McKesson Corporation · NYSE:MCK
McKesson — Technical Presentation
60 slides from McKesson's technical presentation
Slide 1: CAR-T in Community Oncology Practice
CAR-T in Community Oncology Practice Houston Holmes MD MBA FACP Texas Oncology PA Baylor/Charles A Sammons Cancer Center Dallas, TX
Slide 2: CAR-Modified T Cells for ALL: patient history
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia The patient was a 7-year-old girl with a second recurrence of ALL diagnosed 2 years earlier. A remission with a negative test for minimal residual disease had been achieved, then she had a relapse 17 months after the original dia
Slide 3: CAR-Modified T Cells for ALL: cell collection and infusion
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia Peripheral-blood mononuclear cells (PBMCs) were collected by means of apheresis before administration of the intensive chemotherapy, with the anticipation that there might be an insufficient number of circulating T cells availabl
Slide 4: CTL019 infusion and toxicity course
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia She did not receive lymphocyte-depleting chemotherapy before treatment with the CTL019 infusions, with the most recent cytotoxic therapy having been given 6 weeks before CTL019 infusion. No immediate infusion-related toxic effect
Slide 5: Clinical Responses to CTL019 Infusion in Two Children with ALL
Clinical Responses to CTL019 Infusion in Two Children with Relapsed, Chemotherapy-Refractory Acute Lymphoblastic Leukemia (ALL). Grupp SA et al. N Engl J Med 2013;368:1509- 1518
Slide 6: Chimeric Antigen Receptor T-cell Therapy Headlines
Chimeric Antigen Receptor T-cell Therapy Headlines CAR T-Cell Immunotherapy Named Advance of the Year in Annual ASCO Report Immunotherapy: Tisagenlecleucel — the first approved CAR T- cell therapy: implications for payers and policy makers ‘A new frontier:’ US FDA approves Novartis’ $475,000 CAR-T c
Slide 7: Immunoglobulin-T-cell receptor chimeric molecules (1989 paper)
Proc. Natl. Acad. Sci. USA Vol. 86, pp. 10024-10028, December 1989 Immunology Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity (chimeric genes /antibody variable region) GIDEON Gross, TovA WAKS, AND ZELIG ESHHAR* Department of Che
Slide 8: TcR constant domain fused to antibody variable domains
TcR constant domain fused to the antibody’s variable domains… endowed the T cells with a non-MHC-restricted response… chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for t-cell activation and execution of effector function...
Slide 9: T cells from any individual
T cells from any individual… This approach can be exploited...to direct cytotoxic T lymphocytes to kill tumor...
Slide 10: General structure of CAR
General structure of CAR Batlevi, C. L. et al. (2015) Novel immunotherapies in lymphoid malignancies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.187
Slide 11: Chimeric antigen receptors
Chimeric antigen receptors Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Slide 12: A schematic of anti-CD19 CAR T cell therapy
A schematic of our current approach to anti-CD19 CAR T cell therapy Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Slide 13: CAR-Modified T Cells for Acute Lymphoid Leukemia
Original Article: Brief Report Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia Stephan A. Grupp, M.D., Ph.D., Michael Kalos, Ph.D., David Barrett, M.D., Ph.D., Richard Aplenc, M.D., Ph.D., David L. Porter, M.D., Susan R. Rheingold, M.D., David T. Teachey, M.D., Anne Chew, Ph.D
Slide 14: CTL019 expansion and remission
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia CTL019 cells expanded in the peripheral blood and bone marrow to levels that were more than 1000 times as high as the original engraftment levels. Severe cytokine-release syndrome developed. A single course of anticytokine therap
Slide 15: Tisagenlecleucel in Children and Young Adults with B-Cell ALL
Original Article Tisagenlecleucel in Children and Young Adults with B- Cell Lymphoblastic Leukemia Shannon L. Maude, M.D., Ph.D., Theodore W. Laetsch, M.D., Jochen Buechner, M.D., Ph.D., Susana Rives, M.D., Ph.D., Michael Boyer, M.D., Henrique Bittencourt, M.D., Ph.D., Peter Bader, M.D., Michael R.
Slide 16: ELIANA study design and patients
ELIANA 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary endpoint was the overall remission rate. 75 patients received an infusion of tisagenlecleucel, with a median time from enrollment to infusion of 45 days.
Slide 17: ELIANA remission and survival results
ELIANA The overall remission rate was 81% 60% had complete remission and 21% had complete remission with incomplete hematologic recovery. All patients who had a best overall response of complete remission with or without complete hematologic recovery were negative for minimal residual disease; 95% (
Slide 18: Duration of Remission, Event-free Survival, and Overall Survival
Duration of Remission, Event-free Survival, and Overall Survival. Maude SL et al. N Engl J Med 2018;378:439- 448
Slide 19: ELIANA adverse events of special interest
ELIANA Adverse events of special interest included: ● cytokine release syndrome ● neurologic events ● cytopenias not resolved by day 28 ● infections ● tumor lysis syndrome 67 of 75 patients (89%) had an adverse event of special interest within 8 weeks after infusion N Engl J Med, 378(5):439-448, Feb
Slide 20: Cytokine Release Syndrome
ELIANA Cytokine Release Syndrome ● occurred in 58 of 75 patients (77%) ● the median time to onset was 3 days (range, 1 to 22) ● median duration was 8 days (range, 1 to 36) 35 of 75 patients (47%) were admitted to the intensive care unit (ICU) for CRS ● median stay of 7 days (range, 1 to 34) ● 25% tr
Slide 21: Neurologic events
ELIANA Neurologic events occurred in 30 of 75 patients (40%) within 8 weeks after infusion. Ten patients (13%) had grade 3 neurologic events; no grade 4 events reported. The most common neurologic events of any grade were: ● encephalopathy (11%) ● confusional state (9%) ● delirium (9%) ● tremor (8%)
Slide 22: Conclusions
Conclusions • In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects.
Slide 23: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
Original Article Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma Sattva S. Neelapu, M.D., Frederick L. Locke, M.D., Nancy L. Bartlett, M.D., Lazaros J. Lekakis, M.D., David B. Miklos, M.D., Ph.D., Caron A. Jacobson, M.D., M.M.Sc., Ira Braunschweig, M.D., Olalekan O. Ol
Slide 24: ZUMA-1 patient characteristics
ZUMA-1 101 patients received axi-cel, median age 58, range 23-76 ● diffuse large B-cell lymphoma n=77 ● primary mediastinal B-cell lymphoma n=8 ● transformed follicular lymphoma n=16 Patients had refractory disease which was defined as progressive or stable disease as the best response to the most r
Slide 25: ZUMA-1 response results
ZUMA-1 101 patients received axi-cel ● objective response rate 82% ● complete response rate 54% ● median time to response 1.0 month (range, 0.8 to 6.0) ● median duration of response 8.1 months ● progression-free survival 49% at 6 months, 44% at 12 months ● overall survival 78% at 6 months, 59% at 12
Slide 26: Kaplan–Meier Estimates of Response, PFS and Overall Survival
Kaplan–Meier Estimates of the Duration of Response, Progression-free Survival, and Overall Survival. Neelapu SS et al. N Engl J Med ;377:2531-2544
Slide 27: Objective Response Rate among Treated Patients
Objective Response Rate among the 101 Treated Patients. Neelapu SS et al. N Engl J Med ;377:2531-2544
Slide 28: ZUMA-1 adverse events
ZUMA-1 All 101 patients who had received axi-cel had adverse events, grade 3 or higher in 95%. The most common adverse events of grade 3 or higher were neutropenia (in 78%), anemia (in 43%), and thrombocytopenia (in 38%). 43% of patients received tocilizumab and 27% received glucocorticoids for the
Slide 29: ZUMA-1 cytokine release syndrome and neurologic events
ZUMA-1 The cytokine release syndrome occurred in 94 patients (93%) ● 9% of grade 3 and 3% of grade 4, most commonly fever, hypoxia, hypotension ● Vasopressors were used in 17% of the patients. ● Median time after infusion until the onset of CRS was 2 days (range, 1 to 12) ● Median time until resolut
Slide 30: Conclusions
Conclusions • In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
Slide 31: TRANSCEND-1552 JCAR017 Preliminary Safety Profile
TRANSCEND-1552 Preliminary Safety Profile of the CD19-Directed Defined Composition CAR T Cell Product JCAR017 in Relapsed/Refractory Aggressive B-NHL Patients: Potential for Outpatient Administration ASH 2017 JCAR017 is a CD19-directed 4-1BB CAR T cell product administered in a defined composition a
Slide 32: Three-step approach to managing acute CAR-T toxicities
Three-step approach to the assessment and management of acute toxicities associated with chimeric antigen receptor (CAR)-T-cell therapy Neelapu, S. S. et al. (2017) Chimeric antigen receptor T-cell therapy — assessment and management of toxicities Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.14
Slide 33: Treatment algorithm for management of CRS
Treatment algorithm for management of CRS based on the revised CRS grading system. Daniel W. Lee et al. Blood 2014;124:188-195 ©2014 by American Society of Hematology
Slide 34: CAR T-cell therapy program
CAR T-cell therapy program ● PBMC collection--apheresis ● Pharmacy ● Toxicity management ● Nursing services ● FACT/CIBMTR accreditation/REMS ● Social work ● Consultant support-- Critical care, Neurology, ID, Cardiology, ED
Slide 35: Kymriah $475,000 Yescarta $373,000
Kymriah $475,000 Yescarta $373,000 1. All major payers have approved coverage for CAR-T therapy. 2. Cost for CAR-T therapy very high, so major payers are accessing Transplant Network agreements for this treatment (Optum, Aetna Institutes of Excellence, CIGNA LifeSource, etc). 3. Most manufacturer pr
Slide 36: Clinical case study
Clinical case study Neelapu, S. S. et al. (2017) Chimeric antigen receptor T-cell therapy — assessment and management of toxicities Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.148
Slide 37: Modifications in CAR design
Modifications in CAR design Less immunogenic scFv + Evaluation of different co-stimulatory domains (CD28, ae Icos, Cee i *+ Optimize structure of hinge region Expand repertoire of CAR antigens (e.g. CD20, CD22, CD30, and k-light chain) I aipravernants ta vector design * Incorporation of suicide gene
Slide 38: Texas Oncology
A TEXAS) ZONCOLOGY as
Slide 39: CAR T Cells in Multiple Myeloma
CAR T CELLS IN MULTIPLE MYELOMA Jesús G. Berdeja, M.D. Director of Multiple Myeloma Research Sarah Cannon Research Institute Tennessee Oncology
Slide 40: Improving Survival in MM
Improving Survival in MM 1.0 1960–1965 0.9 1965–1970 1970–1975 0.8 1975–1980 Proportion Surviving 0.7 1980–1985 0.6 1985–1990 1990–1995 0.5 1995–2000 0.4 2000–2005 0.3 2005–2010 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Follow Up From Diagnosis (Years) Adapted from Kumar SK et al. Leukemia. 2014;28:11
Slide 41: Despite Progress in Multiple Myeloma There Remains a Need for New Therapies
Despite Progress in Multiple Myeloma There Remains a Need for New Therapies Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD.
Slide 42: Current U.S. Standard of Care in 4th Line MM
Current U.S. Standard of Care in 4th Line MM Current U.S. Standards of Care For Multiple Myeloma 4th Line of Therapy Pomalyst and dex. Daratumamab (Pomalyst Product Monograph) (Lancet 2016, Lonial, S) N 452 106 • ≥2 prior therapies (including REVLIMID and • Previously treated with at least bortezomi
Slide 43: CAR T Cells against CD19 for Multiple Myeloma
CAR T Cells against CD19 for Multiple Myeloma. CASE Report “A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg
Slide 44: Rationale for CTL019 in Multiple Myeloma
Rationale for CTLO19 in Multiple Myeloma * CTLO19: Anti-CD19 CAR T cells (lentiviral gene transfer, CD3zeta/4-1BB signaling domains) with clinical activity in advanced CLL, ALL, and NHL. i ¢ Minor CD19+ components of the myeloma clone CD19 Clonotypic can be identified in patients. Myeloma Bells PC s
Slide 45: Study Design and Patient Characteristics
Study Design and Patient Characteristics High-dose EX x eatures Se 1 48F 10 140 Eligibility Criteria han wv Melphalan + CTLO19 Complex karyotype, ple Myeloma i Progression within Auto-SCT 5x10’ cells +(4;14), del17p, +1q21 one year of te } > Complex karyotype, prior ASCT Ta-14 DAYS > FOLLOW 2 58M (3
Slide 46: Clinical Responses
Clinical Responses Day 100 Response ¢ 2/10 subjects had substantially longer = —> VOPR °% progression-free survival after ASCT + PD 02 CTLO19 compared to prior ASCT. VOPR 08 . . . = 05 asct #1 * Compares favorably with historical _ 08 IB ASCT +CTLO19 cohort of 18 salvage transplants in a » . VGPR 07
Slide 47: BCMA – A Promising Target in Multiple Myeloma
BCMA – A Promising Target in Multiple Myeloma • BCMA is member of the TNF receptor superfamily • Receptor for BAFF and APRIL • Promotes plasma cell pathogenesis • Expressed nearly universally on multiple myeloma cells • Expression largely restricted to plasma cells and some mature B cells Multiple m
Slide 48: BCMA-Directed CAR T Cells in Multiple Myeloma
BCMA-Directed CAR T Cells in Multiple Myeloma NCI PENN BB2121 (NOVARTIS) BLUEBIRD LCAR-B38M LEGEND MCARH171 MSK/JUNO TARGET BCMA BCMA BCMA BCMA (2 epitopes) BCMA Ag-binding scFv (M) scFv (H) scFv (M) 2-VHH (H) scFv (H) domain VECTOR ϒ-Retroviral Lentiviral Lentiviral Lentiviral Lentiviral COSTIMULAR
Slide 49: BCMA-Directed CAR T Cells in Multiple Myeloma: results
BCMA-Directed CAR T Cells in Multiple Myeloma NCI (NOVARTI PENN BB2121 BLUEBIRD LCAR-B38M LEGEND MCARH171 MSK/JUNO S) Population 26 (16*) 24 (19*) 21 (18*) 35 (30*) 6 # Prior Tx 10 7 7 3-4 7.5 CART Dose 9x106/kg 1-5X108 150-800 x106 Varied ? ORR 81%* 53%* 94%* 100% NR CR 18% 56% 63% (sCR) NR CRS (Al
Slide 50: CRB-401 Study Design and Status
CRB-401 Study Design and Status Study Status 3 + 3 Dose Escalation of CAR+ T Cells (Escalation Phase) Cells Collected *1200 x 106 dose cohort no longer planned N=24 1st Response Clinical deterioration bb2121 bb2121 prior to infusion n=3 manufacturing Assessment (Wk 4) Leukapheresis infusion Dosed Ma
Slide 51: Baseline Demographics, Clinical Characteristics and Treatment History
Baseline Demographics, Clinical Characteristics and Treatment History 21 patients have received bb2121 as of the data cut-off of October 2, 2017 from Dose Escalation Demographics and Clinical Characteristics Median follow-up is 35 weeks (min, max: 6.6, 69) MM Treatment History Dosed Patients Dosed P
Slide 52: Dose Escalation Select TEAEs; Generally Well Tolerated
Dose Escalation Select TEAEs; Generally Well Tolerated • No dose-limiting toxicities (DLTs) observed in dose Dose Escalation Patients (N = 21)1 escalation Overall Grade 3 or higher • Cytopenias mostly related to Preferred Term n (%) n (%) Cy/Flu lymphodepletion Cytokine release syndrome 15 (71) 2 (1
Slide 53: Robust bb2121 CAR+ T Cell Expansion with Persistence > 6 months
Robust bb2121 CAR+ T Cell Expansion with Persistence > 6 months Robust bb2121 CAR+ T Cell Expansion with Persistence > 6 months Vector Copies in CD3-enriched Peripheral Blood by Vector Median Copies (Q1,in Q3) CD3-enriched Vector Copies Peripheral in CD3-enriched Blood by Individual Patients Periphe
Slide 54: Deep and Durable Tumor Response in Active Dose Cohorts
High Frequency of Deep and Durable Tumor Response in Active Dose Cohorts (150 – 800 × 106 CAR+ T Cells) • 800 x 106 *15 U 17/18 (94%) ORR, 10/18 14 (56%) CR at active doses 11 • 9/10 evaluable patients MRD negative *12 *21 † • Durable ongoing responses *18 over 1 year • 450 x 106 *16 Responses conti
Slide 55: Legend LCAR-B38M patient characteristics
Legend LCAR-B38M patient characteristics Characteristic Cohort r/r MM patient, total number enrolled 35 Median age (range), years 55 (43-72) Male, n(%) 19(54) Number of prior lines of therapy, 14 (40)/ 16 (46)/ 5 (14) n(%) 3/4/≥5 Refractory subgroup, n(%) 35(100) Refractory to ≥ 2nd line therapy Zha
Slide 56: Safety: Major adverse event is cytokine release syndrome
Safety: Major adverse events is cytokine release syndrome Safety: Major adverse events is Cytokine Release cytokine release syndrome Adverse Event, n (%) Syndrome Patients (N=35) 20 17 CRS (All Grade) 29 (83%) 15 10 CRS Grade ≥3 2 (5.7%) 10 6 5 2 Serious adverse event 0 (0) 0 Fatal events excluding
Slide 57: Efficacy follow-up of LCAR-B38M CAR-T cells
Efficacy follow-up of LCAR-B38M CAR-T cells Patients Treated Total PR VGPR sCR Before April 5, 2017 Best Efficacy 30* 2 9 19 % 100% 6.7% 30% 63.3% - 30 of 35 Patients evaluable for response - 3 Patients have relapsed - LCAR-B38M cells are undetectable in PB beyond 4 months post-infusion - 5 Patients
Slide 58: Future Directions in Myeloma
Future Directions in Myeloma ● Race to FDA Approval ○ Global Pivotal Trial (KarMMa) is open for enrollment ■ bb2121 dose range: 150-300 × 106 CAR+ T cells ○ Legend in partnership with Janssen soon to start pivotal trial of LCAR-B38M ○ Others not far behind ● Some of the New and Improved CARs in Clin
Slide 59: Future Directions
Future Directions ● Improving Efficacy ○ Understand mechanisms of resistance ○ Identify correlates to response & long-term survival ○ Next-generation or “armored” CAR T cells ● ○ Improving Safety Combination with immune checkpoint blockade ○ Identify correlates to predict and reduce rates of CRS & N
Slide 60: Thank You
THANK YOU