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Complete response at 30 months serves as surrogate endpoint in follicular lymphoma
Complete response at 30 months may be a viable surrogate endpoint for PFS in patients who received first-line therapy for follicular lymphoma, according to an analysis of several randomized trials.
“PFS is presently the principal endpoint for regulatory approval of new agents,” Qian Shi, PhD, of the department of health science research at Mayo Clinic in Rochester, Minnesota, and colleagues wrote. “However, advances in treatment and the indolent nature of follicular lymphoma challenge the use of PFS as the primary endpoint in clinical trials, where median PFS now approaches 6 to 8 years. Therefore, the identification of alternative endpoints that are measured earlier but can reliably predict PFS treatment effects is a critical need.”
Shi and colleagues analyzed data from 3,837 patients (median age, 56 years; 50.3% male) who participated in 13 randomized multicenter trials — five maintenance and eight induction randomized trials.
Researchers used linear regression and bivariate copula models to evaluate the correlation between the OR of the 30-month complete response rate and the PFS HR. They used a prespecified criterion of either R2WLS or R2Copula of 0.8 or greater with a lower-bound 95% CI greater than 0.6.
Results met the surrogacy threshold (R2WLS = 0.88; 95% CI, 0.77-0.96; R2Copula = 0.86; 95% CI, 0.72-1). The researchers supported these results with multiple sensitivity and supplemental analyses. An 11% improvement upon the control rate of 50% was predictive of a significant treatment effect on PFS (HR = 0.69).
“As with any surrogate endpoint, the use of complete response rate at 30 months in future trials must be comprehensively considered in the context of disease population and treatment type,” the researchers wrote. “In conclusion, this pooled analysis of randomized chemotherapy, immunotherapy or chemoimmunotherapy trials demonstrates that complete response at 30 months after initiation of induction treatment may serve as a surrogate endpoint for PFS in first-line follicular lymphoma treatment trials.” – by Andy Polhamus
Disclosure: Shi reports no relevant financial disclosure. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Improvements in frontline treatment options for patients with follicular lymphoma have led to a prolongation of expected response, with the median PFS of several combinations reaching 5 years or better. Although improved disease control is a victory for both patients and clinicians, the time required to enroll and run large randomized studies is increasing, and can often extend beyond 10 years. In order to test and deliver some of the most promising new agents to our patients, we need better methods to expeditiously compare novel drugs. In the FLASH project, several international cooperative groups came together to share patient level data and analyze potential novel predictors of PFS. The group identified and validated complete remission rate at 30 months (CR30) as a strong predictor of PFS following several frontline regimens. If accepted, this landmark project has the potential to not only change the design of pivotal phase III studies in follicular lymphoma, but dramatically decrease the time required to deliver effective next generation drugs to our patients.