ABSTRACT
Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy;these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL;overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75);8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2;Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%;Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated;PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follic lar lymphoma and DEL produces high CR rates;survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. [Formula presented] Disclosures: Karmali: BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;Takeda: Research Funding;Karyopharm: Consultancy;EUSA: Consultancy;Janssen/Pharmacyclics: Consultancy;AstraZeneca: Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;Genentech: Consultancy;Epizyme: Consultancy;Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau;Juno: Research Funding;AstraZeneca: Honoraria, Research Funding, Speakers Bureau;Loxo: Research Funding;Janssen: Research Funding, Speakers Bureau;Abbvie: Honoraria, Research Funding;TG Therapeutics: Research Funding;Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board;Agios: Other: Husband: Consultancy;Actinium Pharma: Consultancy;Janssen: Other: Husband: Consultancy;Epizyme: Other: Husband: Data and Safety Monitoring Board;Gilead: Other: Husband: Consultancy;Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board;Karyopharm (Curio Science): Honoraria;Merck: Consultancy, Honoraria, Research Funding;Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties;Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)
ABSTRACT
Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is require to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. [Formula presented] Disclosures: Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding;Celgene/BMS: Research Funding;BeiGene: Research Funding;Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy;BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Takeda: Research Funding;Genentech: Consultancy;AstraZeneca: Speakers Bureau;Roche: Consultancy;Karyopharm: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding;AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharma: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Genmab: Consultancy, Honoraria;Epizyme: Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau;Servier Pharmaceuticals: Consultancy;Seattle Genetics: Speakers Bureau;Sanofi: Speakers Bureau;Pharmacyclics: Consultancy;MorphoSys: Consultancy;Kite (Gilead): Speakers Bureau;KaryoPharm: Consultancy;CSL Therapeutics: Consultancy;Bristol-Myers Squibb: Speakers Bureau;Biogen: Consultancy;Beigene: Consultancy;AstraZeneca: Speakers Bureau;ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;AbbVie: Consultancy. Grover: Genentech: Research Funding;Novartis: Consultancy;ADC: Other: Advisory Board;Kite: Other: Advisory Board;Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months;BMS: Divested equity in a private or publicly-traded company in the past 24 months;Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months;Novatis: Divested equity in a private or publicly-traded company in the past 24 months;Janssen: Divested equity in a private or publicly-traded company in the past 24 months;Morphosys: Divested equity in a private or publicly-traded company in the past 24 months;ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months;Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months;Beigene: Divested equity in a private or publicly-traded company in the past 24 months;Merck: Divested equity in a private or publicly-traded company in the past 24 months;KITE: Divested equity in a private or publicly-traded company in the past 24 months;Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support;Humanigen: Consultancy, Honoraria, Other: Travel support;Celgene: Consultancy, Honoraria, Other: Travel support;Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding;Lonza: Consultancy, Honoraria, Other: Travel support;AbbVie: Consultancy, Honoraria;Precision Biosciences: Consultancy, Honoraria, Other: Travel support;Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support;Nkarta: Consultancy, Honoraria;Axis: Speakers Bureau;Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy;Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.