Recent research published in JAMA Internal Medicine suggested that the use of surrogate end points for overall survival (OS), including progression-free survival (PFS) and response rate (RR), can meaningfully reduce drug development time in oncology.1
While these end points are used in practice already, novel surrogate end points in oncology — or a reconsideration of how to measure or draw conclusions from current surrogate end points — may be necessary to speed up the drug-development pipeline.
Previous work suggests that drug development — the time between initiating a phase 1 trial and receiving drug approval — can be up to 15 years.2 Yet as understanding of tumor biology, epidemiology, and genetics improves, drugs and novel treatment strategies will begin to be developed increasingly quickly, necessitating a means for determining whether a drug may be effective.
The authors of the present study note, for example, that use of surrogate end points led to the approval of bevacizumab for metastatic breast cancer, though the drug later failed to show any OS benefits.3 A meta-analysis of 36 clinical trials in oncology found, furthermore, that more than half of the studies showed a weak correlation between surrogate end points and OS.4
If surrogate end points are used, a pivotal question is: which ones are best? And, when could faster drug approval times — a possible outcome of the acceptance of surrogate end points as grounds for FDA approval — cause more harm than good?
“Surrogate end points are intermediate end points, usually a change in a lab parameter or other biomarkers, which are supposed to predict clinical benefits,” said Bishal Gyawali, MD, PhD, a research fellow at Brigham and Women’s Hospital in Boston, Massachusetts, in an e-mail. “Clinical end points directly measure clinical benefits such as how the patient feels (QoL; quality of life) or how long the patient lives (OS), while surrogate endpoints in oncology (like RR or PFS) are something the patient doesn’t know until we subject them to scans and tell them that the tumor size is increasing or decreasing.”
“Unfortunately, in oncology, most of these changes in tumor size don’t seem to be well-correlated with QoL or OS — the clinical benefits that patients truly care about,” Dr Gyawali added.
Researchers of the study noted that using RR as an end point reduced study time by a mean of just over 1.5 years, while using PFS as an end point reduced mean study time by just 11 months. “The benefits of using surrogate end points are that they are faster to measure, and hence, help trials to be completed early, thereby leading to faster approval and access. However, as [the] recent JAMA Internal Medicine paper showed — the use of surrogate end points, in fact, saves study time by only around a year at most.”
Other, frequently used surrogate end points not evaluated in this analysis include disease-free survival (DFS), cancer-specific mortality, and recurrence-free survival (RFS). These are compared by authors Kemp and Prasad in BMC Medicine with “hard” end points in oncology, OS and quality of life (QoL), which they refer to as being “intrinsically valuable to patients.”5
Replacing these hard end points with any surrogate should then be seen as an attempt to use another metric, which may be found more quickly than a hard end point like OS, to predict whether use of the drug in question will meet a hard end point in the future.
According to Dr Gyawali, the biggest concerns are, however, “approving and exposing patients to potentially toxic drugs that may be inefficacious — or at worst, even harmful — on the basis of surrogates. And [that] we as a society [are] paying huge amounts for access to these drugs that are of no benefit.”
It’s unclear, then, what the PFS or RR threshold should be to say, with certainty, that a novel therapy is likely to improve OS.
Research published in the BMJ Open in 2013 may give some insight. The authors of this paper found, based on analysis of PFS and OS data from 2331 patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy, only “modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC.”6 The authors noted, in particular, that only those treatments with a “major” impact on PFS — corresponding to a risk reduction of at least 50% — were likely to also improve OS.
Research into 3- and 6-month PFS end points in castrate-resistant prostate cancer, however, has suggested that PFS is a strong and significant predictor of OS.7
Regarding the use of RR as a surrogate, a study found that, among 20 reviewed clinical trials involving patients with acute myeloid leukemia, complete response with incomplete blood recovery or better was a valid surrogate marker for OS.8 In 2015, A US Food and Drug Administration (FDA) review of 14 clinical trials in NSCLC suggested there was a correlation between RR and OS.9
These results do not generalize to all markers, disease types, and varieties of treatment, nor do they confirm or refute the possibility that surrogate markers for hard end points are always valid predictive tools.
Yet it is even open question for some of whether OS itself, as it is experienced in clinical trials, actually corresponds to survival among patients in the real world.5
Given that it is not uncommon for phase 2 trials to show favorable survival benefits, and for phase 3 trials of the same drugs to determine there was no overall survival benefit, it’s reasonable to also consider that making predictions about real-world outcomes based on the results from a controlled, phase 3 clinical trial may also be unjustified.
Research published in 2017 showed, based on data from nearly 40,000 patients receiving at least 1 of 30 treatments across 5 therapeutic areas in oncology, that better OS in clinical studies may be only a slightly better predictor of real-world survival than is PFS or time-to-progression.10
It appears, then, that to claim that surrogate end points are uniformly unreliable would be unjustified — although there remains a clear issue of how to determine whether the selection (and reporting) of any given surrogate is likely to be predictive of OS, and therefore, of the most benefit to patients in the real world.
“We should be careful not to hype new drugs as game-changers based on improvements in unvalidated surrogates alone,” said Dr Gyawali. “Using surrogate end points for accelerated approval is fine, but for regular approval, the benchmark has to be true clinical benefits. All randomized clinical trials with a primary end point of surrogates, such as PFS, must mandatorily demonstrate benefits in QoL.”
The pressure, then, should be equally felt by drug developers — those involved in trial design, and those responsible for overseeing the approval process.
Disclosure: Dr Prasad disclosed payments for various projects and entities with the original JAMA Internal Medicine study. For a full list of disclosures, please refer to the original study.
- Chen EY, Joshi SK, Tran A. Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials. JAMA Intern Med [published online before print April 1, 2019]. doi: 10.1001/jamainternmed.2018.8351
- Prasad V, Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med. 2017;177(11):1569-1575.
- Carpenter D, Kesselheim AS, Joffe S. Reputation and precedent in the bevacizumab decision. N Engl J Med. 2011;365(2):e3.
- Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med. 2015;175(8):1389-1398.
- Kemp R, Prasad V. Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Med. 2017;15(1):134.
- Laporte S, Squifflet P, Baroux N, et al. Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials. BMJ Open. 2013;3(3):e001802.
- Halabi S, Vogelzang NJ, Ou SS, Owzar K, Archer L, Small EJ. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol. 2009;27(17):2766-2771.
- Agarwal SK, Mangal N, Menon RM, Freise KJ, Salem AH. Response rates as predictors of overall survival: a meta-analysis of acute myeloid leukemia trials. J Cancer. 2017;8(9):1562-1567.
- Clarke JM, Wang X, Ready NE. Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era? Transl Lung Cancer Res. 2015;4(6):804-808.
- Shafrin J, Brookmeyer R, Peneva D, et al. How well do surrogate endpoints and overall survival endpoints in clinical trials predict real-world survival? J Clin Oncol. 2017;33(15, suppl):6574.
This article originally appeared on Cancer Therapy Advisor