Though progression-free survival showed a moderate correlation with overall survival benefit in patients treated for mantle cell lymphoma, its ability to confidently predict improved OS is limited, according to a study led by Alexander M. Gorzewski, MD, of Brown University Health, and colleagues.
The study was published in Clinical Lymphoma, Myeloma & Leukemia.
PFS is often used as a primary endpoint in MCL trials to reduce the trial duration and cost burden required to reach the gold standard of OS. However, prior studies have not determined the ability of PFS to predict OS in this patient population.
Researchers conducted a systematic review of phase 3 trials to assess the correlation between these two endpoints in MCL studies. The final analysis included 16 trials assessing 19 treatment options in nearly 6,000 adult patients.
Most studies (73.7%) assessed first-line treatments, and the cohort was well balanced in terms of transplant-eligible (31.6%), transplant-ineligible (36.8%), and mixed transplant eligibility (31.6%) patients. The studies comprised various treatment phases, including induction therapy (21.1%), induction plus subsequent treatment (26.3%), and maintenance therapy (21.1%).
A majority of studies (n=11; 57.9%) used PFS as the primary endpoint, while just two (10.5%) assessed only for OS. Across the trials, the median follow-up was 51.2 months, and the median patient size was 303.
The analysis showed that before the introduction of Bruton tyrosine kinase inhibitors in 2013, there was no statistically significant correlation between PFS and OS (P=0.07), though there was a strong correlation post-BTK inhibitor introduction (P<0.001). Correlations between PFS and OS were similar in the first-line and relapsed or refractory settings.
For a hypothetical trial size of 334, the surrogate threshold effect was 0.59, which the authors noted implies “only therapies producing substantial PFS benefits are likely to lead to a consistently favorable effect on OS.”
Just three of 17 (17.6%) treatment comparisons assessed in the analysis showed a statistically significant benefit for the experimental treatment in both PFS and OS endpoints, “underscoring the challenges of translating improved PFS into detectable survival benefit,” the authors noted.
The researchers suggested future studies assess other intermediate endpoints for their association with or ability to predict OS, such as progression within 24 months of treatment, complete response at 30 months, and measurable residual disease status.
They also noted the importance of incorporating quality of life assessments into future clinical trials for this patient population.
The present study is limited by its use of aggregate trial-level data rather than individual patient data, and there was heterogeneity across the studies included.
“The substantial magnitude of PFS benefit required to confidently predict survival improvement limits its reliability as a standalone surrogate endpoint, particularly when treatment effects are modest,” the authors concluded, suggesting the importance of assessing other endpoints to better predict survival outcomes for treatment options in the MCL patient population.
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