Lambert, Jérôme

Abstract Use of surrogates as primary end points is commonplace in hematology/oncology clinical trials. As opposed to prognostic markers, surrogates are end points that can be measured early and yet can still capture the full effect of treatment, because it would be captured by the true outcome (eg, overall survival). We discuss the level of evidence of the most commonly used end points in hematology and share recommendations on how to apply and evaluate surrogate end points in research and clinical practice. Based on the statistical literature, this clinician-friendly review intends to build a bridge between clinicians and surrogacy specialists.

Abstract Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response (CR) at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The International Extranodal Lymphoma Study Group 19 phase 3 trial showed the advantage of double therapy (rituximab + chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used 2 recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at month 24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (hazard ratio, 1.75; P < .001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24, and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% confidence interval [CI], 0.27-1.87). CR24 was also a strong surrogate marker because it mediated 90% (95% CI, 0.51-2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. This trial was registered at www.clinicaltrials.gov as #NCT00210353.

Abstract A recent systematic review reported that trials involving patients with marginal zone lymphoma (MZL) show marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. The main objective of this study was to reach consensus, through a Delphi process, on the definitions of four time‐to‐event endpoints in MZL trials, by surveying clinicians and methodologists involved in the conduct of clinical trials including patients with MZL. We polled a panel of leading international experts involved in MZL trials by means of self‐administered sequential questionnaires in 2021. Of these 105 experts, 62 responded to the Round 1 questionnaire regarding the definitions of progression‐free survival (PFS), event‐free survival (EFS), time‐to‐failure (TTF), and time‐to‐next‐treatment (TTNT). Afterward, we therefore focused the Round 2 and 3 questionnaires among principal investigators, coinvestigators, and trial methodologists. Consensus was reached when there was a >80% agreement on all potential events (11 choices) of each endpoint. Participants in our survey reached consensus on three of the four time‐to‐event endpoints definitions. Consensus was reached on the definitions of PFS and TTNT after Round 1, of TTF after Round 2, and was not reached for EFS after Round 3. The disagreement concerned the event “treatment discontinuation” in EFS definition. The main interest of our study was to elicit investigator's interest in the importance of consistently defining endpoints in MZL trials and to highlight that composite endpoints should not be encouraged. Fifteen years after the last consensus statement on time‐to‐event endpoints definitions issued in Lugano (2007), both the review of literature and survey of international investigators agree on the inconsistency of endpoints definitions used within the MZL community. Hopefully, revised standardized definitions of endpoints shall be provided at the upcoming International Conference on Malignant Lymphoma in 2023.