ALBERT

Description: Introduction: Since its approval in 2014, ibrutinib has replaced chemotherapy to become a preferred therapy for CLL patients. Real-world studies of ibrutinib in CLL patients have shown higher rates of discontinuations due to adverse events (AEs; 14-23%) compared with data from the early clinical trials of ibrutinib (4-9%). Similarly, dose reduction rates due to AEs in the real-world studies were 22-28%, vs 9% in the ibrutinib package insert. These real-world studies have been mostly focused on the academic setting or based on registry data. This study was part of an initiative to collect chart-review data from an academic practice and broader community networks, using an identical protocol to describe ibrutinib dose reductions and discontinuations in CLL patients. Methods: This was a multicenter, retrospective, chart review study of CLL patients and treated with ibrutinib. De-identified data were pooled from 2 community networks and 1 academic practice. Each community network agreed to contribute 50 patients on ibrutinib to the pooled data. To minimize potential bias, the patients were randomly selected from all the ibrutinib-treated patients in each network. All patients meeting inclusion criteria from the academic site were included. Inclusion criteria were: confirmed diagnosis of CLL, initiation of ibrutinib between March 2014 and June 2019, and ≥18 years of age at the initiation of therapy. Patients were excluded if they were actively receiving therapy for other primary cancers or were enrolled in a clinical trial of ibrutinib during the study period. Index date was defined as the date of ibrutinib initiation, and patients were followed for a minimum of 6 months. Variables collected included: patient demographics, clinical and treatment characteristics, molecular profiles, and reasons for dose reduction and discontinuation. Descriptive statistics were used to summarize the results. Results: 180 CLL Patients were included in this analysis. Of these, 56 (31%) patients received ibrutinib in the first line (1L) and 124 (69%) patients received ibrutinib in a relapsed/refractory (R/R) line. Over half (56%) of patients were treated in a community setting. Baseline demographic and clinical characteristics are shown in Table 1. 1L Ibrutinib patients had a median follow-up of 26 months. Twenty-five percent of patients (n=14) experienced at least one dose reduction, mainly due to AEs (n=11, 79%) (Figure 1). There was no single AE primarily responsible for dose reduction (Table 2). Treatment discontinuations were reported in 20% of patients, and they were more commonly due to AEs (73%) than disease progression (9%). Similarly, a variety of AEs led to discontinuations (Table 2). Median time to the first dose reduction for 1L patients was 9.9 months. Among patients who discontinued ibrutinib, median duration of treatment (DOT) was 15 months; with median DOT of 6 months for those who discontinued because of AEs and 28.9 months for those who discontinued because of progression. R/R Ibrutinib patients had a median follow up of 28.5 months. About a quarter (27.5%, n=34) of patients experienced at least 1 dose reduction, mainly due to AEs (n=30 [88%]) (Figure 1). The most common AEs leading to the first dose reductions were gastrointestinal (GI) disorder (43%), fatigue (23%), , and arthralgia/myalgia/musculoskeletal pain (17%) (Table 2). Treatment discontinuation was reported in 40% of patients, with over half due to AEs (58%) rather than disease progression (18%). The most common AEs leading to discontinuation were GI disorders (31%), atrial fibrillation (24%), and infections (21%) (Table 2). Median time to the first dose reduction in R/R patients was 3.1 months. Among patients who discontinued ibrutinib, median DOT was 9 months; with median DOT of 6 months for those who discontinued because of AEs and 30.2 months for those who discontinued because of progression. Conclusions: Dose reductions and discontinuations were frequent in CLL patients receiving ibrutinib in routine clinical practice. Compared with ibrutinib clinical trial data at a similar follow-up time, AEs were the most common reasons leading to discontinuation of ibrutinib rather than disease progression. The rates of dose reduction and discontinuations due to AEs in our study were higher than in clinical trials and were consistent with other real-world studies, indicating similar patterns in both community and academic settings. Disclosures Hou: Verastem: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Other: PI; AbbVie: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ryan:AstraZeneca: Current Employment, Current equity holder in private company. Du:AstraZeneca: Other: Grant. Fang:AstraZeneca: Other: Grant. Marks:Sanofi: Research Funding. Page:AstraZeneca: Other: Grants. Peng:AstraZeneca: Other: Grant. Szymanski:AstraZeneca: Current Employment, Other: Stockholder. Le:AstraZeneca: Current Employment, Current equity holder in private company.

Description: BACKGROUND Since the FDA's initial indication for the use of daratumumab in relapsed/refractory multiple myeloma (RRMM) in November 2015, usage has been expanded by subsequent approvals in newly diagnosed, transplant-ineligible MM patients, and more recently in newly diagnosed transplant-eligible patients. Real World Data (RWD) has been published demonstrating daratumumab's efficacy in RRMM settings[1]and its utility of split dosing for the initial dose[2]. However, no study has been published to examine the real-world dosing patterns of daratumumab compared to the FDA standard dosing schedule. While there are minimal variations in the approved dosing schedule of daratumumab, generally accepted dosing is weekly in week 1 through week 8, q 2 Wks in week 9 through week 24, and q 4 Wks after week 24, all at the standard 16 mg/kg dosage[3]. In its approved dosing schedule, adjustments are made in the frequency of administration, but not in the standard weight-based dosing. METHODS Utilizing the Integra Connect database which contains 17 community oncology network accounts and over 1,900 providers in US, we collected all MM patients treated with daratumumab between January 1, 2016 and March 31, 2020. We then excluded any patient whose first line of therapy (LOT) was ambiguous, in order to correctly identify the daratumumab-containing LOTs. We also excluded LOT 1 daratumumab transplant induction due to the wide variation in daratumumab dosing schedules in clinical trials in the transplant eligible patient[4]. LOTs were determined based on International Myeloma Working Group guidelines[5]. Data were collected on the date of each individual daratumumab administration, counting initial split dose, if utilized, as 1 dose. The duration of daratumumab and number of doses administered were calculated and corrected for any time on treatment breaks. The study was conducted per individual patient by LOT cohorts, and for the entire cohort of patients. We utilized the standard dose schedule for daratumumab noted above to establish the expected doses of daratumumab and calculated the compliance dose ratio (ratio of actual doses to expected doses per time on therapy) to evaluate how closely real-world treatment adhered to the standard dosing schedule. RESULTS 1037 MM patients were included with at least 6 doses of daratumumab administration and without stem cell transplant or uncertain LOT. Across all LOTs, the mean duration of daratumumab treatment was 5.6 months with a median duration of 9.8 months. After week twenty-four, 671 (65%) patients remained on daratumumab-containing regimens, with 330 patients continuing q 1 Wk or q 2 Wks dosing, whereas the standard would employ a switch to q 4 Wks dosing (Figure 1). Overall compliance dose ratio was consistently above 100%, implying a significant proportion of patients were receiving more frequent dosing than expected under the standard dosing schedule (Figure 2). We carefully evaluated patients in various LOTs and combination therapies. Drug combination was not found to exert a significant impact on the daratumumab dosing pattern. Compliance dose ratio of daratumumab is slightly higher in RRMM compared to the dose ratio in LOT 1 newly diagnosed MM, but even LOT 1 has a ratio greater than 1 (Figure 3). It should be noted that this increased compliance dose ratio is present in all LOT cohorts despite 25% of patients being started on doses less frequent than weekly (Figure 1). CONCLUSIONS In real-world community oncology practices, daratumumab is utilized in a more frequent dosing schedule than the FDA approved standard dosing. With standard dosing there are 23 daratumumab doses in the first 52 weeks. The compliance dose ratio found in our RWD implies 27.3 doses in the first year for the entire cohort and 26.9 and 28.3 doses in LOTs 2 and 3 respectively. Thus, significantly increased drug and administrative costs are incurred over those anticipated in respect to daratumumab dosing utilization. This study is limited to the EMR and administrative claims data of those individuals who are being treated in a community oncology setting. Residual confounding and bias may exist due to entry error and unobserved patient characteristics. References [1] Gergely Varga, et al; Blood 2018; 132:3257 [2] Rifkin R, et al; Clin Ther. 2019;41(5):866-881 [3] DARZALEX® [Prescribing Information] [4] Abdallah N, et al. Ther Adv Hematol. 2019 Dec 23 [5] Rajkumar SV, et al Blood. 2015;126(7):921-922 Disclosures Smith: Integra Connect: Current Employment; Sanofi: Research Funding. Xue:Sanofi: Research Funding; Integra Connect: Current Employment. Marks:Sanofi: Research Funding. Scott:Integra Connect: Current Employment; Sanofi: Research Funding. Blanc:Sanofi: Research Funding. Nagovski:Sanofi: Research Funding. Lambert:Sanofi: Research Funding; Integra Connect: Current Employment. Varughese:Integra Connect: Current Employment; Sanofi: Research Funding.