Lunning, Matthew A.

Abstract Lisocabtagene maraleucel (liso-cel) has shown promising efficacy in clinical trials for patients with relapsed/refractory large B-cell lymphoma (LBCL). We present health-related quality of life (HRQOL) results from the TRANSFORM study, the first comparative analysis of liso-cel vs standard of care (SOC) as second-line therapy in this population. Adults with LBCL refractory or relapsed ≤12 months after first-line therapy and eligible for autologous stem cell transplantation were randomized 1:1 to the liso-cel or SOC arms (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale. Patients with baseline and ≥1 postbaseline assessment were analyzed (liso-cel, n = 47; SOC, n = 43). The proportion of patients with meaningful improvement in global health status/quality of life (QOL) was higher, whereas deterioration was lower in the liso-cel arm vs SOC arm from day 126 to month 6. Mean change scores showed meaningful worsening in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC; mean scores for other domains were maintained or improved in both arms. Time to confirmed deterioration favored the liso-cel arm vs SOC arm in global health status/QOL (median: not reached vs 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence interval, 0.24-0.94). HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm vs SOC arm as second-line treatment. This study is registered at clinicaltrials.gov as #NCT0357531.

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Abstract Background and Rationale: Axi-cel is a standard-of-care treatment for relapsed or refractory LBCL after 2 or more lines of systemic therapy. Some patients who would have been ineligible for ZUMA-1 criteria due to comorbidities have been treated with axi-cel in the real-world setting. We interrogated a large registry of patients treated with standard-of-care axi-cel for a definitive report on the impact of age or certain comorbidities on safety and efficacy outcomes after axi-cel infusion. Methods: From October 2017 to August 2020, 1500 patients were enrolled in the postapproval safety observational study of axi-cel treated at 79 centers. Patients eligible for the protocol and followed up for at least 6 months with complete data entry by the time of analyses were included. One patient rescinded consent and 1 was deemed ineligible. Patients previously treated with immune effector cell therapy (n=31), with incomplete follow-up reporting (n=92), or alive but last contacted <180 days postinfusion (n=32) were excluded from analysis. Main efficacy outcomes included complete and objective response rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS). Safety endpoints of interest included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Outcomes were assessed and compared by age and preselected coexisting disease or organ impairment within 3 months prior to the infusion included in the hematopoietic cell transplantation comorbidity index. Multivariate logistic and Cox regression models were used to assess the impact of age or coexistent organ dysfunction on outcomes via odds ratio (OR) or hazard ratio (HR) and their 95% CIs. Results A total of 1343 patients were included in the analysis with a median 25.1 months (range, 10.3-42.7 months) for potential follow-up, defined from infusion to data cutoff date, and a median 11.8 months (range, 0.1-38.8 months) for actual follow-up time, defined from infusion to date of death or last contact. Of these, 38% were 65 years or older (median 62 years), 4% had a performance score ≥2, 13% had cardiac comorbidities, 16% had a prior cancer, 9% were obese, 2% had moderate to severe hepatic comorbidities, and 2% had renal comorbidities. Transformed lymphoma, double or triple-hit by fluorescence in situ hybridization, prior autologous transplant and refractory disease were present in 28%, 15%, 27% and 66%, respectively. Bridging therapy was administered in 21% of patients. Overall, ORR was 74%, (CR 56%), and probabilities of DOR, PFS, and OS at 18 months were 61% (95% CI, 57-65%), 42% (95% CI, 39-45%) and 52% (95% CI, 49-55%), respectively. Overall rates of CRS and ICANS were 83% and 55%, respectively. ORR was 78% (CR 62%, median OS 17.5 [95% CI, 16.0-not evaluated (NE)] months) for patients ≥65 years, ORR 57% (CR 29%; median OS 4.3 [95% CI, 2.5-8.3] months) for patients with hepatic dysfunction, ORR 70% (CR 43%; median OS 8.9 [95% CI, 3.8-NE] months) for patients with renal dysfunction; and ORR 47% (CR 20%, median OS 4 [95% CI, 2.6-6.9] months) for patients with Eastern Cooperative Oncology Group (ECOG) 2 or 3. Multivariate analyses indicated that advanced age (≥65 years vs <65 years; OR 1.38; 95% CI, 1.05-1.83), moderate to severe pulmonary disease (yes vs no; OR 0.74; 95% CI, 0.55-0.98), and ECOG (2-3 vs 0-1; OR 0.31, 95% CI, 0.18-0.53) impacted ORR (Table). Age ≥65 years did not have an impact on survival (HR 1.05, 95% CI, 0.88-1.26), although it was associated with CRS (OR 1.42, 95% CI, 1.03-1.96) and ICANS (OR 1.78, 95% CI, 1.39-2.28). Coexistent cardiac disease (HR 1.44, 95% CI, 1.12-1.83), renal disease (HR 2.13, 95% CI, 1.32-3.46) and hepatic dysfunction (HR 2.65, 95% CI, 1.69-4.14) had an impact on OS, but not on response, CRS, and ICANS. ECOG significantly impacted all efficacy outcomes. None of the other comorbidities tested significantly impacted outcomes. Conclusion: Advanced age (≥65 years) was not associated with worse efficacy outcomes after axi-cel, despite higher rates of CRS and ICANS, which require closer monitoring. Performance status rather than age should be accounted for in patient selection and treatment decisions with axi-cel. Most coexistent organ dysfunctions have no clinically significant impact on axi-cel objective response and safety outcomes. Figure 1 Figure 1. Disclosures Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Wugen: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role. Jacobson: Axis: Speakers Bureau; Nkarta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Ma: Kite, a Gilead Company: Current Employment. Dong: Kite, a Gilead Company: Current Employment. Hu: Kite, a Gilead Company: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; Janssen: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Ghobadi: Atara: Consultancy; Wugen: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Vineti: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Merck: Research Funding; Takeda: Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; NexImmune: Honoraria; Sellas Life Sciences: Honoraria; Cidara: Honoraria; Merck: Honoraria; Omeros: Honoraria; Servier: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Other; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Equilium: Honoraria. Lunning: Daiichi-Sankyo: Consultancy; TG Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy; ADC Therapeutics: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Acrotech: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment. Pasquini: Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding.

Abstract Background Primary bone diffuse large B cell lymphoma (DLBCL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that is relatively rare, accounting for 3-15% of extranodal NHL and less than 1% of all NHL. Patients often present with pain and swelling or pathologic fracture of the affected area of the skeleton, and B symptoms are often less prevalent. Many cases are limited stage at presentation. Patients are usually treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or similar induction therapy. Based on older studies showing improved outcomes associated with the addition of radiation (many completed prior to the rituximab era), patients often still receive combined-modality therapy today. However, it remains unknown whether consolidative radiation therapy (RT) confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction. We sought to address this question in a multicenter retrospective study. Methods We conducted a retrospective analysis of outcomes in a modern cohort of patients who underwent treatment for primary bone DLBCL using chemotherapy regimens in the rituximab era either with or without consolidative RT. Data was collected from 13 academic medical centers in the U.S., with patients treated between 2005 and 2019. Patients were identified using each institution's hematologic malignancy registries. Analysis was limited to patients with primary bone DLBCL, with stage I-II disease (primary site +/- locoregional lymph nodes) that could be encompassed in a radiation field. Patients who received CIT alone or CIT followed by RT were included. Treatment selection was at the treating physician's discretion. Electronic medical records were reviewed for: demographics, chemotherapy regimens, radiation treatments, and PET scan data. Local IRB approval was obtained at sites. All data was distributed in a de-identified fashion. The primary outcomes were overall survival (OS), and relapse-free survival (RFS). Secondary outcomes included: response after induction CIT induction and the need for additional therapies. Chi-square test analysis was used to compare categorical variables and the Wilcoxon rank-sum test was used for continuous and ordinal measures. Survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. Multi-variable analysis (MVA) for OS and RFS was performed using RT vs no RT, PET status post CIT (negative vs positive) and rituximab in induction (Y/N) as variables. Results A total of 127 patients were included: 91 who received CIT and radiation (RT group), and 36 who received CIT alone (no RT group). The median age of patients at diagnosis in the RT group and no RT group was 58.5 and 57.0, respectively. For CIT, the majority of patients received R-CHOP (84%). Despite focusing on 2005-2019, a small percentage of patients (5 - 14%) in each group (RT and no RT) did not receive rituximab with their induction therapy. The OS at 10 years was 74.5% in the RT group and 86.5% in the no RT group (p = 0.29). The RFS at 10 years was 70.9% in the RT group and 78.2% in the no RT group (p = 0.85). Among the 91 patients who received RT, 67 (77.0%) received a dose of 36 Gy or higher. There was no difference in OS (p = 0.63) or RFS (p = 0.90) in patients who received > 36 Gy vs < 36 Gy of radiation. On MVA for OS, RT was not associated with improved OS, although rituximab as part of induction was (p = 0.048). On MVA for RFS, neither RT nor rituximab were associated with improved RFS. For rituximab the trend was in the direction of rituximab benefit (p = 0.11). Conclusion Our results demonstrate that, in the rituximab era, patients with limited stage primary bone DLBCL have excellent outcomes overall. In this study, neither RFS or OS appeared to be improved with the addition of consolidative RT. Rituximab, however, was associated with improved OS on MVA. Outcomes do not appear to differ based on the dose of RT (> 36 Gy vs < 36 Gy). Our data suggests that RT may have less benefit for primary bone DLBCL in the rituximab era, although it is possible that a subset of patients may benefit from consolidative radiation therapy. A larger data set would likely be needed to evaluate this. We plan to present data regarding PET responses at the meeting. Figure 1 Figure 1. Disclosures Lunning: Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Kyowa Kirin: Consultancy; Verastem: Consultancy; Kite, a Gilead Company: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Bartlett: Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Caimi: XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; TG Therapeutics: Honoraria; Seattle Genetics: Consultancy; Verastem: Consultancy; Kite Pharmaceuticals: Consultancy. Rodgers: MJH Lifesciences: Consultancy. Barr: Morphosys: Consultancy; Gilead: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Abbvie/Pharmacyclics: Consultancy. Epperla: Verastem: Speakers Bureau; Beigene: Speakers Bureau; Karyopharm: Other: Ad Board; Genzyme: Honoraria. Hill: AstraZenica: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Epizyme: Consultancy; Karyopharm: Consultancy; Janssen/Pharmacyclics: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Takeda: Research Funding; Genentech: Consultancy; Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Aptitude Health: Honoraria; Morphosys: Honoraria; Targeted Oncology: Honoraria; SeaGen: Research Funding; BeiGene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Fenske: Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Servier Pharmaceuticals: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau; Biogen: Consultancy; ADC Therapeutics: Consultancy; Kite (Gilead): Speakers Bureau; Beigene: Consultancy; AbbVie: Consultancy.

Abstract Background: Pts with LBCL primary refractory to or relapsed ≤ 12 mo after first-line (1L) therapy may have poor outcomes with SOC, including salvage CT and ASCT, which underscores a critical unmet need. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the TRANSCEND NHL 001 study (NCT02631044) in pts with R/R LBCL (≥ 2 prior lines of therapy), liso-cel treatment resulted in an ORR of 73% (CR rate, 53%), 2% grade ≥ 3 cytokine release syndrome (CRS), and 10% grade ≥ 3 neurological events (NE) (Abramson et al. Lancet 2020). Here we present a prespecified interim analysis of TRANSFORM (NCT03575351; SOC vs liso-cel as 2L therapy in pts with R/R LBCL). Methods: TRANSFORM is a pivotal, global, randomized, multicenter, phase 3 study comparing efficacy and safety of SOC (Arm A; R-DHAP, R-ICE, or R-GDP per investigator choice followed by BEAM + ASCT) vs liso-cel (Arm B). Pts were adults (aged ≤ 75 years), eligible for ASCT, and with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function (LVEF ≥ 40%; serum CrCl > 45 mL/min); pts with secondary CNS lymphoma were allowed. Key exclusion criteria were prior gene or anti-CD19-targeted therapy, and active infection. Pts in Arm A were to receive 3 cycles of CT. Responding pts (CR or PR) were to proceed to BEAM + ASCT. Pts in Arm B were to undergo lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Bridging therapy with an Arm A CT regimen was allowed. Crossover to receive liso-cel was allowed in Arm A for pts not achieving CR or PR after 3 cycles of CT or not in CR after ASCT, or demonstrating PD at any time. Primary endpoint is event-free survival (EFS) based on independent review committee per Lugano 2014 criteria, defined as time from randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks after randomization, or start of new antineoplastic therapy, whichever occurred first. Key secondary endpoints included in the testing strategy are CR rate, PFS, and OS. P value significance threshold for endpoints to reject the null hypothesis was ≤ 0.012. Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were well balanced between both arms (Table). Of 91 treated pts in Arm A (1 pt withdrew consent), 43 received BEAM + ASCT, of which 28 achieved CR with CT. Fifty pts crossed over to receive liso-cel. In Arm B, 90 pts received liso-cel infusion; 58 pts (63%) received bridging therapy. Two Arm B pts were not infused (1 each due to manufacturing failure and rapid progression). Median EFS and PFS were significantly longer, and CR rate was significantly improved for Arm B vs Arm A. For Arms A and B, respectively, median EFS was 2.3 vs 10.1 mo (HR, 0.349; P < 0.0001), median PFS was 5.7 vs 14.8 mo (HR, 0.406; P = 0.0001), and CR rate was 39% vs 66% (P < 0.0001). OS data were immature at the time of this analysis with a median follow-up of 6.2 mo (range, 0.9-20.0), but a numerical trend favored Arm B (HR, 0.509; 95% CI, 0.258-1.004; P = 0.0257). Cellular kinetics in Arm B showed a median t max of 10 d (range, 6‒22). No new liso-cel safety signals were detected in the 2L setting. In Arm B, any-grade CRS was reported in 49% of pts, with grade 1 in 37% and grade 2 in 11%. Only 1 pt had grade 3 CRS (onset at Day 9, which resolved in 2 days). Any-grade NEs were reported in 12% of pts and were also primarily low grade (grade 3, 4%). No grade 4 or 5 CRS or NEs were reported. In Arm B, 24% of pts received tocilizumab, 17% received corticosteroids, and none received vasopressors. The most common TEAEs in both arms were cytopenias. Prolonged cytopenias in Arm B (ie, grade ≥ 3 at 35 d after infusion) were reported in 43% of pts; the majority recovered within 2 mo after infusion. Conclusions: In the TRANSFORM study, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint, EFS, as well as in key secondary efficacy endpoints (CR rate and PFS) compared with SOC as 2L therapy in pts with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Safety results in the 2L setting were consistent with the liso-cel safety profile in 3L or later LBCL, and no new safety concerns were identified. Liso-cel improved outcomes vs SOC and exhibited a favorable safety profile, providing support for liso-cel as a potential new SOC for 2L treatment in pts with R/R LBCL. Figure 1 Figure 1. Disclosures Kamdar: SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Celgene: Other; TG Therapeutics: Research Funding; KaryoPharm: Consultancy; Celgene (BMS): Consultancy; Genetech: Other; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ibrahimi: Karyopharm Theraputics: Divested equity in a private or publicly-traded company in the past 24 months. Mielke: Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Hernandez-Ilizaliturri: Kite: Other: Advisory Boards; Amgen: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; BMS: Other: Advisory Boards; Celgene: Other: Advisory Boards; Incyte: Other: Advisory Boards; AbbVie: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Izutsu: Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Morschhauser: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: 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. Lunning: Karyopharm: Consultancy; AstraZeneca: Consultancy; Legend: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Acrotech: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy. Maloney: Amgen: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; A2 Biotherapeutics: Honoraria, Other: Stock options; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Celgene: Other: Research funding was paid to my institution, Research Funding; Umoja: Honoraria; Janssen: Honoraria; Legend Biotech: Honoraria; Genentech: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Stepan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mack: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abramson: Bluebird Bio: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Liso-cel is a CAR T cell therapy approved for use in the third line for R/R LBCL. This trial reports data from the pivotal trial in the second line.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B); 1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1)); other malignancies included squamous cell carcinoma of skin (n=3); sarcoma (n=1); endometrial (n=1); lung (n=1); mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. J.Y.S and M.D.J contributed equally; S.D and M.L contributed equally. Figure 1 Figure 1. Disclosures Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy. Nastoupil: Pfizer: Honoraria, Research Funding; MorphoSys: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Bayer: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Lin: Gamida Cell: Consultancy; Juno: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Oluwole: Curio Science: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. McGuirk: EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Goy: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; Xcenda: Consultancy; Acerta: Consultancy, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Genentech/Hoffman la Roche: Research Funding; MorphoSys: Honoraria, Other; Karyopharm: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Incyte: Honoraria; Medscape: Consultancy; Novartis: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Infinity/Verastem: Research Funding; Rosewell Park: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Hill: Pfizer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding. Muñoz: Seagen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Speakers Bureau; Juno/Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Alexion: Consultancy; BeiGene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Debiopharma: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Acrotech: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol Myers Squibb: Speakers Bureau; Genentech: Speakers Bureau; Aurobindo: Speakers Bureau; Physicians' Education Resource: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; OncView: Honoraria; Targeted Oncology: Honoraria. Westin: AstraZeneca: Consultancy, Research Funding; 47 Inc: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Morphosys: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Genentech: Consultancy, Research Funding. Chavez: Bristol Myers Squibb: Speakers Bureau; Karyopharm Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kite/Gilead: Consultancy; Abbvie: Consultancy; MorphoSys: Speakers Bureau; BeiGene: Speakers Bureau; Novartis: Consultancy; Adaptive: Research Funding; Epizyme: Speakers Bureau; AstraZeneca: Research Funding. Bennani: Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Locke: GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Umoja: Consultancy, Other; Cowen: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role. Dahiya: Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; Miltenyi Biotech: Research Funding; Jazz Pharmaceuticals: Research Funding; BMS: Consultancy. Lunning: Spectrum: Consultancy; AstraZeneca: Consultancy; Acrotech: Consultancy; Legend: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Myeloid Therapeutics: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy.

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade >3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a <3 weeks gap since prior ibrutinib therapy. Primary objectives include CR or ORR and DOR compared to (matched) historical controls (closely matched if possible). 2nd objectives include tolerance/safety, PFS, and pop-PK sampling for CA-4948. Exploratory objectives; response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance. Treatment: CA-4948 at RP2D+ibrubinib at labelled doses; 21-day cycles to be repeated in the absence of toxicity or progression. Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: 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; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.