ALBERT

Description: Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure. Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses. Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR-L 13%] and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p

Description: Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive. Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. 〈 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1). Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized. Figure 1 Figure 1. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

Description: Introduction: The MURANO study demonstrated that venetoclax (VEN) plus rituximab is an effective regimen for pts with relapsed/refractory (R/R) CLL, but included 2 years of treatment and an infusional component (Seymour et al., NEJM, 2018). Duvelisib (DUV) is an oral inhibitor of PI3K-δ/γ approved for R/R CLL/SLL after two prior therapies. We hypothesized that DUV + VEN would lead to deep remissions that allow for oral, time-limited therapy. DUV + VEN is also promising for Richter's Syndrome (RS), as this combination was synergistic in preclinical models (Iannello et al., ASH, 2019). Here we report the safety and preliminary efficacy of DUV + VEN in pts with R/R CLL/SLL and RS. Methods: This is an ongoing investigator-initiated phase I/II trial (NCT03534323) with primary endpoints: DLTs, MTD, and RP2D (phase I) and CR rate (phase II). Secondary endpoints: PK, preliminary efficacy. Pts are treated with a 7-day lead in of DUV 25 mg BID. In the phase I trial, on day 8, DUV was continued and VEN initiated at 10 mg or 20 mg (inpt) with weekly ramp-up to 20/50/100 (dose level (DL)1), 200 mg (DL2), and 400 mg (DL3) using a 3+3 design. In phase II VEN is started at 10 mg (outpt) or 20 mg (inpt) on day 8 and ramped up to 400 mg on a weekly basis. Pts with RS have the option of an accelerated VEN ramp-up to 400 mg over 5 days (inpt). Pts are treated with DUV + VEN for 12 cycles. If undetectable for minimal residual disease (uMRD), pts can discontinue therapy and reinitiate VEN with recurrence. Pts with persistent MRD after 12 cycles continue VEN. Eligibility criteria for CLL pts: ≥1 prior therapy, requiring therapy by 2008 iwCLL criteria, ECOG PS ≤2, adequate hematologic/organ function, no prior VEN/DUV. For RS, no prior therapy and prior VEN 〉 1 yr ago was allowed. CTCAE v5 and 2008 iwCLL were used to evaluate toxicity and efficacy. MRD was assessed by 8-color flow at 10-4 in the peripheral blood (PB) and bone marrow (BM) (Mayo Laboratories). Results: As of July 19, 2020, 22 pts were treated (phase I (n=12), phase II (CLL n=7, RS n=3)). Median age: 69 yrs (range 50-78). Del(17p): 7/22 (32%), TP53 mutation: 10/22 (45%), del(11q): 2/22 (9%), unmutated IGHV: 20/22 (91%), mutation in NOTCH1: 10/22 (45%). Median prior treatments was 3 (range 1-6), including 2 pts who relapsed after alloSCT. 15/22 (68%) pts had prior BTKi, including 7 progressors. No DLTs occurred in phase I, and PK data showed only modest increase in VEN exposure in the presence of DUV. The RP2D of VEN in combination with DUV was the approved dose of 400 mg. Heme toxicities and all grade non-heme toxicities in 〉25% of pts are shown in Table 1. SAEs included: gr3 febrile neutropenia and lung infection (n=2), gr3 amylase/lipase, gastritis, arthralgia (n=1), gr2 colitis (n=1), and g5 hepatic failure (n=1). All SAEs were reversible with the exception of the gr5 hepatic failure in a pt with RS involvement of the liver. Eleven pts held, 9 pts dose-reduced, and 6 pts discontinued DUV for toxicity. No laboratory or clinical tumor lysis syndrome (TLS) was observed per Cairo-Bishop criteria. VEN was briefly held during ramp-up in 2 pts for elevated LDH and K, then later in 2 pts for neutropenia and thrombocytopenia. At data cutoff, the median number of cycles was 7.5 (range 1-22) and 21 pts were evaluable after at least cycle 4 restaging (CLL n=18, RS n=3). The ORR for CLL/SLL pts was 94% (17/18), with 56% CR (primary endpt) and 39% PR. 61% (11/18) pts had uMRD in the PB, first occurring after cycle 3 (n=4), cycle 6 (n=5), or cycle 10 or 12 (n=1 each). 56% (10/18) pts have thus far achieved BM-uMRD and 4 pts have not yet reached the point of evaluation. 58% (7/12) pts who have to date completed 1 year of DUV + VEN had CR with uMRD in the PB and BM and discontinued therapy, including 2 pts with del(17p). All 4 CLL pts who had progressed on BTKi have responded thus far. Three CLL pts have come off study. One pt with minimal nodal disease achieved uMRD in PB and BM and proceeded to alloSCT. Two pts at DL1 came off study for PD (1 CLL and 1 RS). Of the 3 pts with RS, 1 had disease reduction but was in SD after 3 cycles and started new therapy, and 2 pts had early PD and came off study. 3 pts have died, all with RS. Conclusions: DUV + VEN has a manageable safety profile to date and is active for pts with R/R CLL/SLL, including those who have relapsed after BTKi. High rates of CR and uMRD for this 1-year MRD-guided, time-limited, all oral regimen have already been observed despite short follow-up. Updated results of this actively accruing study will be presented at the meeting. Disclosures Crombie: Bayer: Research Funding; Abbvie: Research Funding. Francoeur:Verastem: Current Employment, Other. Montegaard:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: KOL lecture seires guest lecturer. Soumerai:BostonGene: Research Funding; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; GlaxoSmithKine: Research Funding; Genentech/Roche: Research Funding; Beigene: Consultancy, Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Gilead, Loxo, Sun, Verastem: Research Funding. Davids:Eli Lilly: Consultancy; Verastem: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Duvelisib and venetoclax are not approved in combination for CLL.