Page 164 - Haematologica Vol. 109 - July 2024

ARTICLE - MAIC in 3L+ FL
M.J. Maurer et al.
an agreed-upon standard.3 As such, selection of therapy in the third line or later requires thoughtful consideration of patient characteristics, prior therapy, expected toxic- ity, and disease behavior. Several reports of longitudinal FL patient cohorts illustrate that, on average, patients experience progressively shorter response durations or treatment-free intervals over sequential treatment lines.4-7 Thus, patients needing treatment after two or more prior therapies (especially if refractory to prior agents) represent a population with unmet needs that may be addressed by novel strategies.
Mosunetuzumab is a novel T-cell engaging bispecific anti- body targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell-mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781; clinicaltrials.gov identifier: NCT02500407) demonstrated that mosunetuzumab induced an overall response rate (ORR) of 80%, a complete response (CR) rate of 60%, and a median progression-free survival (PFS) of 17.9 months in patients with R/R FL following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy.8 Single-arm clinical trial designs such as GO29781 result in limited ability to determine how well unmet clinical needs have been addressed due to lack of a control cohort. Historical data from cohorts receiving therapy for R/R FL can provide some context for interpre- tation,4,9 but may suffer from a composition of patients that differ substantially from the trial cohort of interest in any of several relevant characteristics such as prior treatment histories, drug class refractoriness, and evolving patterns of care. We have recently demonstrated that, in expert academic US practices, treatment selection for R/R FL is quite variable and reflects disease heterogeneity.9 The aims of the present study were to provide a focused compar- ison of outcomes in a comparator real-world population to the GO29781 trial and evaluate potential best practices for implementing these types of comparison studies in the setting of R/R FL.
Methods
The Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence (LEO CReWE) was used to build a real-world evidence cohort of patients with R/R FL who received at least two prior lines of systemic therapy; full details can be found in our previous publication.9 The study was approved by the Mayo Clinic Institutional Review Board. The population for the primary analysis comprised patients who met all of the following eligibility criteria: i) received systemic therapy for FL grade 1-3A after at least two prior lines of systemic therapy that included an an- ti-CD20-directed therapy and an alkylating agent; ii) met all key eligibility criteria from the GO29781 trial (listed in Online Supplementary Appendix) for a potential index line
of therapy with no missing eligibility or matching data; and iii) did not have transformed disease prior to a potential index line of therapy (Figure 1). Matching variables were as follows: age (years) at index therapy (mean, Standard De- viation [SD]); prior lines of therapy (mean, SD); progression of disease within 24 months (POD24) following front-line IC (yes vs. no vs. did not receive IC); double-refractory to anti-CD20 and alkylator therapy (yes vs. no); and elevated lactate dehydrogenase (LDH) at index therapy (yes vs. no). Matching-adjusted indirect comparison10 (MAIC) weighting was performed on the LEO CReWE dataset to select the index line for each patient and generate weights for com- parison to the GO29781 study. The primary outcome mea- sure for this study was ORR, defined as the proportion of patients with best response as CR or partial response (PR) during the available follow-up beginning from the start of therapy (index line) to the earliest of the following: docu- mented progression of disease, initiation of a new line of anti-lymphoma therapy, transformation to an aggressive lymphoma, death, or end of follow-up as per the pre-spec- ified clinical cut-off date. Secondary outcome measures were CR rate and PFS. Further details are provided in the Online Supplementary Appendix.
Statistical analysis
The statistical analysis plan (SAP) was jointly developed and finalized prior to the primary analysis. All analyses were performed by members of the LEO Cohort Statistics and Informatics Core (MJM, MCL). MAIC,10 a form of propensity score weighting, was applied to individual patient data (IPD) from the LEO CReWE study.11 A series of sensitivity analyses was performed to evaluate the impact of study outcomes when utilizing alternate approaches to the fol- lowing: i) inclusion/exclusion criteria; ii) choice of matching variables; and iii) method for selecting which line of therapy to use for a given patient when multiple lines of therapy meet study eligibility. Continuous variables were summa- rized using descriptive statistics (median, interquartile range [IQR], or mean, SD); categorical variables, including response rates, were summarized as proportions and/or rates. Time-to-event variables were summarized using Kaplan-Meier curves and 95% Confidence Intervals (CI). Associations between groups and categorical endpoints (e.g., ORR and CR) were assessed using logistic regression and summarized with Odds Ratios and 95% CI. Further details on the study analyses can be found in the SAP (Online Supplementary Appendix).
Results
LEO CReWE cohort
The starting population for the study consisted of 441 patients who received systemic therapy for FL grade 1-3A following at least two prior lines of systemic therapy that
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