This article is more than 5 years old. Information may no longer be current.
PFS, response rate appropriate surrogates for OS in soft tissue sarcoma trials
Click Here to Manage Email Alerts
PFS and response rate appeared to be appropriate surrogates for OS in randomized controlled trials investigating advanced or metastatic soft tissue sarcoma, according to the results of a meta-analysis.
However, 3-month and 6-month PFS appeared poorly correlated with OS in these trials, which also often reported toxicity data unsatisfactorily, according to the researchers.
“Soft tissue sarcomas are a cluster of rare and heterogeneous tumors, making trial design and interpretation particularly challenging,” Alona Zer, MD, staff medical oncologist and site leader for sarcoma at Tel Aviv University’s Davidoff Cancer Center, told HemOnc Today. “In our day-to-day work, my colleagues and I found that some aspects of trial design are compromised in sarcoma studies — namely, a more permissive endpoint selection, compared with other, more common tumor sites.”
The correlation between intermediate endpoints and OS in randomized controlled trials of advanced soft tissue sarcoma had been unknown. Further, the quality of efficacy and toxicity reporting in these trials is also unstudied, according to the researchers.
Zer and colleagues used Medline and Embase to identify 52 randomized controlled trials that evaluated systemic therapies for soft tissue sarcoma. The trials were conducted between 1974 and 2014, and comprised 9,762 patients with the disease.
The majority of studies (61%; n = 5,962) were phase 3; the remaining studies were phase 2 (23%; n = 2,216) or phase unknown (16%; n = 1,584).
The researchers explored the surrogacy relationship between intermediate endpoints — including PFS, response rate, 3-month PFS and 6-month PFS — and OS, as well as the extent to which toxicity and efficacy data were reported.
Overall, OS appeared significantly associated with PFS (R = .61) and response rate (R = .51).
However, neither 3-month PFS nor 6-month PFS significantly correlated with OS.
Despite the association between OS and response rate, the use in response rate as a primary endpoint declined over time, with a preference given to time-based events (P = .02 for trend).
Fourteen percent of soft tissue sarcoma trials (n = 4) did not meet their primary endpoint; however, in these studies, the results were reported as positive. Industry funding supported the majority (n = 3) of these studies.
Overall, the researchers observed a borderline significant association between industry sponsorship and positive reporting bias (OR = 4.22; 95% CI, 0.9-19.92).
Twenty studies (47%) comprehensively reported toxicity data, with six studies (14%) poorly reporting these data. The researchers did not observe a change in toxicity reporting trends over time.
Limitations to this study include the relatively small number of randomized controlled trials investigating soft tissue sarcoma, as well as the variances in trial sample size. Further, the researchers acknowledged that they assumed endpoints based on sample size calculations and study objectives for those that lacked clearly defined endpoints.
“OS is the ultimate primary endpoint, although it requires larger, longer and more expensive studies,” Zer said. “If a surrogate endpoint is chosen in place of OS, our study suggests that it should be PFS. The endpoints of 3-month PFS and 6-month PFS should be used with caution — and probably not as primary endpoints in sarcoma randomized controlled trials. Trial design in soft tissue sarcoma is improving over time; however, endpoint selection and accurate reporting of efficacy and toxicity of the investigated agents are worthy of special attention.”
Surrogate endpoints remain an important tool for the validation of new therapies, especially in orphan diseases, according to Fengmin Zhao, PhD, MPH, biostatistician at Dana-Farber Cancer Institute, who wrote an accompanying editorial.
“[T]he FDA’s accelerated approval program relies on surrogate endpoints,” Zhao wrote. “This program was initiated in 1992 to allow for the earlier approval of drugs that treat serious conditions and that fill a previously unmet medical need on the basis of a surrogate endpoint. In this era of personalized medicine and rapid development of oncology drugs, many drugs are in the pipeline, waiting for testing in phase 3 trials.
“It is difficult, if not impossible, to conduct a phase 3 trial with OS as the primary endpoint for a rare disease, and the current research-funding situation prohibits large trial,” Zhao wrote. “Surrogate endpoints usually allow for smaller trials and shorter completion times and, once validated, could help resolve these issues.” – by Cameron Kelsall
For more information:
Alona Zer, MD, can be reached at alonaz@clalit.org.il.
Disclosure: Zer reports travel expenses from Boehringer Ingelheim. The other researchers and Zhao report no relevant financial disclosures.
Click Here to Manage Email Alerts