S101 EFFICACY AND SAFETY OF PROLONGED MAINTENANCE WITH SUBCUTANEOUS RITUXIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY INDOLENT NON-HODGKIN LYMPHOMA: RESULTS OF THE PHASE III MABCUTE STUDY
Authors: S. Rule, W. Gois Barreto, J. Briones, A.M. Carella, C. Pocock, C.-M. Wendtner, F. Zaja, S. Robson, R. R. Tschopp, M. Dreyling
Journal: HemaSphere (2019)

Background: Rituximab (R)-chemotherapy (chemo) induction plus R maintenance is an established treatment for indolent non-Hodgkin lymphoma (iNHL). However, the optimum duration of R maintenance is unknown. A subcutaneous (SC) form of R (R-SC) is now available. Aims: MabCute (NCT01461928) is an international, randomised, open-label Phase III trial evaluating the efficacy and safety of prolonged R-SC maintenance after standard R-SC-based induction and maintenance in relapsed or refractory (R/R) iNHL patients (pts). We report the results of the primary analysis. Methods: Eligible pts were aged ≥18 years with R/R CD20+ follicular lymphoma (grade [Gr] 1, 2 or 3a) or other iNHL (Waldenström's macroglobulinemia, lymphoplasmacytic lymphoma or marginal zone lymphoma). Pts received 8 cycles of R (375 mg/m2 IV in cycle 1 then 1400 mg SC in cycles 2–8) in combination with 6–8 cycles of chemo as induction. Responders (CR/PR) then received a 2 year maintenance comprising 12 cycles of 1400 mg R-SC every 8 weeks. Responding pts (CR/PR) were then randomised 1:1 to prolonged R-SC maintenance or observation until PD. The primary endpoint was PFS from randomisation (PFSrand) in all randomised pts (ITTrand). Sample size calculation assumed a median PFSrand of 38 months in the R-SC arm and 23 months in the observation arm. On this basis, 129 PFSrand events were needed to achieve 80% power for the log-rank test at a significance level of 5%. To observe this number of events, approximately 300 pts were needed and followed for ≥15 months. In the observation arm, Gr 1 and 2 adverse events (AEs) were collected until 28 days after the last R administration, leading to an imbalance in AE collection between the randomised arms. End of study was defined as the time when all randomised pts had been followed for ≥15 months, or earlier if at least 129 PFS events had been observed. Results: Of 693 pts who entered the induction part of the study, 276 were randomised to prolonged maintenance or observation (n = 138 in both arms). Pt and disease characteristics were generally well balanced (Table 1). A total of 46 PFSrand events were observed in the randomised groups (19 in maintenance and 27 in observation), corresponding to 36% of the 129 events needed to achieve 80% power. Median PFSrand was not reached in either arm (Figure 1) and the difference in PFSrand between the two treatment arms was not statistically significant (p = 0.410, stratified log rank test). At the end of the study, 10 pts in the maintenance group and 8 pts in the observation group had died. Median OS was not reached. Gr > 3 AEs (34.8% vs 29.0%) and serious AEs (22.5% vs 23.2%) were reported with a similar frequency in the maintenance and observation arms, respectively. Common (≥2%) Gr ≥3 AEs were: neutropenia (8.7% vs 5.8%); pneumonia (5.1% vs 2.9%); decreased neutrophil count (2.2% vs 0%); and hypertension (2.2% vs 0%). The most common serious AE was pneumonia (5.8% vs 2.9%). Five pts (3.6%) in each arm died due to an AE. In the maintenance group, fatal AEs were: pneumonia; septic shock; acute myocardial infarction; Crohn's disease (starting during initial maintenance); and abdominal infection and diverticulitis (same pt). ORR (CR/PR) at end of induction (EOI) was 84.7%, and 77 of 357 pts with a PR at EOI achieved a CR by end of initial maintenance (conversion rate: 21.6%).Summary/Conclusion: MabCute was unable to fully address the primary study endpoint of PFSrand due to the limited number of events observed. The safety profile of R-SC during prolonged maintenance was consistent with the known profile of R-SC.