Rationale for Requested Change: Jan Bassali, PharmD Vice President, Medical Affairs Autolus Therapeutics Phone: 312-933-8213 Email: j.bassali@autolus.com Date of Request: December 12, 2024 NCCN Guidelines® Panel: Acute Lymphoblastic Leukemia (ALL) Dear NCCN Guidelines® ALL Panel Members, On behalf of Autolus Ltd, we respectfully request the NCCN Guideline Panel for Acute Lymphoblastic Leukemia (ALL) to review the enclosed data for inclusion of Aucatzyl® (obecabtagene autoleucel) as treatment for adults with relapsed or refractory (R/R) B cell precursor acute lymphoblastic leukemia (B-ALL). Specific Changes Requested: Please consider the following suggested changes: • ALL-D 26 OF 28: The addition of obecabtagene autoleucel under the regimens for relapsed or refractory Ph-Positive B-ALL (following therapy that has included TKIs) • ALL-D 27 OF 28: The addition of obecabtagene autoleucel under the regimens for relapsed or refractory Ph-Negative B-ALL (CD19 antigen directed) o ALL-C 2 OF 4: The addition of obecabtagene autoleucel with the bullet: Note: Obecabtagene autoleucel is not associated with a REMS program. Please see obecabtagene autoleucel prescribing information and follow institutional guidelines for supportive care measures FDA Clearance: Aucatzyl® (obecabtagene autoleucel) was approved by the FDA on November 8th, 2024 for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Please see enclosed prescribing information for additional considerations. Rationale: Unmet Medical Need Adult patients with R/R B-ALL have a dismal prognosis, with median overall survival (OS) ranging from 2 to 6 months and 3-to-5-year survival rates of <10% with worse survival rates in older adults with ALL (aged ≥60 years of age), many of whom are unable to benefit from intensive therapies.1-3 The introduction of new treatment strategies, including antibody-drug conjugates and bispecific antibodies, have improved on the response rates of standard chemotherapy (44%-74%) in R/R B-ALL; however, OS remains poor (median, 7.7 months) and durable remissions usually require allogeneic stem cell transplantation (SCT) consolidation.4,5 Autologous CD19 Chimeric antigen receptor (CAR)-T cell therapy has emerged as a significant innovation with remarkable response rates (70%) in the treatment of adult R/R B-ALL, including in multi-agent chemotherapy-refractory disease. However, durable long-term response of CAR-T cells in the adult R/R B-ALL setting remains limited for a subset of patients (median duration of remission, 12.8 months [95% CI, 8.7-not reached [NR]), with rates of relapse ranging from 21% to 45%.6 In addition, adverse events (AEs) such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), the severity of which often correlates with the pretreatment tumor burden, still represent significant challenges to current CAR-T cell therapy (Grade ≥3: 24% and 25%, respectively).6 Clinical Data FELIX (NCT04404660) is a Phase 1b/2, single-arm, open-label, multicenter, global study evaluating the safety and efficacy of obecabtagene autoleucel, an autologous 41BB-ζ anti-CD19 CAR T-cell therapy which uses an intermediate-affinity CAR designed to improve efficacy, with prolonged persistence and safety with lower rates of severe toxicity, in adult patients with R/R B-ALL.7 Eligible patients were ≥18 years of age with R/R CD19+ B-ALL who had either primary refractory disease (not achieving CR after two cycles of induction chemotherapy), had their first relapse following a remission lasting ≤12 months, were R/R after ≥2 prior lines of systemic therapy, or were R/R <3 months after allogeneic SCT. Patients with Ph+ ALL were eligible if intolerant to a tyrosine kinase inhibitor (TKI), had treatment failure with two lines of any TKI or one line of second-generation TKI, or if TKI was contraindicated. The study had phase 1b and phase 2 components. Phase 1b involved two cohorts: cohort 1A, for patients with morphologic disease (≥5% bone marrow blasts), and cohort 1B, for those with MRD (<5% bone marrow blasts). The phase 2 component involved a main pivotal cohort — cohort 2A, for patients with morphologic disease at enrollment — as well as two exploratory cohorts: cohort 2B, for patients with MRD, and cohort 2C, for those with isolated extramedullary disease. Bridging therapy was allowed at the physician’s discretion, however the use of blinatumomab as bridging therapy was not permitted. The primary endpoint for cohort 2A was overall remission: complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) by independent response review committee. Patients underwent leukapheresis followed by lymphodepletion with fludarabine 30 mg/m2 IV on Days -6, -5, -4, -3, and cyclophosphamide 500 mg/m2 IV on Day -6 and -5. 7 Following lymphodepletion, obecabtagene autoleucel was administered as a split dose infusion based on tumor burden (total target dose, 410 × 106 CD19 CAR-positive viable T cells) to proactively mitigate the risk of CRS and ICANS, particularly in patients with higher disease burden:7, 8 • Patients with low tumor burden (≤20% bone marrow blasts at lymphodepletion): Dose 1 = 100 ×106 at Day 1 and Dose 2 = 310 ×106 CAR T-cells at Day 10 • Patients with high tumor burden (>20% bone marrow blasts at lymphodepletion): Dose 1 = 10 ×106 at Day 1 and Dose 2 = 400 ×106 CAR T-cells at Day 10 In total, 153 patients with relapsed or refractory B-cell ALL were enrolled in the combined phase 1b–2 FELIX study. Obecabtagene autoleucel was successfully released for 146 of 153 patients (95.4%) at a median of 21 days (range, 18 to 50) after leukapheresis. Of the 153 enrolled patients, 127 (83.0%) received at least one obecabtagene autoleucel infusion and were evaluable; 26 of 153 did not receive an infusion, owing to physician choice in 1 patient, manufacturing failure in 7, and death or uncontrolled disease in 18. Four patients did not receive the full target dose owing to low manufacture yield7. Among the 94 infused patients in Cohort 2A, the median age was 50 years (range, 20-81), with 22% of patients aged ≥65 years. In total, 74% of patients were White, 31% were Hispanic or Latino, 11% were Asian, and 2% were Black or African American. Approximately 36% of patients had >75% blasts in bone marrow, 27% were Ph+ B-ALL, 20% had EMD at screening and 86% had history of CNS1 (no lymphoblasts in cerebrospinal fluid regardless of the white-cell count). Overall, 54% of patients were refractory to the last prior line of therapy, and 44% relapsed after first-line therapy within 12 months. The median number of prior lines of therapy was 2 (range, 1-6), with 31% receiving ≥3 prior lines of therapy. Prior blinatumomab or inotuzumab ozogamicin was received by 35% and 32% of patients, respectively, while 16% received both blinatumomab and inotuzumab ozogamicin. In addition, 38% had prior allogeneic SCT. Eighty-eight patients (94%) received bridging therapy for disease burden control, with chemotherapy alone in 59 patients (63%) and chemotherapy with inotuzumab in 8 patients (9%). The efficacy of obecabtagene autoleucel was established based on CR/CRi rates, duration of response (DOR), and event-free survival (EFS)in Cohort 2A at a median follow-up of 20.3 months (Table 1).7 Table 1. Key Efficacy Results in the FELIX Phase 2 Study Cohort 2Aa Efficacy Outcome Efficacy population (N=94) CR/CRi, % (95% CI) 77 (67-85) CR, % 55 CRi, % 21 Median DOR, months (95% CI) 14.1 (8.2-NR) Median EFS, months (95% CI) 9.0 (6.1-15.0) Median follow-up, 20.3 months. a Patients with R/R B-ALL and ≥5% bone marrow blasts at screening who received at least 1 infusion of obecabtagene autoleucel. CR, complete remission; CRi, complete remission with incomplete count recovery; DOR, duration of response; EFS: Event-free survival; NR, not reached Of the 91 of 127 patients with 5% or more bone marrow blasts before lymphodepletion, 68 of 91 (75%; 95% CI, 64 to 83) had overall remission (complete remission or complete remission with incomplete hematologic recovery). A total of 62 of 68 patients with a response had MRD data available, and 58 of 62 (94%) were MRD-negative after obecabtagene autoleucel infusion. CR/CRi rates were generally high, even in high-risk subgroups: prior allogeneic SCT therapy (84%); >75% bone marrow blasts pre-lymphodepletion (65%); CNS1 status at screening (76%); and presence of EMD prior to lymphodepletion (59%). Efficacy for all the patients who received at least one obecabtagene autoleucel infusion is summarized on Table 2. Bone marrow burden before lymphodepletion correlated with Event-free survival (EFS) and Overall survival (OS). Table 2. Key Efficacy Results in the FELIX Study on all patients receiving at least one obecabtagene autoleucel infusion across cohortsa Efficacy Outcome Efficacy population (N=127) Bone marrow blasts before lymphodepletion <5% (N=36) ≥5-≤75% (N=51) >75%(N=40) CR/CRi, % (95% CI) 78 (70-85) 86 (71-95) 82 (69-92) 65 (48-79) Median EFS, months (95% CI) 11.9 (8-22.1) NR 15.0 (6.1-NR) 5.1 (1.6-9.0) 12-month EFS, % 50 68 55 25 Median OS, months (95% CI) 15.6 (12.9-NR) NR 15.6 (10.6-NR) 12.8 (6.9-15.3) 12-month OS, % 61 72 59 55 Median follow-up, 21.5 months (range, 8.6-41.4).aPatients who received at least 1 infusion of obecabtagene autoleucel across all cohorts of FELIX: Cohort A (≥5% blasts in bone marrow at screening, n=107); Cohort B (MRD-positive at screening, n=13); and Cohort C (isolated EMD at screening, n=7). CR, complete remission; CRi, complete remission with incomplete count recovery; EFS, event-free survival; NR, not reached; OS, overall survival. The safety of obecabtagene autoleucel was evaluated across all cohorts of the FELIX study.7 The severity of AEs was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy/American Society for Blood and Marrow Transplantation (ASTCT/ASBMT) consensus grading. The most common AEs (≥20%) were CRS (69%), pyrexia (29%), nausea (26%), diarrhea (25%), febrile neutropenia (24%), anemia (24%), headache (24%), neutropenia (23%), ICANS (23%), hypotension (22%), hypokalemia (21%), and neutrophil count decreased (20%). The most common Grade 3/4 AEs (≥5%) were febrile neutropenia (24%), anemia (21), neutropenia (21%), neutrophil count decreased (20%), platelet count decreased (13%), thrombocytopenia (13%), pneumonia (7%), ICANS (7%), hypokalemia (6%), and hypotension (5%). A low rate of grade ≥3 CRS and ICANS was observed, with rates lower than reported with currently available autologous CAR T-cell therapy in adults with R/R B-ALL, including in patients with <5% and >75% bone marrow blasts before lymphodepletion (Table 3). There were two (2%) deaths attributed to obecabtagene autoleucel: one patient died of neutropenic sepsis and one died of acute respiratory distress syndrome with ongoing ICANS. Table 3. Key Safety Results in the FELIX Phase 2 Study Across Cohortsa Safety population (N=127) Bone marrow blasts before lymphodepletion Grade ≥3 AEs of Special Interest, N <5% (N=36) ≥5-≤75% (N=51) >75% (N=40) CRS 3 0 2 1 ICANS 9 0 4 5 a Patients who received at least 1 infusion of obecabtagene autoleucel from all cohorts of FELIX: Cohort A (≥5% blasts in bone marrow at screening, n=107); Cohort B (MRD-positive at screening, n=13); and Cohort C (isolated EMD at screening, n=7). CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity. We appreciate the opportunity to submit this information for consideration by the NCCN Guidelines® ALL Panel. If you have any questions or require additional information, please do not hesitate to contact us via phone 312-933-8213 or email at J.Bassali@autolus.com Sincerely, Jan Bassali, PharmD Vice President, Medical Affairs Autolus Enclosures References below. References 1. Gökbuget N, , et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012; 120(10):2032–41. 2. Kantarjian HM, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer. 2010;116(24):5568–74. 3. Geyer MB, et al. Overall survival among older US adults with ALL remains low despite modest improvement since 1980: SEER analysis. Blood. 2017;129 (13): 1878–1881. 4. Kantarjian H, et al. Blinatumomab for Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376:e49. 5. Kantarjian HM, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125:2474-2487. 6. Shah BD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398:491-502. 7. Roddie C, et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. N Engl J Med. 2024; 10.1056/NEJMoa2406526. Online ahead of print 8. Auctazyl® [package insert]. Gaithersburg, MD,: Autolus, Inc.; 2024.
