Abstract: Introduction: Idelalisib is a first-in-class PI3Kδ-inhibitor. In clinical studies idelalisib demonstrated significant efficacy in patients with CLL, including patients with TP53 aberrations (del17p and/or TP53m). On this basis national and international guidelines in Europe recommend idelalisib as one treatment option in this high-risk CLL patient population. However, it is unclear how efficacy reported in clinical studies translates into real world experience. Considering the importance of such data, we initiated a real world study soon after market authorization of idelalisib in the European Union prospectively investigating efficacy and safety of idelalisib in routine clinical practice. Concomitant PJP prophylaxis is a risk minimization measure that was introduced after market authorization of idelalisib. Nevertheless, the impact on patient outcomes in routine clinical practice has not been studied in detail. We therefore also analyzed the impact of PJP prophylaxis on overall survival (OS) within this real world cohort. Methods: A prospective, two-cohort, multicenter, non-interventional post-authorization safety study (PASS) reporting real world safety and efficacy data on the use of idelalisib in Germany. Inclusion of patients was based on the physician's decision to initiate treatment with idelalisib in accordance with the European Summary of Product Characteristics. Descriptive statistics were used for data analysis. Results: This analysis included 84 CLL patients with a median age of 74 years. 88% of patients were older than 65 years, 70% were male and 86% presented with one or more co-morbidities. Binet stage A, B, C was reported in 25%, 33% and 37% of patients, respectively. The median time from diagnosis to start of idelalisib therapy was 89.5 months and patients received a median number of two prior lines of therapy, including treatment with the BTK inhibitor ibrutinib in 11 patients (13%). With a median observation time of 11.5 months the median overall survival (OS) for the entire CLL patient population was not reached. Our CLL cohort included 24 patients (29%) that did not receive PJP prophylaxis for idelalisib therapy. We therefore compared OS in patients with and without concomitant PJP prophylaxis. In patients receiving PJP prophylaxis survival rates were higher in the first 6-12 months of therapy, with 6-month and 12-month survival rates in patients with vs without PJP prophylaxis of 98% vs 76% and 84% vs 76%, respectively (Figure 1). 19% of CLL patients (n=16) had documented TP53 aberrations, including five patients that received idelalisib as first-line treatment. In patients with TP53 aberrations the overall response rate (ORR) was 77% compared to 67% in patients without TP53 aberrations. Importantly, the 12-month survival rates for patients with and without TP53 aberrations were similar with 81% and 83%, respectively. Median OS was not reached for either patient population (Figure 2). Conclusion: This prospective real world study started collecting data on the efficacy and safety of idelalisib in routine clinical practice soon after market authorization of idelalisib in Europe. Results demonstrate similar efficacy of idelalisib irrespective of the patients' TP53 status confirming the efficacy previously reported in pivotal clinical studies. Additionally, our results provide evidence that PJP prophylaxis is an effective risk minimization measure impacting on survival. Disclosures Hoechstetter: Hexal: Other: Travel Grants; Abbvie: Other: Travel Grants; Gilead Sciences: Consultancy, Other: Travel Grants. Eissmann:Gilead Sciences: Employment. Hucke:Gilead Sciences: Employment. van Troostenburg:Gilead Sciences: Employment. Ramroth:Gilead Sciences: Employment. Knauf:Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy; Janssen: Consultancy; Mundipharma: Consultancy; Roche: Consultancy; Amgen: Consultancy, Honoraria; AbbVie: Consultancy.

Abstract: Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

Abstract: Background: Malignant lymphoid cells are characteristically dependent on signals mediated by the phosphatidylinositol 3-kinase delta isoform (PI3Kδ). Idelalisib is an oral, selective, PI3Kδ inhibitor approved by the FDA and EMA as monotherapy for the treatment of advanced follicular lymphoma (FL). The approval was based on a phase 2 trial in patients with indolent non-Hodgkin lymphoma including 72 patients with FL who were refractory to at least 2 prior regimens (NCT01282424; Study 101-09). Interim safety analysis of this large, pan-European, noninterventional study of refractory FL patients treated with idelalisib monotherapy (EUPAS19618; NCT03568929) showed that the adverse event (AE) profile in clinical practice corroborates the known safety profile of idelalisib reported from clinical trials. Herein, we report the effectiveness and updated safety analysis from this study. Methods: This was a non-interventional, retrospective, cohort study. Adult patients treated with idelalisib for FL in routine clinical practice in 10 European countries were included. Data were collected retrospectively from sites by study personnel from remotely source data-verified medical records using electronic case report forms. Safety and effectiveness data for each patient were collected from time of idelalisib initiation until 6 months post-discontinuation of idelalisib, start of next treatment, or death. For this analysis, the data cut-off date was 16 June 2021. Effectiveness of idelalisib was assessed by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). The overall safety profile of idelalisib was assessed by estimating the incidence of AEs, serious AEs, adverse drug reactions (ADRs), and serious ADRs. Focus was given to special health outcomes of interest (HOIs), including transaminase elevation, hepatocellular injury, severe diarrhea/colitis, pneumonitis, neutropenia, rash, Stevens-Johnson syndrome, and serious infections. Multivariate Poisson regression analyses are used to estimate rates of ADRs, serious ADRs, and HOIs, and are adjusted for potential confounders. Time-to-event data were analyzed using Kaplan-Meier methods. Results: Overall, there were 257 eligible patients in the study from 85 sites. The Full Analysis Set (FAS) consisted of 242 patients excluding those with deviations (n=10) or those without any data contribution at the cut-off date (n=5). Of the 242 patients, 183 initiated idelalisib at least 12 months prior to data cut-off date and were included in the Effectiveness Analysis Set (EAS; n=49 patients did not have effectiveness data recorded, and 10 did not meet effectiveness inclusion criteria). For the 183 patients in the EAS, median age was 67 years and 54.6% (n=100) were male (Fig. 1A). Median number of prior therapies was 3 (range 1-10) and median time since diagnosis was 5.8 years (range: 0.4-32). At treatment initiation, 64% (n=117) had Ann Arbor stage III/IV disease. Median duration of idelalisib exposure was 6.8 months (IQR 3.0-15.6); 41.5% (n=76) had dose interruptions. Patients received doses of 150 mg only (67.8%), both 150 mg and 100 mg (28.4%), or 100 mg only (3.8%). Patients were observed for a median of 9.8 months (IQR 5.2-19.3). In the EAS, 103/183 patients achieved a response with 30 patients (16.4%) achieving a complete response (CR) and 73 (39.9%) achieving a partial response (PR), yielding a best ORR of 56.3% (95% CI: 48.8-63.6; Fig. 1B). Median DOR, PFS, and TTNT were 22.5 (95% CI: 15.1-27.9), 11.1 (95% CI: 8.1-18.1) and 15.4 months (95% CI: 9.9-22.2), respectively (Fig. 1B, C). Median OS had not been reached at the time of data cut-off (Fig. 1D). Updated safety information was available from the 242 patients in the FAS. The most frequent AEs recorded were infections, diarrhea and/or colitis, and transaminase elevation. The proportion of patients in the FAS experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Fig. 1E. Conclusions: We report to our knowledge the largest cohort of FL patients treated with idelalisib outside of the clinical trial setting. Our effectiveness findings are remarkably similar to those from the registrational study 101-09 (Gopal 2014 N Engl J Med). Safety profile of idelalisib was consistent with trial experience, and no new safety signals were identified. Idelalisib remains an effective treatment option for FL patients. Figure 1 Figure 1. Disclosures Gyan: Gilead Sciences, Inc.: Consultancy; Novartis: Research Funding; Mundipharma: Research Funding; Fresenius Kabi: Research Funding; Sanofi: Honoraria; AbbVie: Other: Hospitality; AstraZeneca: Honoraria. Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Merli: Takeda: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Novartis: Consultancy. Di Raimondo: Amgen: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria; Jazz Pharmaceutical: Honoraria. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vandenberghe: Janssen Pharmaceuticals: Honoraria; AbbVie: Honoraria. Boland: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah Gupta: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. van Troostenburg: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Dunnill: Gilead Sciences, Inc.: Current equity holder in publicly-traded company, Other: Contractor. Ramroth: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Salles: Genentech/Roche: Consultancy; Incyte: Consultancy; Regeneron: Consultancy, Honoraria; Miltneiy: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Velosbio: Consultancy; Novartis: Consultancy; Ipsen: Consultancy; Morphosys: Consultancy, Honoraria; Allogene: Consultancy; Debiopharm: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Takeda: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Abstract: Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus–infected (CHB) patients with renal impairment (RI). Aims To compare real‐world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate‐to‐severe RI. Methods Retrospective, non‐interventional, cohort study analysing medical records for TDF/ETV‐treated CHB patients (54 European centres). Included patients experienced moderate‐to‐severe RI (creatinine clearance 20‐60 mL/min [Cockcroft‐Gault]) either before TDF/ETV initiation (‘before’ subgroup [baseline = treatment initiation] ) or after TDF/ETV initiation (‘after’ subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal‐related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. Results ‘Before’ subgroup included 107 TDF‐ and 91 ETV‐treated patients; ‘after’ subgroup included 212 TDF‐ and 77 ETV‐treated patients. Mean baseline creatinine clearance was higher for TDF‐ vs ETV‐treated patients (both subgroups). Median follow‐up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV (‘before’: 18.7% vs 8.8%; ‘after’: 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF‐treated patients experienced renal tubular dysfunction (6.5% ‘before’; 1.9% ‘after’) as well as renal adverse events leading to treatment discontinuation (8.4% ‘before’; 7.1% ‘after’). Effectiveness was similar between treatments. Conclusions Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.