The Illusion of Progression-Free Survival

Readers of Sensible Medicine, and those who followed Vinay’s work on cancer treatments, highlighted in his book Malignant, are well aware of the shortcomings of the “progression-free survival” (PFS) endpoint. PFS is an endpoint that includes both disease progression and survival. Disease progression is usually defined as an increase in tumor size (at least 20%) or the development of new lesions. Although PFS can be an important outcome, there are examples where a treatment improves PFS but treated patients die sooner. Here, Dr. Develtere takes us through a recent article in which an improved PFS masks more important findings. Adam Cifu Modern cancer care increasingly relies on combination therapies—stacking multiple drugs together in the hope that more treatment upfront leads to better outcomes down the line. The phase III COSMIC-313 trial is a good example of this trend. It tested whether adding a third drug to an effective regimen could further improve outcomes for patients with advanced kidney cancer. The study results looked encouraging, with the triple therapy showing improvements in progression-free survival (PFS). A closer look reveals a more complicated story—one that raises broader questions about how we interpret clinical trials. The COSMIC-313 Trial The COSMIC-313 study enrolled patients with previously untreated advanced clear-cell renal cell carcinoma, the most common type of kidney cancer. Patients were randomly assigned to receive one of two treatments: Standard treatment (doublet) nivolumab + ipilimumab (two immune checkpoint inhibitors) Experimental treatment (triplet) cabozantinib (a targeted therapy) nivolumab ipilimumab The hypothesis was that adding cabozantinib, a drug that targets tumor growth pathways, might enhance the immune therapy and improve outcomes. The primary endpoint was progression-free survival (PFS)—the time until the cancer worsens. After a median follow-up of 45 months, the results showed an improvement in PFS 11.2 months in the doublet group compared to 16.6 months in the triplet group, Notably, there was no difference in overall survival between the groups. Patients receiving three drugs experienced a delay in tumor progression, but they did not live longer. The Hidden Cost: Much More Toxicity The triplet treatment came with a substantial downside: far more toxicity. Severe treatment-related side effects occurred in 75% of patients receiving the triplet and “only” 43% of patients receiving the doublet. Nearly half of the patients on triplet therapy had to stop at least one drug because of side effects. In the end, patients receiving the triplet therapy experience more severe side effects, spend more time on a more toxic treatment, but do not live longer. Why PFS Without OS Can Be Misleading Progression-free survival is commonly used in cancer trials because it can be measured earlier than overall survival. This can translate into faster approval and earlier patient access to the therapy. The progression part of PFS can be a surrogate endpoint, an endpoint that is invisible to patients, maybe only visible to radiologists. PFS does not necessarily translate into meaningful patient benefit. One way to understand this is to think about the entire treatment journey. If patients stay longer on a first-line treatment that is more toxic, but eventually receive similar second- and third-line treatments, then the overall sequence of therapies remains the same. This is fine if patients live longer (and maybe better) with the new treatment. But if they don’t, at least the extended time on the first-line treatment should be better tolerated compared to the alternative. If the treatments are equally tolerated, the new therapy regimen should be cheaper or more convenient. But if there is no apparent benefit, you might want to stick with the well-established treatment regimen. In COSMIC-313 trial, treatments that were given after there had been disease progression were similar between the two groups. Without an OS benefit, this means patients receiving the triplet therapy spent more time on the toxic first-line treatment and consequently spent less time receiving later therapies. From a patient perspective, the result is straightforward: More toxicity, without longer life. Although the positivity of cancer trials often rests on improvements in PFS, meaningful outcomes for patients remain: Do I live longer? Do I live better? In COSMIC-313, the answer appears to be that patients don’t live longer, but possibly live worse, due to more side effects. There is also a societal dimension. Triple therapy means higher drug costs, more toxicity management, and longer exposure to expensive medications. All without clear evidence that patients ultimately benefit. A Reminder for the Future COSMIC-313 is not a failed trial—it provides valuable information. But it also reminds us that more treatment is not always better treatment. When new combinations increase PFS but fail to improve survival, we need to look for another benefit before accepting a new treatment regimen. We want patients to live longer and/or better, and if that’s not the case, keep “First, do no Harm” in mind. Dries Develtere, MD, is a Urologist at the General Hospital of Ypres, Belgium. He specializes in robotic surgery, with a focus on prostate and bladder procedures, as well as urological oncology. He is the founder of Surgical Vision, a video platform that provides high-quality surgical training videos designed to advance surgical education.