THERAPEUTIC ADVANCES IN HODGKIN AND T-CELL LYMPHOMAS

Transcription

1 THERAPEUTIC ADVANCES IN HODGKIN AND T-CELL LYMPHOMAS Jakub Svoboda, MD UPDATE IN HEMATOLOGIC MALIGNANCIES with Proceedings from International Medical Meetings January 26, 2018

2 DISCLOSURES Jakub Svoboda Research funding: Seattle Genetics, BMS, Merck, Celgene, Pharmacyclics Consultancy: Seattle Genetics, BMS, Kite, Kyowa 2

3 American Society of Hematology Annual Meeting and Exposition December 9-12, 2017 Atlanta, GA 3

4 OUTLINE: Classical Hodgkin lymphoma: Frontline ABVD vs AVD plus BV for stage III and IV Nivolumab plus AVD for stage IIB, III, and IV Relapsed/refractory disease Nivolumab/brentuximab as first salvage Nivolumab therapy beyond progression Real world data with PD-1 inhibitors Non-viral RNA CART19 T-cell lymphomas: Mogamuzulimab vs vorinostat for relapsed CTCL 4

5 HODGKIN LYMPHOMA: FRONTLINE TREATMENT 5

6 Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) as Frontline Therapy Demonstrates Significantly Improved Modified Progression-Free Survival versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma: The Phase 3 ECHELON-1 Study Joseph M. Connors, Wojciech Jurczak, David J. Straus, Stephen M. Ansell, Won Seog Kim, Andrea Gallamini, Anas Younes, Sergey Alekseev, Árpád Illés, Marco Picardi, Ewa Lech-Maranda, Yasuhiro Oki, Tatyana Feldman, Piotr Smolewski, Kerry J. Savage, Nancy L. Bartlett, Jan Walewski, Robert Chen, Radhakrishnan Ramchandren, Pier Luigi Zinzani, David Cunningham, Andras Rosta, Neil C. Josephson, Eric Song, Jessica Sachs, Rachael Liu, Hina A. Jolin, Dirk Huebner, John Radford Slides: courtesy of Dr. Connors

7 ECHELON-1: Open-label, global, randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced chl 218 study sites in 21 countries worldwide Follow-up Screening CT/PET scan 1:1 randomization (N=1334) ABVD x 6 cycles (n=670) A+AVD x 6 cycles (n=664) Brentuximab vedotin: 1.2 mg/kg IV infusion Days 1 & 15 EOT CT/PET scan Every 3 months for 36 months, then every 6 months until study closure Inclusion criteria chl stage III or IV ECOG PS 0, 1 or 2 Age 18 years Measurable disease Adequate liver and renal function chl, classic Hodgkin lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EOT, end-of-treatment; PFS, progression-free survival Slides: courtesy of Dr. Connors

8 ECHELON-1: Primary endpoint definition Primary endpoint: modified PFS per IRF A modified PFS event was defined as the first of: Progression Death from any cause PET6 = D3, 4, 5 after completion of frontline therapy followed by subsequent anticancer therapy D, Deauville score; Dx, diagnosis; IRF, independent review facility; PD, progressive disease; PET6, end-of-cycle-6 PET; Tx, treatment Slides: courtesy of Dr. Connors

9 Disease characteristics comparable between A+AVD and ABVD Baseline patient characteristics A+AVD N=664 ABVD N=670 Male, % Not Hispanic or Latino, % White, % Median age, years (range) 35 (18 82) Age, years, % < Median time since initial diagnosis, months Region, % Americas Europe Asia 37 (18 83) Baseline disease characteristics Ann Arbor stage, % III IV IPS risk factors, %* ECOG PS, % A+AVD N=664 *Percentages do not total 100% due to rounding; Unknown/missing data for 5% and 4% in the A+AVD and ABVD groups, respectively; IPS, International Prognostic Score ABVD N= B symptoms, % Bone marrow involvement, % Sites of extranodal involvement, % None 1 > Slides: courtesy of Dr. Connors

10 Modified PFS per independent review Probability of modified PFS HR 0.77 (95% CI: ) Log-rank test p-value: A+AVD ABVD Censored Censored Number of events Category A+AVD N=117 ABVD N=146 Progression Death Modified progression Chemotherapy Radiotherapy Time from randomization (months) No. of patients at risk: A+AVD ABVD Modified PFS estimates Time 2- year A+AVD (95% CI) 82.1 ( ) ABVD (95% CI) 77.2 ( ) Median follow-up (range): 24.9 months ( ) Slides: courtesy of Dr. Connors

11 Forest plot of modified PFS per IRF: subgroup analysis Event / N (%) Subgroup A+AVD ABVD Overall 117/664 (17.6) 146/670 (21.8) 0.77 ( ) Age <60 years 93/580 (16.0) 117/568 (20.6) 0.73 ( ) Age 60 years 24/84 (28.6) 29/102 (28.4) 1.01 ( ) Age <45 years 70/451 (15.5) 83/423 (19.6) 0.73 ( ) Age 45 years 47/213 (22.1) 63/247 (25.5) 0.86 ( ) Region: Americas 41/261 (15.7) 58/262 (22.1) 0.65 ( ) Region: North America 38/250 (15.2) 57/247 (23.1) 0.60 ( ) Region: Europe 62/333 (18.6) 74/336 (22.0) 0.83 ( ) Region: Asia 14/70 (20.0) 14/72 (19.4) 0.91 ( ) IPS: /141 (15.6) 25/141 (17.7) 0.83 ( ) IPS: /354 (16.1) 68/351 (19.4) 0.79 ( ) IPS: /169 (22.5) 53/178 (29.8) 0.70 ( ) Stage III 40/237 (16.9) 43/246 (17.5) 0.92 ( ) Stage IV 77/425 (18.1) 102/421 (24.2) 0.71 ( ) B symptoms: Present 77/399 (19.3) 94/381 (24.7) 0.74 ( ) B symptoms: Absent 40/265 (15.1) 52/289 (18.0) 0.79 ( ) Extranodal sites: 0 40/217 (18.4) 39/228 (17.1) 1.04 ( ) Extranodal sites: 1 36/217 (16.6) 45/223 (20.2) 0.75 ( ) Extranodal sites: >1 39/194 (20.1) 57/193 (29.5) 0.67 ( ) Gender: Male 64/378 (16.9) 90/398 (22.6) 0.71 ( ) Gender: Female 53/286 (18.5) 56/272 (20.6) 0.86 ( ) Hazard ratio Favors A+AVD Favors ABVD Hazard ratio (95% CI) Slides: courtesy of Dr. Connors

12 Most clinically important treatment-emergent adverse events Incidence (any grade) 20% + febrile neutropenia A+AVD (N=662) ABVD (N=659) Common adverse events, %* Any grade Grade 3 Any grade Grade 3 Neutropenia Constipation <1 Vomiting Fatigue Peripheral sensory <1 neuropathy Diarrhea <1 Pyrexia Peripheral neuropathy <1 Abdominal pain <1 Stomatitis <1 Febrile neutropenia *Partial list focusing on the most clinically important adverse events. Adverse events ( 20% any grade in either arm) excluded from the table include nausea, alopecia, weight decreased, and anemia Slides: courtesy of Dr. Connors

13 Summary of deaths during treatment and during follow-up Patient (n) Neutropenia or associated 5 complications* n=7 0 Deaths during treatment 9 (1%) A+AVD 13 (2%) ABVD Associated with pulmonaryrelated toxicity n=11 *All neutropenia-associated deaths occurred in patients who had not received G-CSF primary prophylaxis before the onset of neutropenia with the exception of 1 patient who entered the trial with pre-existing neutropenia Patient (n) Deaths during follow-up 19 (3%) A+AVD Total deaths during treatment plus deaths during follow-up: A+AVD: n=28; ABVD: n=39 26 (4%) ABVD Slides: courtesy of Dr. Connors

14 Summary and Conclusions ECHELON-1 results Significantly superior modified PFS with brentuximab vedotin in combination with AVD compared to ABVD 23% reduction in risk of progression, death or need for additional anticancer therapy 2-year modified PFS 82% vs 77% Manageable toxicity profile Bleomycin can be omitted G-CSF primary prophylaxis is recommended for all patients 67% of pts with PN in the A+AVD arm had resolution or improvement by 1 grade at last follow-up Slides: courtesy of Dr. Connors

15 Slides: courtesy of Dr. Ramchandren

16 Slides: courtesy of Dr. Ramchandren

17 Slides: courtesy of Dr. Ramchandren

18 Slides: courtesy of Dr. Ramchandren

19 Slides: courtesy of Dr. Ramchandren

20 HODGKIN LYMPHOMA: RELPASED/REFRACTORY DISEASE 20

21 Interim Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma Alex F. Herrera 1, Alison J. Moskowitz 2, Nancy L. Bartlett 3, Julie M. Vose 4, Radhakrishnan Ramchandren 5, Tatyana A. Feldman 6, Ann S. LaCasce 7, Stephen M. Ansell 8, Craig H. Moskowitz 2, Keenan Fenton 9, Carol Anne Ogden 9, David Taft 9, Qu Zhang 9, Kazunobu Kato 10, Mary Campbell 9, Ranjana H. Advani 11 1 City of Hope National Medical Center, Duarte, CA, USA; 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3 Washington University School of Medicine, St. Louis, MO, USA; 4 University of Nebraska Medical Center, Omaha, NE, USA; 5 Karmanos Cancer Institute, Detroit, MI, USA; 6 Hackensack University Medical Center, Hackensack, NJ, USA; 7 Dana Farber Cancer Institute, Boston, MA, USA; 8 Mayo Clinic, Rochester, MN, USA; 9 Seattle Genetics, Inc., Bothell, WA, USA; 10 Bristol-Myers Squibb, Princeton, NJ, USA; 11 Stanford University Medical Center, Palo Alto, CA, USA American Society of Hematology Annual Meeting; Atlanta, Georgia, December 9 12, 2017, Abstract #649 Slides: courtesy of Dr. Alex F. Herrera

22 Methods Patients received treatment every 3 weeks (1 cycle) for up to 12 weeks (4 cycles) Cycle 1: BV was given on Day 1 and Nivo on Day 8 Cycles 2 4: Both BV and Nivo were given on Day 1 Samples for biomarker analyses were taken on Days 1, 8, and 15 of Cycle 1; Days 1 and 8 of Cycle 2; Day 1 of Cycles 3 and 4; and at EOT After completion of the EOT response assessment, patients were eligible to undergo ASCT AEs were recorded from the start of treatment through 100 days post last dose of Nivo including the ASCT period, as applicable Slides: courtesy of Dr. Alex F. Herrera

23 Patient Characteristics and Disposition n=62 Age (y), median (range) 36 (18 to 69) Gender, n (%) Male 30 (48) Female 32 (52) Disease stage at initial diagnosis, n (%) I/II 37 (60) III/IV 24 (39) Unknown 1 (2) Prior systemic therapy regimens, n (%) ABVD / ABVE-PC / R-ABVD 59 (95) BEACOPP * 2 (3) Stanford V 2 (3) Disease status relative to frontline treatment, n (%) Primary refractory 28 (45) Relapsed, remission duration 1 year 19 (31) Relapsed, remission duration >1 year 15 (24) * One patient received BEACOPP after discontinuing ABVD due to inadequate interim response 62 patients enrolled; 61 patients received at least one dose of study drug 58 patients completed all 4 cycles of BV + Nivo** 4 patients discontinued from the study early: Patient decision, non-ae (n=2) Investigator decision (n=1) Adverse event (n=1, peripheral neuropathy) ** One patient discontinued prior to receiving study treatment; one patient withdrew consent after Cycle 1; one patient discontinued after Cycle 2 due to lack of response; one patient discontinued during Cycle 4 BV administration due to an AE Slides: courtesy of Dr. Alex F. Herrera

24 Immune-Related Adverse Events Potential immune-related adverse events (IrAEs, based on a predefined list of preferred terms) occurred in 50 patients (82%), excluding IRRs 5 patients received systemic steroids for treatment of an IrAE: Grade 3 diarrhea and Grade 2 colitis Grade 3 aspartate aminotransferase elevation Grade 4 colitis and Grade 4 pneumonitis (both after receiving additional salvage therapy) Grade 2 pneumonitis Grade 4 pneumonitis (after BEAM, as part of the conditioning regimen) No patients discontinued treatment due to an IrAE Slides: courtesy of Dr. Alex F. Herrera

25 Tumor Response Objective response rate (CR + PR) n (%) 50 (83) Complete response 37 (62) Deauville score = 1 14 (23) Deauville score = 2 15 (25) Deauville score = 3 7 (12) Deauville score = 5 * 1 (2) Partial response 13 (22) Deauville score = 4 7 (12) Deauville score = 5 6 (10) 95% CI 72, 92 48, 74 12, 34 Stable disease 5 (8) 3, 18 Deauville score = 5 5 (8) Progressive disease 4 (7) 2, 16 Deauville score = 5 4 (7) Clinical progression 1 (2) * Residual area of FDG-avidity on PET was biopsied and was not consistent with residual Hodgkin lymphoma SPD change from baseline SUV change from baseline Efficacy Evaluable Patients (n=60) 83% ORR, 62% CR among efficacy evaluable patients (n=60) (82% ORR, 61% CR among all treated patients,; n=61) Slides: courtesy of Dr. Alex F. Herrera

26 ASCT and Long-Term Follow-up ASCT Summary Treatment with BV + Nivo did not appear to impact stem cell mobilization and collection yields or engraftment Follow-up 41 of 42 patients with ASCT post-bv + Nivo remain in follow-up Patients did not appear to have increased toxicity during or after the transplant period ASCT Mobilization and Engraftment Median days of apheresis sessions (range) Median number of CD34+ cells (10 6 cells/kg) harvested (range) Median days to neutrophil engraftment (range) Median days to platelet engraftment (range) n=44 * 2 (1 to 4) 4.7x10 6 (3 to 60) 11.5 (8 to 29) 16 (7 to 63) * Stem cell mobilization/engraftment data includes all 42 patients who underwent ASCT post-bv + Nivo and 2 patients who underwent ASCT post-subsequent salvage therapy 16 of 17 patients with salvage therapy post-bv + Nivo remain in follow-up Median follow-up time: 8 months Median DOR not reached 6 month PFS: 89% (95% CI: 75%, 95%) Slides: courtesy of Dr. Alex F. Herrera

27 Conclusions A high ORR was demonstrated with BV + Nivo (83%), with a 62% CR rate among efficacy evaluable patients BV + Nivo was well-tolerated in patients with classical R/R HL: 44% of patients experienced IRRs, of whom, 41% had Gr 1 or 2 and 3% had Gr 3 No patients discontinued treatment due to IRRs <10% of patients had potential IrAEs requiring treatment with systemic steroids No patients discontinued treatment due to an IrAE Treatment with BV + Nivo did not adversely impact mobilization and stem cell collection; patients were able to proceed to ASCT uneventfully BV + Nivo treatment appeared to result in: Increased circulating T cell numbers, and increased innate and adaptive immune activating cytokines and chemokines Increased ability of memory T cells to mount an immune response, potentially leading to increased ability of patients immune system to fight disease A high proportion of patients with classical R/R HL achieved a CR with this chemotherapy-free regimen. The encouraging activity of BV + Nivo will be further evaluated in multiple settings, including a pivotal phase 3 trial in patients with advanced HL who are ineligible for ASCT or after failure of ASCT (CheckMate 812, NCT ) Slides: courtesy of Dr. Alex F. Herrera

28 Slides: courtesy of Dr. Jonathon B. Cohen

29 Slides: courtesy of Dr. Jonathon B. Cohen

30 Slides: courtesy of Dr. Jonathon B. Cohen

31 Characteristics of Progressive Disease Primary causes of radiographic progression reported per IWG 2007, n TBP n = 70 Non-TBP n = 35 Increase in overall tumor burden a 13 7 Non-target lesion growth b 17 2 Development of new lesion c Patients may have had multiple findings, and other characteristics may have been used by investigators to assess disease progression a 50% increase from nadir in sum of the product of the diameters. b Defined as unequivocal progression as determined by investigator assessment per protocol. c Appearance of any new lesion >1.5 cm in any axis, even if other lesions decreasing in size Slides: courtesy of Dr. Jonathon B. Cohen

32 Baseline Patient Demographics Characteristic All patients N = 243 TBP n = 70 Non-TBP n = 35 Age, years 34 (18 72) 37 (18 72) 34 (23 63) Male, % ECOG PS, % 0 1 Stage IV disease at initial diagnosis, % Previous lines of therapy 4 (2 15) 3 (2 5) 4 (3 9) B symptoms, % Bulky disease, % Extra lymphatic involvement, % Time from diagnosis to first dose of nivolumab, years 4 (1 31) 6 (1 30) 3 (1 31) Time from first dose of nivolumab to initial progression date, months - 6 (1 22) 7 (1 22) Compared with patients who progressed but did not receive further treatment (non- TBP), patients in the TBP group had better ECOG PS and fewer B symptoms at baseline Data are median (range) unless stated otherwise. ECOG PS, Eastern Cooperative Oncology Group performance status; TBP, treated beyond progression Slides: courtesy of Dr. Jonathon B. Cohen

33 Best Overall Response Prior to Initial Progression Best overall response prior to progression, n (%) TBP n = 70 Non-TBP n = 35 Complete remission 5 (7) 8 (23) Partial remission 31 (44) 12 (34) Stable disease 20 (29) 9 (26) Progressive disease 13 (19) 4 (11) Non-evaluable 1 (1) 2 (6) Slides: courtesy of Dr. Jonathon B. Cohen

34 Time to Response and Duration of Response in Patients TBP Lines show time from first dose to last dose, according to reduction in tumor burden after initial progression Treatment before progression Patients First PR First CR First progression On treatment Off treatment Death Next therapy start Best reduction in tumor burden a 50% >25 <50% >0 25% 0% Not determined Median duration of treatment beyond progression was 5 (95% CI 3 9) months Median overall time from first dose to next therapy in patients TBP was 17 (95% CI 14 NE) months a Best change is defined as the maximum reduction or minimum increase in tumor burden recorded after the first progression date Time since first dose (weeks) Slides: courtesy of Dr. Jonathon B. Cohen

35 Time From Initial Progression to Next Therapy 1.0 Probability of patients free of next treatment TBP, median 8.8 (5.5, NE) months Non-TBP, median 1.5 (0.6, 3.3) months Number of patients at risk TBP Time since first progression (months) Non-TBP Time to next treatment is defined as time of first progression date to first subsequent therapy date or death, whichever occurs first. Data are median (95% CI) unless stated otherwise NE, not estimable 20 Slides: courtesy of Dr. Jonathon B. Cohen

36 Overall Survival 1.0 Probability of survival PGF TBP Non-TBP month OS, % (95% CI) Overall N = 243 PGF n = 138 TBP n = 70 Non-TBP n = (88, 95) 96 (90, 98) 93 (83, 97) 80 (62, 90) Number of patients at risk OS (months) PGF TBP Non-TBP PGF, progression-free patients Slides: courtesy of Dr. Jonathon B. Cohen

37 Summary and Conclusions Summary In CheckMate 205, 70 of 105 (67%) patients with investigator-assessed disease progression were TBP New lesions were the most common cause (67%) of initial progression in patients TBP Stable reductions in tumor burden were seen with continued nivolumab treatment in patients TBP OS from first dose of study drug was 93% at 12 months for patients TBP (vs 80% for non-tbp) Median time from initial progression to next therapy was 8.8 months for patients TBP (vs 1.5 months for non-tbp) Nivolumab was well tolerated and had an acceptable safety profile consistent with previous studies Conclusions Patients who have stable performance status and progression according to conventional response criteria may derive long term clinical benefit from continued nivolumab treatment Two proposed updates to conventional response criteria LYRIC and RECIL may help better assess the long-term efficacy of checkpoint inhibitors and help evaluate which patients may benefit from TBP LYRIC, LYmphoma Response to Immunomodulatory therapy Criteria; RECIL, Response Evaluation Criteria in Lymphoma Clinical Trials Slides: courtesy of Dr. Jonathon B. Cohen

38 Toxicities, and Patterns of Use of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Multicenter Retrospective Study Steven M. Bair, MD 1, Lauren Elizabeth Strelec, BA 1*, Tatyana A Feldman, MD 2, Nirav N Shah, MD 3, Nishitha Reddy, MD, MSCI, MBBS 4, Scott Huntington, MD 13, Smith Giri, MD 13, Nadia Khan, MD 5, Charalambos Andreadis, MD, MSCE 6, Chaitra S. Ujjani, MD 7, Arun K Singavi, MD 8, Christina Howlett, PharmD 9,10*, Khoan Vu, MD 11*, Malik Faheem, MD 12*, Matthew R. Youngman, BS 1*, Sunita Dwivedy Nasta, MD 1, Daniel J. Landsburg, MD 1, Anthony R. Mato, MD 1, Stephen J. Schuster, MD 1 and Jakub Svoboda, MD 1 December 11, 2017 Slides: courtesy of Dr. Steven M. Bair

39 Results Patient Characteristics Patient Characteristics Total patients Median age at diagnosis Median age at PD-1 inhibitor initiation Sex Male Female Histologic subtype Nodular sclerosing Mixed cellularity Unknown Frontline therapy ABVD (or AVD) Other (CHOP, ABVE-PC, NDVP, alternative medicine, mantle XRT) Treatments prior PD-1 inhibitor AutoSCT AlloSCT Brentuximab vedotin 46 patients, 8 institutions 30.5 years 34.5 years 63% 37% 32 (70%) 6 (13%) 8 (17%) 39 (84.8%) 7 (15.2%) 24 (52%) 4 (8.7%) 44 (96%) Slides: courtesy of Dr. Steven M. Bair 39

40 Results - Outcomes 12-month PFS: 68.0% (95% CI: ) 12-month OS: 91.1% (95% CI: ) Overall response rate: 63.0% CR 45.6% PR 17.4% SD 6.5% PD 19.6% Slides: courtesy of Dr. Steven M. Bair 40

41 Results - Toxicities 45.7% experienced toxicity (33% Gr 3/4) Drug discontinued in 4 cases for GVHD (skin), encephalitis, psoriasis flare, and pneumonitis Dose interruptions occurred for colitis (n=1) and elevated LFTs (n=1) No treatment-related deaths GVHD of skin in 3 pts, treated with Discontinuation Systemic steroids, ATG Topical corticosteroids Toxicity N % Rash Colitis Hypothyroidism Pneumonitis/dyspnea GVHD (skin) Liver enzyme abnormalities Infusion reaction Aseptic meningitis/ecephalitis Hypercalcemia Management strategy N % Systemic steroids Topical steroids Thyroid replacement Drug discontinuation Dose interruption Other Slides: courtesy of Dr. Steven M. Bair 41

42 Results Subsequent Therapies Next line of systemic therapy immediately after PD-1 inhibitor Systemic Therapies brentuximab ifosfamide/carboplatin/etoposide gemcitabine/vinorelbine/peg doxorubicin gemcitabine/carboplatin bendamustine bendamustine gemcitabine lenalidomide pembrolizumab brentuximab clinical trial clinical trial Hematopoietic Transplantation AutoSCT AutoSCT AutoSCT AlloSCT Best overall response CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease CR PR PR PR PR PR SD SD SD PD PD PD CR PR SD PR Marked heterogeneity among next line of treatment after PD-1 inhibitor therapy HSCT 4 pts (3 auto, 1 allo) Checkpoint inhibitors 4 pts - pembrolizumab Cellular therapy 2 pts CAR T cell therapy Radiation therapy 3 pts Slides: courtesy of Dr. Steven M. Bair 42

43 Conclusions First analysis of the real-world experience with PD-1 inhibitors in the setting of R/R HL in the US Compared to published data from clinical trials of PD-1 inhibitors in R/R HL, our data demonstrate: Similar PFS and OS Similar ORR, but a higher CR (46%) compared to previous studies (9-22%) More frequent dose interruption or discontinuation, though did not have effect on response, PFS, or OS Systemic therapies following PD-1 blockade show antitumor activity in R/R HL Slides: courtesy of Dr. Steven M. Bair 43

44 Pilot Study of Non-Viral, RNA-Redirected Autologous Anti-CD19 Chimeric Antigen Receptor Modified T-Cells in Patients with Refractory/Relapsed Hodgkin Lymphoma Jakub Svoboda, Susan R. Rheingold, Saar I. Gill, Stephan A. Grupp, Simon F. Lacey, J. Joseph Melenhorst, Irina Kulikovskaya, Brandon Loudon, Naseem Kerr, Katherine T. Marcucci, Kim-Marie Shea, Aliza Schmidt, Lester Lledo, Amy Marshall, Anthony R. Mato, Sunita Dwivedy Nasta, Daniel J. Landsburg, Matthew R. Youngman, Bruce L. Levine, David L. Porter, Carl H. June and Stephen J. Schuster

45 RATIONALE FOR TARGETING CD19 WITH CAR-T CELLS IN chl Indirect effect by eliminating CD19 positive B-cells in tumor microenvironment Circulating clonotypic, progenitor CD19 positive B-cells with identical IgH rearrangements found in HRS/primary tumor 4 Circulating CD19+ progenitor B-cells in blood HRS cells in lymph nodes Anti-tumor effect of cytokines/cytotoxic molecules From Jones et al, Blood 2009; 113(23): Activity of CART19 therapy in multiple myeloma (CD19 negative B-cell malignancy) 5 4) Jones et al, Blood 2009; 113(23): ) Garfall et al, N Engl J Med 2015; 373: Svoboda et al, ASH

46 INVESTIGATIONAL AGENT: NON-VIRAL RNA CAR T-CELL Non-Viral RNA CAR T-cells: -Transfected ex vivo with mrna using electroporation -Not integrated into cell genome -Transient expression Viral Vector CAR T-cells: -Transduced ex vivo with viral vector (e.g. lentivirus, gamma retrovirus) -Intergrated into the genome -Persistent expression Modified RNA CAR T-cells Express Anti-CD19 Chimeric Antigen Receptor (single chain variable fragment linked to 4-1BB and CD3-zeta signaling domains) Svoboda et al, ASH

47 STUDY SCHEMA Patients are treated with 6 intravenous doses of RNA CART19 Intravenous cyclophosphamide (30 mg/kg) is administered prior to the first and fourth infusion to enhance engraftment Response assessment by PET/CT on D28, Month 3 and Month 6 Cell dose is based according to subject weight a) < 80kg: 8x x10 6 RNA CART19 cells/kg/dose (maximum per dose, 1.2x10 8 cells) b) 80kg: 1x10 8 RNA CART19 cells/dose ±20% (maximum per dose, 1.2x10 8 cells) Svoboda et al, ASH

48 OBJECTIVES Primary: Manufacturing feasibility of RNA CART19 cells Safety in chl patients Biologic effects of RNA CART19 cells Secondary: Describe response rates 6 and survival Evaluate impact of RNA CART19 on systemic soluble immune factors and microenvironment 6) Cheson et al, JCO 2007; 25:5, Svoboda et al, ASH

49 RESULTS PATIENT CHARACTERISTICS (N=5) Median age in years (range) 24 (21-42) Median number of prior Rx (range) 5 (4-9) Stage IV (%) 4 (80%) Median ALC at pheresis (range) 1030 /µl ( ) Previous alkylating agent 5 (100%) Previous brentuximab (%) 4 (80%) Previous PD-1 inhibitor (%) 3 (60%) Previous auto transplant (%) 4 (80%) Previous allo transplant (%) 1 (20%) Svoboda et al, ASH

50 RESULTS: FEASIBILITY All 5 patients had successful manufacturing of RNA CART19 One patient was taken off study (diagnosed with MDS prior RNA CART19 therapy) Four patients infused with RNA CART19 and evaluable for toxicity/response Median number of infused RNA CART19 cells/kg/dose was 1.4x10 6 (range 7.3x x10 6 ) Each patient received 6 infusions over 2 weeks Svoboda et al, ASH

51 RESULTS: EFFICACY Evaluable patients (N=4) Patient Lines of Rx Transplant Hx of BV Hx of PD-1 inh. Bridging Rx CART19 Dose 1 Month 3 Months Alive 1 8 Auto Yes Yes No 1.5x10 6 PD - No 2 5 Auto Yes Yes Pembro 7.3x10 5 SD PD Yes 3 9 Auto/Allo No* No** No 1.5x10 6 CR PD Yes Yes No BV 1.2x10 6 PR - Yes CR complete response PR partial response SD stable disease PD progressive disease *) hx of neuropathy **) hx of GVHD Svoboda et al, ASH

52 PERSISTENCE OF RNA CART19 IN PD vs. CR PATIENT Patient 1 (PD at 1 month) qrt PCR: RNA CART detected only immediately post-infusion, but not 48 hours later Patient 3 (CR at 1 month) qrt PCR: RNA CART detected immediately postinfusion and also 48 hours later Patient #1 Before RNA CART19 Patient #1 After RNA CART19 Patient #3 Before RNA CART19 Patient #3 After RNA CART19 Svoboda et al, ASH

53 CONCLUSIONS Manufacturing of RNA CART19 in chl patients is feasible RNA CART19 is transiently detected by qrt PCR in peripheral blood at least up to 48 hours after infusion RNA CART19 therapy appears safe Response was very short lived in this small sample We plan studies in chl with lentivirus-transduced CART19 capable of in vivo expansion Svoboda et al, ASH

54 T-CELL LYMPHOMAS 54

55 Slides: courtesy of Dr. Youn H. Kim

56 Slides: courtesy of Dr. Youn H. Kim

57 Slides: courtesy of Dr. Youn H. Kim

58 Slides: courtesy of Dr. Youn H. Kim

59 Slides: courtesy of Dr. Youn H. Kim

60 Slides: courtesy of Dr. Youn H. Kim

61 Slides: courtesy of Dr. Youn H. Kim

62 Slides: courtesy of Dr. Youn H. Kim

63 Slides: courtesy of Dr. Youn H. Kim

64 Slides: courtesy of Dr. Youn H. Kim

65 SUMMARY Classical Hodgkin lymphoma: Frontline ABVD vs. AVD plus BV for stage III and IV Nivolumab plus AVD for stage IIB, III, and IV Relapsed/refractory disease Nivolumab/brentuximab as first salvage Nivolumab therapy beyond progression Real world data with PD-1 inhibitors Non-viral RNA CART19 T-cell lymphomas: Mogamuzulimab vs. vorinostat for relapsed CTCL 65

66 PENN HODGKIN LYMPHOMA PROGRAM STUDIES: Frontline: Limited stage: AVD+BV x 3 followed by Nivo (PET-) or Nivo+BV (PET+) Relapsed/refractory: Pre or post-transplant: Nivo+Ipi+BV Post-transplant or transplant ineligible: Pembro vs BV Nivo+BV vs BV JAK inhibitor + everolimus CART19 (pediatrics up to age 24) BTKi+Imid+mTORi Correlative study: Molecular profiling and patient experiences 66