Abedi, Mehrdad

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7–58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups. Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Abstract ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

Abstract Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.