the new therapy and the standard of care, which can unnecessarily delay access to medical advances for the general public.

Oncology clinical trials are increasingly using endpoints that can be measured sooner, like tumor shrinkage, blood cell counts, the presence of tumor DNA in blood or other signals that suggest a drug is having an effect. Unfortunately, these early endpoints do not always correlate with overall survival benefit after a study has been completed. There have been several examples of clinical trials with very positive early endpoints, but patients taking the investigational therapy were significantly more likely to die compared with patients taking the standard of care. Results like these give pause to the Food and Drug Administration (FDA) when it considers whether to approve a drug using these early endpoints, as the discrepancy may be caused by toxic side effects of the new drug.

In 2022, the FDA initiated Project Endpoint to engage stakeholders in addressing these issues by identifying and developing timely strategies to determine if a new drug is safe and effective. Project Endpoint led to a joint workshop co-hosted by the FDA, the American Association for Cancer Research (AACR) and the American Statistical Association (ASA) in July 2023, and an upcoming scientific article in the AACR journal Clinical Cancer Research. (The AACR also publishes Cancer Today.) Key recommendations from the workshop and paper were that late-stage clinical trials should collect overall survival data for all patients, and researchers should plan ahead to analyze overall survival data to determine if there are signs of toxicity that impact survival. Pre-specified plans are particularly important to minimize biases and prevent cherry-picking of data during the analysis. Additionally, new statistical methods can be used to look at overall survival data from a safety perspective that are not as burdensome for researchers as a formal analysis for drug efficacy.

While the FDA-AACR-ASA workshop made significant progress in addressing the challenges that surround the use of overall survival as a measure of drug efficacy, more work needs to be done to validate and build confidence in earlier endpoints. The AACR and the FDA will continue these important conversations with stakeholders to build a scientific consensus that provides clarity on the benefits and risks of new therapies and to improve the lives of patients. 

Kenneth Anderson, MD, is the Kraft Family Professor of Medicine at Harvard Medical School, as well as director of the LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston. Dr. Anderson also serves as the chair of the AACR Regulatory Science and Policy Subcommittee.