Abstract
Introduction: Follicular lymphoma (FL) is a disease of older adults (age≥65 years, yrs) (OA) with a median age at diagnosis of 64 yrs, and around 50% patients (pts) diagnosed over the age of 65 yrs and 20% pts over the age of 75 yrs. The U.S. Food and Drug Administration (FDA) has published a guidance document on adequate representation of older adults in cancer clinical trials that particularly emphasizes the importance of including adults older than age 75 (Inclusion of Older Adults, 2022). Differences may exist in drug response and toxicity due to age-related physiologic changes and comorbidities. We evaluated the patterns of OA enrolment and age subgroup reporting in FL registrational clinical trials leading to FDA and European Medicines Agency (EMA) therapeutic approvals between 2015 and 2025.
Methods: Drug approvals in FL and associated clinical evidence were collected from the FDA and EMA websites. Data from each registrational trial was searched in public databases using drug name, trial name and/or registration number. Details regarding the total number of pts, median age, and proportion of pts ≥65 and 75 yrs were recorded.
Results: Between 2015 and 2025, there were 13 new FDA and EMA therapeutic approvals for FL based on 13 individual registrational trials, with 3 of the drugs (umbralisib, duvelisib, copanlisib) subsequently withdrawn from the U.S. market. Of the drugs approved, 2 were bispecific antibodies (BsAb, epcoritamab, mosunetuzumab), 3 were chimeric antigen receptor-T (CAR-T) products (lisocabtagene, axicabtagene, tisagenleucel), 3 were PI3K inhibitors (umbralisib, copanlisib, duvelisib), 2 were monoclonal antibodies (obinutuzumab with chemotherapy, obinutuzumab with bendamustine), and 1 each of selective EZH2 inhibitor (tazemetostat), immunomodulator (lenalidomide with rituximab), and BTK inhibitor (zanubrutinib). One drug was approved in the 1st line setting (GALLIUM-obinutuzumab with chemotherapy), two drugs were approved in the 2nd line setting (GADOLIN-obinutuzumab with bendamustine, AUGMENT-lenalidomide with rituximab), nine drugs were approved in the 3rd line setting (EPCORE NHL-1-epcoritamab, TRANSCEND-FL- lisocabtagene maraleucel, ROSEWOOD- zanubrutinib with obinutuzumab, GO29781- mosunetuzumab, ELARA- tisagenleucel, ZUMA-5- axicabtagene ciloleucel, E7438-G000-101- tazametostat, DYNAMO- duvelisib, CHRONOS-1- copanlisib) and one drug was approved in the 4th line setting (UNITY-NHL- umbralisib). The median age in these trials ranged between 57 to 65 yrs (overall median 63 yrs), with an overall age range of 23 to 90 yrs. None of the trials had an upper age limit as an exclusion criterion. Age subgroup reporting was unavailable in the UNITY-NHL and GADOLIN studies.
A total of 3226 pts were included. Of the 2713 pts in trials with OA subgroup data), 1007 (37%) were OA (defined as pts≥65 yrs). OAs constituted 31% of pts (376/1202) in the first-line setting compared to 42% (631/1511) in the relapsed/refractory setting. Trials of CAR-T products included 31% OA, the proportion of OA was higher in BsAb (44%) and PI3K inhibitor (48%) trials. Only EPCORE NHL-1 (52%) and DYNAMO (50%) had equal or higher proportion of OA, inclusion of OA in other trials was <50% (ELARA-25%, GO29781-31%, ZUMA-5-31%, GALLIUM-31%, TRANSCEND-FL-37%, E7438-G000-101-42%, AUGMENT-43%, CHRONOS-1-45%, ROSEWOOD-47%). Participants over 75 yrs were reported in 5 out of 13 trials (31%) (ELARA-0%, TRANSCEND-FL-7%, GALLIUM-8%, ROSEWOOD-12%, GO29781-17%), involving 144/1730 pts (8%) in those trials.
Conclusion: Most registrational trials for FL do report a subgroup of OA, although inclusion of OA remains suboptimal at 37%. Representation and reporting of pts≥ 75 yrs is significantly low at only 8%, despite this group representing 20% pts at diagnosis. Reporting of trials should include and distinguish pts ≥65 yrs and ≥75 yrs for subgroup analyses. Standardization of age subgroup reporting with subpopulation analysis will better enable the risk-benefit profile of new agents for OA with FL.
