The progression-free survival metric has helped shepherd many products across the regulatory finish line. Experts say the FDA’s new emphasis on overall survival will be felt especially by small biotechs.
Pictured: A cancer treatment heads toward a goalpost/Nicole Bean for BioSpace
When it comes to evaluating cancer drugs, their ability to lengthen patients’ survival is crucial. Progression-free survival and overall survival might sound like two sides of the same coin, but there are key differences. A recent workshop, along with statements made by top FDA officials, signaled to drugmakers that the latter metric will play a more important role in regulatory approval decisions going forward.
Drugmakers are not typically able to calculate overall survival (OS) when they apply for FDA’s Accelerated Approval designation—a pathway that allows the greenlighting of medicines for serious or life-threatening diseases based on surrogate endpoints that are reasonably likely to predict clinical benefit—said Mizuho biotechnology analyst Mara Goldstein. Instead, they use progression-free survival (PFS) as a surrogate endpoint and are expected to report OS as part of a confirmatory study for full approval.
Goldstein said that while the FDA has not been particularly vigilant at ensuring companies do these confirmatory trials in the past, the agency is increasingly making this a priority in order to ensure drugs confer a benefit beyond PFS.
Experts told BioSpace that while OS has long been considered the best metric for determining efficacy, the shift away from it happened over time as a result of the breakneck pace of advances in oncology. They cautioned that an overreliance on PFS and other intermediate endpoints may not tell a drug’s full story. Importantly, they noted, it may take years to see the full effect that re-emphasizing OS will have on biopharma.
Accurately Defining Benefit vs. Risk
Overall survival, simply put, is a measure of how many patients are alive after a certain period of time. When divided by the total number of patients in a study arm, it can be used to compare the treatment arm to the control arm and determine whether the intervention had an impact on survival. Progression-free survival is the time from random assignment in a clinical trial to either disease progression or death from any cause.
According to the FDA, OS is “usually considered the ‘gold standard’ (or ideal) primary endpoint in oncology because patients with cancer often want to take medications that can help them live longer.”
Even so, “It’s [an endpoint] that can be challenging in oncology,” Goldstein said, adding that, especially in this space, there is a significant need to evaluate potentially lifesaving experimental treatments and fast-track them for approval. Gathering data on progression-free survival takes less time than determining overall survival, particularly because patients in control arms of clinical oncology trials typically receive standard-of-care treatment as opposed to placebo or no treatment at all, prolonging their survival. Thus, meaningful differences in OS are often impossible to measure in short time spans, Goldstein said.
This is where other intermediate clinical endpoints can more quickly hint at a drug’s potential safety and efficacy. Indeed, Richard Pazdur, director of the FDA’s Oncology Center of Excellence, acknowledged a shift toward these endpoints in his opening address for the workshop, which was co-hosted by the American Association for Cancer Research, FDA and the American Statistical Association, in July 2023.
“When I first came to the FDA, the edict on the street was you needed two randomized trials, both [of] which showed a survival advantage. And if you didn’t have that—get lost, basically,” said Pazdur, who has been at the agency since 1999. “Well, things have definitely changed, and I think changed for the better because we would not have witnessed the evolution and revolution in cancer therapies that we have had over the past 25 years if we’d have stuck to that.”
This progress—with more available treatments and patients now living longer—has put clinicians and statisticians in a tough spot when it comes to calculating overall survival. Kenneth Anderson, an oncologist at Dana-Farber Cancer Institute and the chair of the July workshop, told BioSpace that the utility of OS as an endpoint has shifted to be as much about safety as it is about efficacy.
“Overall survival as an endpoint is really not feasible any longer due to the marked advances and efficacy” of standard-of-care treatments, Anderson said. “Nonetheless, if you use earlier endpoints such as progression-free survival, event-free survival, response rate or durability of response, you still need to follow overall survival as a metric for adverse effects or impact on overall length of life.”
Workshop presenters noted that relying on intermediate clinical endpoints is not ideal due to a potential for bias, nonuniform definitions across trials, the omission of safety signals and discrepancies between PFS and OS readouts. Though one might assume PFS and increased OS would go hand-in-hand, officials cautioned against conflating these signals.
One slide titled “BELLINI Trial: A Cautionary Tale” described results from Genentech/Roche’s Phase III study of venetoclax combined with bortezomib and dexamethasone for relapsed/refractory multiple myeloma. While preliminary data showed significant increases in response rate and PFS with the combination treatment, researchers later found venetoclax was associated with double the risk of overall mortality compared to the placebo arm. While the side effects were similar between treatment and control arms, the relationship between the treatment and survival was more complicated. This case shows that a divergence between PFS and OS without a clear reason “underscores . . . the need for evaluation of both early and late time points that provide definitive evidence of clinical benefit,” Nicole Gormley, acting division director for the FDA’s division of hematologic malignancies II, said during the presentation.
Conflicting OS and PFS data have emerged for other treatments. In the 2010s, for example, studies of Avastin (bevacizumab) to treat metastatic breast cancer showed benefits in PFS but no significant impact on OS.
“Whatever the reasons” for these discrepancies, “the idea is that we really need to follow overall survival in order to get a true assessment of the benefit-risk ratio,” Anderson said.
What the Shift Means for Biopharma
The renewed emphasis on reporting OS will mean that accelerated approval might not be as strong a predictor of full approval as it has previously been, Goldstein said. She added that this will have an outsized impact on smaller biopharma companies with less cash on hand.
“It certainly puts a bigger burden on some of the smaller companies that have looked to do accelerated approvals as a way to minimize capital outlays,” Goldstein said. Now, drugmakers may not be able to rely on guaranteed, continued profits from a drug while it’s going through the full approval process, making funding confirmatory studies more difficult.
Larger pharmas, which have more financial flexibility to pursue confirmatory studies, should not be as affected, Goldstein said. A spokesperson for Novartis—which has at least 30 cancer drugs in development—told BioSpace in an email that for patients who will quickly progress to more advanced stages of cancer and lack options, regulators should continue to also consider the totality and consistency of evidence demonstrating meaningful outcomes.
Despite the shift, indications with the highest patient need may not immediately see enhanced scrutiny. Last January, the FDA granted full approval to elacestrant for metastatic/advanced ER-positive, HER2-negative, ESR1-mutated breast cancer in postmenopausal women or adult men after the drug showed PFS of 3.8 months in the treatment arm vs. 1.9 months for those treated with standard of care.
That such a “modest PFS benefit” was enough to win the drug full approval may indicate that certain drugs will be held to different standards when it comes to reporting OS, said eFFECTOR Therapeutics CEO Steve Worland. “I think it very much depends on what is available for the patient,” he said.
One outstanding question is how the FDA will handle future conflicting readouts where primary endpoints like PFS are met, but the OS data is less than rosy, Goldstein noted. “I think that is going to be very much a judgment call because, for some populations, progression-free survival is meaningful.”
The bottom line for the FDA, she said, is “that there have been too many drugs approved that have had marginal benefit. They really want to understand the true profile of the drugs, and you can only really do that if you have overall survival.”
Maddie Bender is a science journalist based in Honolulu, HI. You can contact her through her website, maddiebender.com.
