Introduction: Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies. We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040).

Methods: Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or 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 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020.

Results: 307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]; MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443 [0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R.

Conclusions: C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes.

Citation Format: Matthew J. Matasar, Marcelo Capra, Muhit Özcan, Fangfang Lv, Wei Li, Eduardo Yañez, Katya Sapunarova, Tongyu Lin, Jie Jin, Wojciech Jurczak, Aryan Hamed, Ming-Chung Wang, Ross Baker, Igor Bondarenko, Qingyuan Zhang, Jifeng Feng, Klaus Geissler, Mihaela Lazaroiu, Guray Saydam, Árpád Szomor, Krimo Bouabdallah, Rinat Galiulin, Toshiki Uchida, Lidia Mongay Soler, Anjun Cao, Florian Hiemeyer, Aruna Mehra, Barrett H. Childs, Yuankai Shi, Pier Luigi Zinzani. CHRONOS-3: Randomized Phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT001.