An External Control for Mosunetuzumab Using Real-World Data in Follicular Lymphoma in the Third or Subsequent Lines of Systemic Therapy

Background: Follicular lymphoma (FL) is an incurable indolent disease characterized by a series of remissions and relapses, with generally increasing refractoriness and decreasing duration of response to therapy. Despite the availability of many new therapeutic options, there is no clear standard of care in the relapsed/refractory (R/R) FL setting, especially in the third or subsequent lines of systemic therapy (3L+ FL). As a result, there is a clear need for more effective, tolerable, and accessible treatment options. Mosunetuzumab (M) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that showed manageable safety and a significantly higher rate of complete response (CR) compared with a historical control in a single-arm, Phase II trial (Budde et al. Lancet Oncol 2022). This study compares clinical outcomes in 3L+ FL in a real-world data (RWD) external control cohort with M single-arm trial (SAT; NCT02500407) data.

Methods: RWD from Flatiron Health, a US nationwide, electronic health record-derived, de-identified database, were obtained for patients with an initial FL diagnosis on or after January 2011. The RWD cohort was selected by applying key eligibility criteria from the M SAT, with follow-up censored at the latest follow-up from the M SAT. Patients in the RWD cohort received commonly available treatments for 3L+ FL in usual US clinical practice. The RWD and M SAT cohorts were balanced on key prognostic factors in 3L+ FL through propensity score model (PSM) re-weighting of the RWD using inverse probability of treatment weights to estimate average treatment effect in the treated population. The PSM considered the following pre-specified prognostic factors in 3L+ FL: age at initiation of index therapy, progression of disease within 24 months (POD24) status, double refractory (i.e. refractory to prior anti-CD20 and prior alkylator therapy) status, refractory status to last prior therapy, number of prior lines of systemic therapy, and duration in months between initial FL diagnosis and initiation of index therapy. The latest eligible line of therapy with complete data on all prognostic factors and availability of outcomes data was selected as the index line per patient. Due to lack of adequate balance between cohorts as well as to improve balance on the other prognostic factors and reduce extreme weights in the RWD cohort, time from initial diagnosis to initiation of index was omitted from the PSM post-hoc and instead adjusted for in outcome models. Logistic regression models were used to estimate overall response rate (ORR) as the primary endpoint along with CR rate as a secondary endpoint. Cox proportional hazards models were used to estimate progression-free survival (PFS) and overall survival (OS) as secondary endpoints and time-to-next-treatment (TTNT) as an exploratory endpoint.

Results: The M SAT cohort included 90 patients and has been described by Budde et al. 2022. The RWD cohort included 125 and 158 eligible patients, reducing to 87 for response and 88 for time-to-event, respectively, after propensity score weighting. The M SAT cohort was more heavily pretreated, with a higher proportion of patients who were POD24 and refractory to the last prior line than the unweighted RWD cohort, which had a higher proportion of double-refractory patients. PSM addressed the imbalance between the cohorts on the prognostic factors (standardized mean difference < 0.10, Table 1).

Table 2 describes the results from the comparative analysis between M SAT and weighted RWD cohorts. While the ORRs were similar, the CR rate was higher for the M cohort compared with the RWD cohort. Longer OS was observed for M, whereas PFS and TTNT were similar between the M and RWD cohorts.

Sensitivity analyses applying a set of stricter eligibility criteria from the M SAT, selecting the earliest instead of latest eligible index line, and subsetting to a RWD cohort treated with anti-CD20 chemoimmunotherapy, showed consistent findings.

Conclusions: An external control study using RWD from commonly available treatments for 3L+ FL suggests a higher CR rate and longer OS for M monotherapy. Findings were consistent across sensitivity analyses; however, results should be interpreted with caution due to small effective sample sizes. These findings support a clinically meaningful benefit of M and may be useful to inform treatment decisions regarding M monotherapy as a chemotherapy-free option for the 3L+ FL patient population.

McGough:Genentech, Inc.: Current Employment; F. Hoffmann La Roche, Ltd.: Current equity holder in publicly-traded company. Shamas:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in publicly-traded company. Wang:Genentech, Inc.: Current Employment; F. Hoffmann La Roche, Ltd.: Current equity holder in publicly-traded company. Jaber:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in publicly-traded company. Swarup:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in publicly-traded company. Blanchet Zumofen:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company; Moderna: Current equity holder in private company, Current equity holder in publicly-traded company. Lautié:F. Hoffmann La Roche, Ltd.: Current Employment. Parreira:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Honoraria. Wei:Genentech, Inc.: Current Employment; F. Hoffmann La Roche, Ltd.: Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Shewade:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in publicly-traded company.

Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent in the United States