Sunita D Nasta MD FACP Associate Prof of Clinical Med January 26, 2018

Transcription

1 Sunita D Nasta MD FACP Associate Prof of Clinical Med January 26, 2018

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3 Escalated dosing (100, 150, 200, and 300 mg) of oral azacitadine combined with R-CHOP21 Untreated DLBCL, grade 3B follicular lymphoma, or transformed FL :IPI score >2 ECOG PF <2 Ann Arbor stage II-IV Primed with CC-486 for 7 days prior to R-CHOP on day 1 of cycle 1. Thereafter, given for 14 days (Day 8-21) Standard G-CSF administration allowed Given for 6 cycles (Cycle=21 days) Endpoints Safety DLT Maximal administered dose of CC-486 combined with R-CHOP Secondary endpoints:pk, Preliminary efficacy(orr, CR)

4 33 patients enrolled Median age=65 years (25-80) >60 years (67%) Male (55%) DLBCL (97%, 32 patients including 5 transformed from FL) 3B FL = 1 patient Stage III-IV disease (91%) IPI >3 (58%) 91% completed 6 full cycles CC-486 dose reduction occurred in 9 patients (27%) due to adverse events 150 mg discontinued in 1 patient due to febrile neutropenia

5 Neutropenia (70%), Grade 3-4 (58%), Grade 3-4 febrile neutropenia (21%) Nausea (64%) Constipation (58%) Fatigue (55%) Vomiting (48%) Diarrhea (48%) DLT seen in 2 patients including grade 4 neutropenia (200 mg cohort) and 1 grade 4 neutropenia (300 mg cohort) Maximal administered dose was 300 mg and identified as the recommended phase II dose

6 97% ORR (85% PET-negative CR) IPI score patients >3, ORR=100% (84% CR) Correlative analysis Decreased IFN- α2a and increased IFN-β and IFN-λ in blood (n=24), and significant tumor and cf-dna hypomethylation Similar toxicities consistent with R-CHOP and azacitidine Promising efficacy in high-risk previously untreated DLBCL or grade 3B FL

7 Jakub Svoboda, Daniel J. Landsburg, Sunita Dwivedy Nasta, Stefan K. Barta, Nadia Khan, Henry C. Fung, Carlyn Rose Tan, Joanne Filicko- O'Hara, Sameh Gaballa, Lauren Strelec, Sarah J. Nagle, Steven M. Bair, Sheryl Mitnick, Terease S. Waite, Rachel L. Sargent, Agata M. Bogusz, Ziver Sahin, Anthony R. Mato, and Stephen J. Schuster Svoboda et al, ASH 2017

8 A phase I/II multicenter study Enrollment began in 1/2014 and completed in 6/2017 Key eligibility criteria Age 18 years and above Histologically confirmed CD30+ PMBL, DLBCL, or grey zone lymphoma Previously untreated No specific cut off percentage for CD30 stain required, but tumor had to be positive by immunohistochemistry Measurable disease Any stage ECOG PS 0-3 Primary Objectives Phase I: safety and maximum tolerated dose of combination Phase II: overall response rate (ORR) at the end of systemic treatment 7 Secondary Objective Phase I: ORR Phase I and II: progression free survival (PFS), overall survival (OS) Correlative studies: outcomes for each lymphoma subtype, correlation with CD30 expression and customized NanoString assay 7) Cheson et al, JCO 2007; 25:5, Svoboda et al, ASH 2017

9 33 PATIENTS CONSENTED PENN (N=26), FCCC (N=6), TJUH (N=1) 1 PATIENT RE-CLASSIFIED FROM GZL TO chl 32 PATIENTS ENROLLED 1 PATIENT WITHDREW CONSENT 31 PATIENTS EVALUABLE FOR TOXICITY 2 PATIENTS WITHOUT EOT ASSESSMENT 29 PATIENTS EVALUABLE FOR EFFICACY Svoboda et al, ASH 2017

10 ALL PATIENTS (N=31) Age Median 37 years Range years Female 15 (48%) Elevated LDH 21 (68%) Stage III-IV 13 (42%) Lymphoma subtype PMBL 23 (74%) DLBCL 6 (19%) GZL 2 (7%) ECOG PS Median 1 Range 0-2 PMBL: TUMOR SIZE (N=23) Bulky ( 7.5 cm) 21 (91%) Median size 9.5 cm Range cm Svoboda et al, ASH 2017

11 HEMATOLOGICAL ADVERSE EVENTS (AE) AE Total (N=31) G1 G2 G3 G4 Leukopenia 77% 13% 32% 16% 16% Neutropenia* (NTP) 68% 3% 23% 13% 29% Lymphopenia 94% 6% 16% 45% 26% Febrile NTP** 23% % - Anemia 25% 19% 3% 3% G3/4 AEs BV-R-CHP/R-CHOP/DA-EPOCH-R Grade 3 or 4 AE BV+R-CHP N=31 R-CHOP 8 N=233 EPOCH-R 8 N=232 All AE 87% 76% 97% Hematologic 74% 73% 97% Nonhematologic 35% 41% 71% 8) CALBG/Alliance Wilson et al, Blood 2016, Abstract 469 Thrombocytopenia 6% 3% 3% - - No treatment related deaths NON-HEMATOLOGICAL AES IN 10% OF PATIENTS AE Total (N=31) Sensory neuropathy 45% 35% 10% Fatigue 42% 42% G1 G2 G3 G4 Nausea 42% 29% 10% 3% Diarrhea 26% 16% 10% Mucositis 19% 16% 3% Motor neuropathy 10% 7% 3% Constipation 10% 10% Early discontinuation due to AE: 1 patient discontinued protocol treatment due to G3 sepsis and G3 cardiomyopathy after C4 1 patient discontinued BV due to G2 pneumonitis after C5 Dose reduction: 2 patients required BV dose reduction to 1.2 mg/kg due to sensory neuropathy 1 patient developed AML at 2 years from completion of therapy *) 16% had no G-CSF, 6% had G-CSF support 2 cycles **) Total of 9 NTP fever episodes in 7 patients Svoboda et al, ASH 2017

12 Phase I (N=6): no DLT with the starting dose of BV 1.8 mg/kg in combination with R-CHP Phase I/II (N=29): overall response rate at the end of treatment PET/CT imaging TOTAL N=29 PMBL N=22 DLBC L N=5 GZL N=2 ORR 100% 100% 100% 100% CR 86% 82% 100% 100% PR 14% 18% Pre-treatment Post-treatment ORR: overall response rate CR: complete response PR: partial response Svoboda et al, ASH 2017

13 Phase III randomized prospective trial September 2012-July 2015 Randomized Obinutuzumab 1000 mg IV on D1 and D8 cycle 1 and 2 then day 1 of cycle 3-4 Rituximab 375 mg/m2 IV D1 of each cycle PET Scan Performed at baseline, after 2 and 4 cycles of induction immunochemotherapy PET2+/PET4- patients received autologous stem cell transplant PET4+ were treated according to investigator choice Primary endpoint 2y-event free survival defined by PET positivity after 2 or 4 induction cycles, progression or relapse Secondary objectives Safety Response rates Progression free survival Overall survival

14 670 patients enrolled: Median age=48 y; Male 55.7%;IPI>2=41.8% N=336 randomized to obinutuzumab plus chemotherapy N=165 G-ACVBP N=171 G-CHOP N=334 randomized to rituximab plus chemotherapy N=162 R-ACVBP N=172 R-CHOP 455 SAEs N=250 obinutuzumab (N=10 fatal; N=7 G-ACVBP arm) N=205 rituximab (N=1 fatal) Median follow-up=25.2 months 42.4% had an event Third interim analysis; recommended stopping trial Stratified 2y-EFS not statistically different between arms (p=0.1321, above the futility bound of 0.069) For IPI 1 patients, 2-year EFS was 61.3% (95%CI; ) for G-CHOP versus 59.9% (95%CI; ) for R-CHOP

15 Consistent with previous studies, obinutuzumab plus chemotherapy is not superior to rituximab plus chemotherapy Cell of origin data is currently under investigation using nanostring technology

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17 Patients with relapsed or refractory DLBCL have a poor prognosis Low rate of response to salvage therapy (CR 8%; PR 18%)1 Short survival (median OS 4 months)2 SOC for these patients is high dose chemotherapy followed by auto-sct Only about a quarter of these patients can receive a transplant 1. Crump M, et al. Blood. 2017;130(16): Van den Neste E, et al. BMT. 2016;51:51-57.

18 100 r/r DLBCL ~ 50 transplant eligible ~ 50 transplant ineligible (age, comorbidit y) ~ 25 responded to chemother apy and proceeded to transplant ~ 25 transplant ineligible (nonresponsiv e to chemotherapy ) ~ 10 cured ~ 15 relapsed after transplant ~ 90 No available SOC chemo options Figure adapted from Friedberg JW. J Am Soc Hematol Educ Book. 2011;1: DLBCL, diffuse large B-cell lymphoma; R/R, relapsed/refractory; SOC, 18 standard of care.

19 ASH Abstract First Author Description LBA-6 Neelapu 3026 Schuster Pivotal Phase 2 ZUMA-1 Trial of Kte- C19 in Patients With Relapsed/Refractory DLBCL Phase 2a Study of CTL019 in Patients With Relapsed/Refractory DLBCL and tfl

20 Original Article Chimeric Antigen Receptor T Cells in Refractory B- Cell Lymphomas Stephen J. Schuster, M.D., Jakub Svoboda, M.D., Elise A. Chong, M.D., Sunita D. Nasta, M.D., Anthony R. Mato, M.D., Özlem Anak, M.D., Jennifer L. Brogdon, Ph.D., Iulian Pruteanu-Malinici, Ph.D., Vijay Bhoj, M.D., Ph.D., Daniel Landsburg, M.D., Mariusz Wasik, M.D., Bruce L. Levine, Ph.D., Simon F. Lacey, Ph.D., Jan J. Melenhorst, Ph.D., David L. Porter, M.D., and Carl H. June, M.D. N Engl J Med Volume 377(26): December 28, 2017

21 Study Overview

22 Progression-free Survival, Response Duration, and Overall Survival. Schuster SJ et al. N Engl J Med ;377:

23 Characteristics of the Patients at Baseline. Schuster SJ et al. N Engl J Med ;377:

24 Adverse Events of Special Interest That May Have Been Related to CTL019 Therapy. Schuster SJ et al. N Engl J Med ;377:

25 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. Oluwole, M.B., B.S., M.P.H., Tanya Siddiqi, M.D., Yi Lin, M.D., Ph.D., John M. Timmerman, M.D., Patrick J. Stiff, M.D., Jonathan W. Friedberg, M.D., M.M.Sc., Ian W. Flinn, M.D., Ph.D., Andre Goy, M.D., Brian T. Hill, M.D., Ph.D., Mitchell R. Smith, M.D., Ph.D., Abhinav Deol, M.D., Umar Farooq, M.D., Peter McSweeney, M.D., Javier Munoz, M.D., Irit Avivi, M.D., Januario E. Castro, M.D., Jason R. Westin, M.D., Julio C. Chavez, M.D., Armin Ghobadi, M.D., Krishna V. Komanduri, M.D., Ronald Levy, M.D., Eric D. Jacobsen, M.D., Thomas E. Witzig, M.D., Patrick Reagan, M.D., Adrian Bot, M.D., Ph.D., John Rossi, M.S., Lynn Navale, M.S., Yizhou Jiang, Ph.D., Jeff Aycock, B.A., Meg Elias, R.N., B.S.N., David Chang, M.D., Ph.D., Jeff Wiezorek, M.D., and William Y. Go, M.D., Ph.D. N Engl J Med Volume 377(26): December 28, 2017

26 Study Overview

27 Objective Response Rate among the 101 Treated Patients. Neelapu SS et al. N Engl J Med ;377:

28 Kaplan Meier Estimates of the Duration of Response, Progression-free Survival, and Overall Survival. Neelapu SS et al. N Engl J Med ;377:

29 CAR T-Cell Expansion and Correlations with Response and Adverse Events. Neelapu SS et al. N Engl J Med ;377:

30 Treatment Disposition and Baseline Characteristics of the Patients. Neelapu SS et al. N Engl J Med ;377:

31 Adverse Events, the Cytokine Release Syndrome, and Neurologic Events Associated with Treatment. Neelapu SS et al. N Engl J Med ;377:

32 Conclusions

33 Single-arm global pivotal trial of tisagenlecleucel in patients with r/r DLBCL (NCT ) Screening, apheresis, and cryopreservatio n Enrollm ent Bridging chemotherapy Tisagenlecl eucel manufactur ing Restagi ng, lymphodepl etion a Tisagenlecl eucel infusion b Safety and efficacy follow-up Imaging at months 1, 3, 6, 9, a To be completed 2 to 14 days prior to tisagenlecleucel infusion. b Infusion conducted on an in- or outpatient basis at investigator discretion. 33 DLBCL, diffuse large B-cell lymphoma; r/r, relapsed/refractory.

34 Global clinical trial with centralized manufacturing of tisagenlecleucel 27 sites in 10 countries across North America, Europe, Australia and Asia * * * Manufacturing sites 34

35 Key eligibility criteria 18 years of age Central confirmation of histology 2 prior lines of therapy for DLBCL PD after or ineligible for auto-sct No prior anti-cd19 therapy No active CNS involvement Endpoints Primary endpoint: best overall response rate (ORR: CR + PR) Lugano criteria used for response assessment by IRC 1 Null hypothesis of ORR 20% Secondary endpoints: DOR, OS, safety 1. Cheson BD, et al. J Clin Oncol. 2014;32(27): auto-sct, autologous stem cell transplant; CNS, central nervous system; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; IRC, Independent Review Committee; ORR, overall response rate; OS, overall survival; PD, progressive disease; PR, partial response.

36 Pending infusion n = 5 Enrolled n = 147 Infused n = 99 Enrollment began July 2015 Discontinued before Total = infusion 43 Inability to manufacture Patient status related a = 9 = 34 n n Evaluable for response b n = 81 a Death (n = 16); physician decision (n = 12); patient decision (n = 3); adverse event (n = 2); protocol deviation (n = 1). b Patients who had 3 months of follow-up or earlier progression of disease 3

37 Patients (N = 99) Age, median (range), years 56 (22-76) 65 years, % 23 ECOG performance status 0/1 55/45 Central histology review Diffuse large B-cell lymphoma, % 80 Transformed follicular lymphoma, % 19 Double/triple hits in CMYC/BCL2/BCL6 genes, % 15 a Cell of origin b Germinal center B-cell type, % 52 Nongerminal center B-cell type, % 42 Number of prior lines of antineoplastic therapy, % 2/3/4-6 44/31/19 Refractory/relapsed to last therapy, % 52/48 Prior auto-sct, % 47 Bridging chemotherapy: 89/99 Lymphodepleting chemotherapy: 92/99 a CMYC + BCL2, n = 4; CMYC + BCL2 + BCL6, n = 8; CMYC + BCL6, n = b Determined by the Choi algorithm. auto-sct, autologous stem cell transplant; ECOG, Eastern Cooperative Oncology Group.

38 Response Rate, % Best Overall Response Rate a (N = 81) a P <.0001; (95% CI, 42%-64%). Null hypothesis of ORR 20%. Response at 3 Months (N = 81) 38 Response at 6 Months (n = 46) ORR (CR + PR) CR PR Durability of responses is shown by the stability between 3 and 6 month response rates Response at 3 months is indicative of the long term benefit of this treatment CR, complete response; ORR, overall response rate; PR, partial response.

39 ORR n/n (%) [95% CI] All patients Null hypothesis of ORR 20% 43/81 (53.1) [ ] Age, years < 65 32/64 (50.0) [ ] 65 11/17 (64.7) [ ] Sex Female 18/29 (62.1) [ ] Male 25/52 (48.1) [ ] Prior antineoplastic therapy 2 lines 22/41 (53.7) [ ] > 2 lines 21/40 (52.5) [ ] Cell of origin a Nongerminal center 19/34 (55.9) [ ] Germinal center 19/41 (46.3) [ ] Rearranged MYC/BCL2/BCL6 Double/triple hits 5/12 (41.7) [ ] Other 38/69 (55.1) [ ] a Data from 6 patients are missing ORR, overall response rate.

40 100 Probabilty of Relapse Free, % Time From Onset of 0 Patients at risk Response, months Efficacy analysis set = all patients who received a tisagenlecleucel infusion 3 months prior to data-cut date Median DOR and OS not reached Almost all patients in CR at month 3 remained in CR No patients proceeded to transplant while in response CR, complete response; DOR, duration of response; OS, overall response.

41 AESI a All Grades, % a Occurring within 8 weeks of tisagenlecleucel infusion. b Cytokine release syndrome was graded using the Febrile Penn scale. neutropenia c At day No deaths due to tisagenlecleucel, CRS or cerebral edema 26 patients (26%) were infused as outpatients 20/26 patients (77%) remained outpatient for 3 days after infusion 41 (N = 99) Grade 3, % Grade 4, % Cytokine release syndrome b Neurological events Prolonged cytopenia c Infections AESI, adverse events of special interest; CRS, cytokine release syndrome.

42 1. Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139. Patients (N = 99) Time to onset, median (range), days a,b 3 (1-9) Duration, median (range), days a 7 (2-30) Hypotension that required intervention, % High-dose vasopressors 6 Intubated, % 8 a Calculated based only on patients who had cytokine release syndrome (n = 57), excluding 1 patient Corticosteroids who had onset on day b Cytokine release syndrome was graded using the Penn scale and managed by a protocolspecific algorithm Anticytokine therapy, % 16 Tocilizumab 15

43 Durable responses were associated with persistent transgene levels in blood Tisagenlecleucel Transgene, copies/µg DNA 100, , CR (n = 26) / PR (n = 5) LLOQ = 50 copies/µg Time From Infusion, days 1. Awasthi R, et al. Blood. 2017;130(suppl 1) [abstract 5211]. CR, complete response; PR, partial response. 4

44 Response (tumor response at month 3) No apparent relationship Responses observed across full range of doses Dose ( CAR- positive viable T cells) a Safety (CRS and neurological events) No relationship observed between dose and neurological events Higher probability of CRS with higher doses CRS is manageable per algorithm Exposure (maximal expansion from qpcr data) a 1 patient received a dose < CAR-positive viable T cells. Dose and exposure were independent No expansion (AUC 0-28d and C max )- response relationship observed 1. Awasthi R, et al. Blood. 2017;130(suppl 1) [abstract 5211]. CRS, cytokine release syndrome. 44

45 Best ORR 53% (CR 40%); P <.0001 ORR 38% (CR 32%) at 3 months; ORR 37% (CR 30%) at 6 months Almost all patients in CR at month 3 remained in CR Median DOR and OS were not reached AEs were effectively managed by appropriately trained studysite personnel No deaths were attributed to tisagenlecleucel, CRS or cerebral edema Tisagenlecleucel was safely administered in both the inpatient and outpatient settings 45 AE, adverse event; CR, complete remission; CRS, cytokine release syndrome; DOR, duration of response; ORR, overall response rate; OS, overall survival.

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47 Goal: Validate a lower intensity therapy, DA- EPOCH-R, in adult patients with BL, including HIV+ patients Use risk-adapted approach based on baseline risk category and interim PET scans after 2 cycles Population Newly diagnosed BL 18 and older Any HIV status Low risk(lr):normal LDH, ECOG PF 0-1, <Stage II, and no tumor lesion >7 cm

48 Low risk patients received 2 cycles of DA-EPOCH-R without IT followed by PET If interim PET was negative Receive 1 more cycle High risk patients with negative brain MRI and CSF cytology/flow cytometry received 2 cycles of DA- EPOCH-R without IT therapy followed by PET If interim PET was negative Received 4 additional cycles of DA-EPOCH-R including IT MTX 12 mg on day 1 and 5 (Total of 8 doses) High-risk patients with active CNS disease at baseline received concurrent MTX 12 mg IT twice weekly for 2 weeks past negative (minimum of 4 weeks), followed by MTX 12 mg once weekly x 6 and MTX 12 mg monthly x 6 No cranial radiation administered

49 113 patients enrolled 110 patients completed therapy, 3 patients on treatment Median age =49y (18-86y) >50y (49%) >60y (26%) Male (79%) Stage III-IV (69%) Elevated LDH (66%) CNS involvement (10%) HIV+ (26%) Low risk (12%); high risk (88%) Median follow-up=35.7 months PFS for all patients beyond 10.2 months= 85.7% (95% CI: %) Freedom-from-progression= 91.8 (95% CI: %) Overall survival= 85.9% (95% CI: %) HIV status did not impact survival and therapy was equally effective across all age groups Patients with BM and/or CNS involvement were at highest risk of treatment failure No progression or death in the LR group 14 deaths in HR arm (7 due to disease progression, 3 occurred during treatment)

50 DA-EPOCH-R cures most adult patients with BL irrespective of HIV status Low risk treated with 3 cycles of systemic therapy and no IT therapy High risk patients are more favorably treated with more intensive regimens Patients with BM and/or CNS involvement are at the highest risk of treatment failure

51 Hua-Jay J. Cherng, Rachel Lynn Sargent, Sunita Dwivedy Nasta, Jakub Svoboda, Stephen J. Schuster, Anthony R. Mato, April Schrank-Hacker, Jennifer J.D. Morrissette and Daniel J. Landsburg Blood :4136;

52 Hua-Jay J. Cherng et al. Blood 2017;130: by American Society of Hematology

53 Elise A. Chong, J. Joseph Melenhorst, Jakub Svoboda, Sunita Dwivedy Nasta, Daniel J. Landsburg, Anthony R. Mato, Lifeng Tian, Harit Parakandi, Simon F. Lacey, Carl H. June, Stephen J. Schuster

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57 PD1 blockade with pembrolizumab appears safe and results in clinical responses in some patients with progression of DLBCL after anti-cd19 directed chimeric antigen receptor modified T cell therapy. Analysis of the pharmacokinetics of CAR T- cells in patients treated with pembrolizumab appears to identify responding patients, and supports the hypothesis that CAR T cells may be rejuvenated by infusion of PD1 antagonists.