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Background: Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators. Aim: To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*. Patients and methods: Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) – with deferiprone, and 8 (17.3%) – with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA. Results: In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 – 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014. Conclusion: A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.

Magnetic resonance imaging (MRI) of the breast has been increasingly used for the detailed evaluation of breast lesions. Diffusion-weighted imaging (DWI) gives additional information for the lesions based on tissue cellularity. The aim of our study was to evaluate the possibilities of DWI, apparent diffusion coefficient (ADC) value and ADC ratio (the ratio between the ADC of the lesion and the ADC of normal glandular tissue) to differentiate benign from malignant breast lesions. Materials and methods: Eighty-seven patients with solid breast lesions (52 malignant and 35 benign) were examined on a 1.5 T MR scanner before histopathological evaluation. ADC values and ADC ratios were calculated. Results: The ADC values in the group with malignant tumors were significantly lower (mean 0.88 ± 0.15 × 10−3 mm2/s) in comparison with the group with benign lesions (mean 1.52 ± 0.23 × 10−3 mm2/s). A significantly lower ADC ratio was observed in the patients with malignant tumors (mean 0.66 ± 0.13) versus the patients with benign lesions (mean 1.12 ± 0.23). The cut-off point of the ADC value for differentiating malignant from benign breast tumors was 1.11 × 10−3 mm2/s with a sensitivity of 94.23%, specificity of 94.29%, and diagnostic accuracy of 98%, and an ADC ratio of ≤0.87 with a sensitivity of 94.23%, specificity of 91.43%, and a diagnostic accuracy of 95%. Conclusion: According to the results from our study DWI, ADC values and ADC ratio proved to be valuable additional techniques with high sensitivity and specificity for distinguishing benign from malignant breast lesions.

Introduction: In the Phase III CHRONOS-3 trial investigating the efficacy and safety of the PI3K inhibitor copanlisib in combination with rituximab (C+R), superior efficacy in progression-free survival (PFS) was demonstrated vs placebo plus rituximab (P+R) in patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL; hazard ratio [HR] 0.52), including in the subset with follicular lymphoma (FL; HR 0.58) (data cut-off Aug 31, 2020) (Matasar et al. Lancet Oncol 2021). Here we report an updated 1-year follow-up analysis for the subset of pts with FL (data cut-off Aug 6, 2021).Methods: Eligible pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to C+R or P+R. Treatment continued until progression or unacceptable toxicity. C 60 mg flat dose was administered i.v. on days 1, 8, and 15 (28-day cycle) and R 375 mg/m2 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 PFS. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). As part of biomarker analysis, PTEN expression level was evaluated using immunohistochemistry.Results: The FL subset comprised 275 pts (184 C+R and 91 P+R). C+R reduced the risk of progression or death by 43% vs P+R; median PFS was 23.2 mo (95% confidence interval [CI] 19.2, 33.1) for C+R and 16.6 mo (11.0, 19.6) for P+R (HR 0.57 [95% CI 0.41, 0.80]. ORRs were 85% vs 56% for C+R vs P+R; CRRs were 38% vs 21%. Median DoR was 25.7 mo (17.2, 31.5) for C+R vs 18.2 mo (12.3, 26.3) for P+R (HR 0.75 [95% CI 0.49, 1.14]); for pts achieving a complete response, median DoR was not reached for C+R vs 24.7 mo (10.8, 29.7) for P+R (HR 0.41 [0.19, 0.87]), with DoR rates at 36 months 63% vs 23%. Median OS was not estimable, and no significant benefit was seen for C+R over P+R (HR 0.95 [95% CI 0.52, 1.74]). Hyperglycemia (76%), hypertension (54%), and decreased neutrophil count (38%) were the most common TEAEs in the C+R arm, consistent with the study population. Grade 5 events occurred in 5 pts (3%) in the C+R arm; 1 (1%) was deemed treatment-related. Of 119 pts with FL who were evaluable for PTEN analysis, 41 (34%) were positive. Percent PTEN positivity was not correlated to best overall response (p=0.44) or responsiveness (p=0.08). Median PFS was improved in PTEN-negative pts regardless of treatment. PTEN-positive pts had improved PFS with C+R vs P+R (p=0.005).Conclusion: Pts with FL from the CHRONOS-3 trial continued to show superior efficacy with C+R vs P+R and an acceptable safety profile 1 year after the primary disclosure, supporting the long-term use of C+R in pts with relapsed FL. Exploratory analysis suggests pts with PTEN-positive disease may experience significant benefit with C+R. Citation Format: Marcelo Capra, Fangfang Lv, Wei Li, Tongyu Lin, Eduardo Yañez, Jifeng Feng, Aryan Hamed, Xiaoling Li, Toshiki Uchida, Ming-Chung Wang, Koji Izutsu, Antonio Salar, Katya Sapunarova, Guray Saydam, Jan Zaucha, Lidia Mongay Soler, Shalini Chaturvedi, Anjun Cao, Barrett H Childs, Pier Luigi Zinzani, Matthew J Matasar. Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A32.

Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m(2) given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19.2 months (IQR 7.4-28.8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21.5 months (95% CI 17.8-33.0) versus 13.8 months (10.2-17.5; hazard ratio 0.52 [95% CI 0.39-0.69]; p, Bayer, Bayer.

Aim of the study: To assess serum sclerostin in transfusion-dependent beta-thalassaemia patients versus healthy controls and to examine its associations with bone mineral density, bone metabolism markers and beta thalassaemia alterations. Material and methods: Sixty-two transfusion-dependent beta-thalassaemia (TDßT) patients and 30 healthy controls were evaluated for serum sclerostin, osteocalcin, beta-cross laps, osteoprotegerin and serum level of receptor activator of nuclear factor kappa-Β ligand (sRANKL). Bone mineral density was measured at the lumbar spine and femoral neck. Thalassaemia characteristics were collected from the patients’ medical records. Results: A significantly higher sclerostin level (median 565.50 pmol/L) was observed in the transfusion-dependent beta-thalassaemia patients vs. the healthy controls (median 48.65 pmol/L, p

Introduction: Copanlisib plus rituximab (C+R) was recently shown to be superior to placebo plus rituximab (P+R) in prolonging progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma (iNHL) (hazard ratio 0.52; 95% confidence interval [CI] 0.39, 0.69; 1-sided p=0.000002; Matasar et al. Lancet Oncology 2021). The objective response rate and complete response (CR) rates were also significantly higher in the C+R arm (81% and 34%, respectively) vs the P+R arm (48% and 15%, respectively). Whereas R administration was limited (odd cycles 1 to 9), C was administered until progression or unacceptable toxicity. Patients who discontinued then entered active follow-up and had CT scans on a regular schedule. This included a number of patients with objective responses who stopped treatment prior to documented progression. To provide insight on the optimal treatment duration for patients achieving a best overall response of partial response (PR) or CR with C+R treatment, we compare the duration of response (DoR) in patients after stopping treatment vs DoR in those who remained on treatment. Methods: CHRONOS-3 was a randomized, double-blind, placebo-controlled, Phase III study. Patients with iNHL (follicular lymphoma grades 1-3a, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, marginal zone lymphoma, small lymphocytic lymphoma) who relapsed after the last R-containing regimen and were progression-free and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to receive C+R or P+R. C 60 mg flat dose was given via a 1-h i.v. infusion on days 1, 8, and 15 (28-day cycle) and continued until disease progression or unacceptable toxicity. R 375 mg/m 2 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. Tumors were assessed by CT or MRI at screening and every 8 weeks during year 1, every 12 weeks during year 2, and every 24 weeks during year 3 and onwards. Response was assessed by blinded central review. DoR for patients with a PR or CR after stopping treatment was based on either the date of the last dose or the date of first response for patients whose scans occurred after stopping treatment. Results: As of August 31, 2020, 307 patients were randomized to C+R and 151 patients to P+R. In the C+R arm, 104 patients (34%) had a best overall response of CR, 137 patients (45%) had a PR, 5 patients (2%) had a minor response, and 2 patients (0.7%) had a very good partial response. Overall, median DoR was 20.4 mo (95% CI 17.0, 30.8) with a median time to first objective response of 1.8 mo and a median time to CR of 3.7 mo. Patients with a CR did not reach median DoR; 80% estimated response rate at 12 mo and 69% at 24 mo. Patients with a PR had a median DoR of 12.3 mo (95% CI 10.2, 15.3). A total of 57 patients with a CR and 65 patients with a PR stopped treatment before progression, with 71/122 (58%) patients discontinuing due to an adverse event. Median DoR before treatment discontinuation was 3.8 mo for patients with a CR and 1.7 mo for patients with a PR. Of patients with objective responses stopping treatment before progression, the total median DoR was 18.7 mo (95% CI 10.0, not evaluable) for those with a CR (n=57) and 5.3 mo (95% CI 2.9, 8.2) for those with a PR (n=65; Figure 1A). In contrast, of patients with objective responses who remained on treatment until progression or until the time of database lock, the median DoR was not reached for those with a CR (n=47; 89% estimated response rate at both 12 and 24 mo; Figure 1B) and the median DoR was 14.8 mo (95% CI 9.4, 17.2) for those with a PR (n=72; Figure 1B). Conclusions: For patients with iNHL treated with C+R and achieving a CR, sustained responses were seen in some patients upon cessation of treatment before disease progression, although the DoR was longer for patients with a CR who remained on treatment. The DoR for those achieving a PR was markedly less upon cessation of treatment than for patients who remained on treatment. Together, these results support the trial design of treatment to progression, but further suggest that discontinuation of treatment for patients with relapsed iNHL treated with C+R may be an option for some patients achieving a CR. Analysis of factors associated with a sustained CR upon stopping treatment are ongoing. Figure 1 Figure 1. Disclosures Matasar: Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Teva: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy; TG Therapeutics: Consultancy, Honoraria; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Özcan: AbbVie: Other: Travel support, Research Funding; Archigen Biotech: Research Funding; Bayer: Research Funding; Celgene: Research Funding; F. Hoffmann-La Roche Ltd.: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding; MSD: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support; Bristol Myers Squibb: Other: Travel support; Abdi İbrahim: Other: Financial relationships; Jazz Pharmaceuticals: Other: Financial relationships; Sanofi: Other: Financial relationships. Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months. Mongay Soler: Bayer HealthCare Pharmaceuticals Inc.: Current Employment. Cao: Bayer HealthCare Pharmaceuticals Inc.: Current Employment. Hiemeyer: Bayer AG: Current Employment. Childs: Bayer HealthCare Pharmaceuticals Inc.: Current Employment. Zinzani: ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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.

7510 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.