Representation of Older Adults in FDA and EMA Registrational Trials for Diffuse Large B Cell Lymphoma (DLBCL)

Introduction:

DLBCL is predominantly a disease of older adults (OA) with the median age at diagnosis of 67 years and over 50% of patients (pts) diagnosed above 65 years of age. Traditionally, OA are under-represented in clinical trials. Differences may exist in drug response and toxicity due to age-related physiologic changes and comorbidities, hence it is important to have adequate representation of OA in clinical trials studying new therapies. The U.S. Food and Drug Administration (FDA) has recently published a guidance document on including adequate representation of OA in cancer clinical trials that particularly emphasizes the importance of including adults older than 75 years (Inclusion of Older Adults, 2022). We evaluated the patterns of OA enrollment and age subgroup reporting in DLBCL clinical trials leading to FDA and EMA therapeutic approvals between 2014 and 2024.

Methods:

Drug approvals in DLBCL 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 subjects, median age, and proportion of pts greater than 65 and 75 years were recorded.

Results

There were 11 new FDA and EMA approvals between 2014-2024. A cumulative total of 2521 pts were involved in registrational clinical trials associated with these approvals (2017-ZUMA-1 trial; 2018-JULIET trial; 2019-GO29365 trial; 2020-L-MIND trial; 2021- TRANSCEND trial, LOTIS-2 trial; 2022-ZUMA-7 trial, TRANSFORM trial; 2023-POLARIX trial, EPCORE NHL-1 trial, NP30179 trial). Median age at enrolment ranged from 56 to 72 years. All trials reported the percentage of OA enrolled in the study. The age cut off chosen almost universally was >65 years with the exception of the POLARIX study which had an age cut off of >60 years to define OA. The cumulative number of OA in all trials combined was 1287 (51%). Only 4/11 trials reported the number of pts >75 years of age, these included TRANSCEND (10%), TRANSFORM (1%), LOTIS-2 (14%), and EPCORE NHL-1 (19%). Except for the ZUMA-1, JULIET and TRANSFORM studies (all 3 evaluating CAR-T cell products), other trials included octogenarians. The oldest pt in NP30179 (evaluating glofitamab in 3L+ setting) was 90 years of age and the older pt in LOTIS-2 (evaluating Loncastuximab in 3L+ setting) was 94 years of age. Overall, studies evaluating CAR-T cell therapies had lower proportion of OA (ZUMA-1- 24%, ZUMA-7- 30%, JULIET-23%, TRANSCEND-42%, TRANSFORM-33%) as opposed to other drug trials where OA comprised >50% of subjects (GO29365-61%, L-MIND-72%, LOTIS-2-55%, POLARIX-69%, NP30179-54%).

Conclusion:

Overall, the proportion of OA enrolled in DLBCL registrational trials is encouraging at 51%. Inclusion of pts >75 years of age remains suboptimal with most trials not reporting data about this subset of pts. OA do represent a majority of participants in non-CAR-T drug trials in DLBCL. OA were under-represented in the initial CAR-T trials due to safety concerns; however, with recent data showing good risk-benefit profile of CAR-T in OA, this disparity is expected to improve in the future.

Neuendorff:Pfizer: Consultancy; Hexal: Consultancy. Torka:Genentech: Consultancy; Abbvie: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Seagen: Consultancy; Lilly Oncology: Consultancy; TG Therapeutics: Consultancy.