Background: Rituximab (R) monotherapy is an approved treatment for patients (pts) with relapsed indolent NHL (iNHL) who have a prolonged progression-free and treatment-free interval after last R-based therapy or who are unwilling/unfit to receive chemotherapy. Copanlisib (C) is a PI3K inhibitor approved as monotherapy in pts with relapsed FL who have progressed after ≥2 systemic therapies. The recent Phase III CHRONOS-3 study in pts with relapsed iNHL treated with C+R vs placebo (P)+R (NCT02367040) met its primary endpoint with a significant 48% reduction in the risk of disease progression or death (Matasar et al. AACR 2021). We report here a pre-planned subset analysis in pts with relapsed FL or MZL. Methods: Pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after last R-based therapy or ≥6 mo if unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m² was given i.v. on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed progression-free survival (PFS) by Cheson 2014 criteria. Secondary endpoints included objective response rate (ORR), duration of response (DoR), complete response rate (CRR), time to progression (TTP), and treatment-emergent adverse events (TEAEs). All randomized pts were assessed for efficacy; pts were assessed for safety if they received ≥1 dose of C/P or R. The data cut-off date was August 31, 2020. Results: From a total dataset of 458 iNHL pts, 250 pts with FL/MZL (184 FL/66 MZL) were randomized to C+R and 120 (91 FL/29 MZL) to P+R. Median age was 62 years (range 28-91) and the arms were well balanced. With a median follow-up of 18.5 mo, C+R significantly reduced the risk of disease progression/death vs P+R (HR = 0.55 [95% CI 0.40, 0.76]; 1-sided p = 0.0001); median PFS was 22.2 mo (95% CI 19.1, 33.1) vs 15.4 mo (95% CI 11.0, 19.2), respectively. Median TTP was 27.5 mo for C+R vs 15.4 mo for P+R (HR = 0.500; 1-sided p = 0.00001). ORRs were 82.4% (CRR 37.6%) for C+R and 50.8% (CRR 18.3%) for P+R; median DoR was 23.9 mo vs 17.9 mo, respectively. Most common TEAEs (all grades [G]/G3+) in pts with FL/MZL receiving C+R (n = 249) were hyperglycemia (72.7%/59.0%), hypertension (53.8%/43.0% [all G3]), and diarrhea (35.3%/5.6% [all G3]). For pts receiving P+R (n = 116), the most common TEAEs were hyperglycemia (23.3%/7.8% [all G3]), hypertension (19.8%/8.6% [all G3]), neutropenia (18.1%/13.8%), and upper respiratory tract infection (18.1%/0%). Conclusions: C+R demonstrated superior efficacy vs P+R in pts with relapsed FL/MZL and had a manageable safety profile, consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed FL/MZL, representing a potential new therapeutic option. Clinical trial information: NCT02367040