What is the best second-line approach to induce remission prior to stem cell transplant? Single agent brentuximab vedotin

Transcription

1 What is the best second-line approach to induce remission prior to stem cell transplant? Single agent brentuximab vedotin Alison Moskowitz, MD Assistant Attending, Lymphoma Service Memorial Sloan Kettering Cancer Center

2 Case 27 yo woman with stage IVB chl (involving liver, bone) ABVDx6 with CR 1 year later B Sx, pancytopenia, diffuse bone disease BM bx confirmed relapsed chl WBC 1.3, ANC 0.8, hgb 10, plt 61K

3 Approach to relapsed/refractory disease Relapse/Refractory Disease The standard approach to rel/ref HL is second-line therapy followed by ASCT 1,2 Second-line chemo At least 50% patients are cured with with this approach HDT/ASCT 1 Schmitz, et al. Lancet Lynch, et al. Lancet. 1993

4 Current second-line therapy options are similar Regimen N ORR (%) CR (%) - by CT CR (%) by PET ICE/augICE % DHAP % 21% GVD % 19% GDP % 17% IGEV % 53.8% 1. Moskowitz CH, et al. Blood 2012; 119(7): Baetz T, et al. Annals of Oncology 2003; 14(12): Josting A, et al. Annals of Oncology 2002; 13(10): Santoro A, et al. Haematologica 2007; 92(1): Bartlett NL, et al. Annals of Oncology 2007; 18(6):

5 Pre-ASCT PET is consistently prognostic Reference n PET neg definition PFS/EFS PET pos PFS/EFS PET neg Gentzler, et al. BJH Deauville 2** 52% 85% Akhtar, et al. BMT < Mediastinal blood pool 49% 74% Devillier, et al. Haematologica Harmonization 23% 79% Smeltzer, et al. BBMT Harmonization 41% 82% Mocikova, et al. Leukemia&Lymphoma Harmonization 36% 73% Moskowitz, et al. Blood 2010* 153 Harmonization 31% 75% Jabbour, et al. Cancer 2007* 211 < Background 27% 69% *Publications included gallium scans **Results similar when PET negative defined as Deauville 3

6 Pretransplant functional imaging in rel/ref HL ( ) Risk adapted therapy administered based upon risk factors: B symptoms Extranodal disease Relapse < 1year Pre-transplant functional imaging was the most significant determinant of outcome Moskowitz, AJ, et al. Blood. December 2010.

7 PET-adapted salvage therapy for rel/ref HL at MSKCC ICE-based salvage + PET - GVD HDT/ASCT Moskowitz, CH, et al. Blood. February 2012.

8 Brentuximab vedotin (BV) as salvage therapy in rel/ref HL: Rationale Weekly BV increased dose intensity = earlier CRs Phase I study evaluated weekly schedule for brentuximab vedotin mg/kg weekly, 3 weeks on, 1 week off 41 patients; 86% with HL CR rate 34% 12/14 CRs seen at first re-staging (8 weeks) 1 Fanale, et al. Clin Cancer Res January 1, ; 248.

9 MSKCC : Relapsed/refractory HL First TX following upfront therapy Weekly BV x 2 cycles + PET - Augmented ICE x2 cycles PET - HDT/ASCT + Further treatment according to treating physician

10 FDG-PET assessment Deauville criteria or 5 point scale Score FDG-PET/CT scan result 1 No uptake above background 2 Uptake mediastinum 3 Uptake > mediastinum but liver 4 Uptake moderately more than liver uptake, at any site 5 Markedly increased uptake at any site or new sites of disease Score of 1 or 2 = PET negative

11 Patient characteristics Characteristic N=45 Male 25 (56%) Median age (range) 31 (13-65) Initial stage I: 1 (2%) II: 20 (44%) III: 10 (22%) IV: 14 (31%) Stage at enrollment II: 20 (44%) III: 6 (13%) IV: 19 (42%) Prior radiation 8 (18%) Relapse > 1 year from initial Rx 7 (16%) Relapse within 1 year of initial Rx 15 (33%) Primary refractory 23 (51%) Extranodal disease 19 (44%) B symptoms 11 (24%)

12 MSKCC evaluable patients 1 pt lost to follow-up 33 pts Augmented ICE x2 cycles Weekly BV x 2 cycles 45 enrolled + PET - 45 pts 12 pts (27%) 10 pts PET pts (69%) HDT/ASCT 44 pts transplanted Further treatment according to treating physician

13 Deauville response to salvage therapy BV (n=45) Deauville score n AugICE (n=32) Deauville score n

14 EFS according to treatment and PET status Moskowitz, AJ, et al. Lancet Oncol 2015;16:

15 Phase II trial of BV as first line salvage therapy in rel/ref HL prior to ASCT Chen R, et al. ASH 2014 First treatment following front-line therapy 2-4 cycles BV Additional chemotherapy for patients achieving SD,PD, +/- PR BV x 2 cycles CT or PET CR PR SD BV x 2 cycles CT or PET CR PR ASCT PD Salvage chemo SD PD Salvage chemo

16 Response to BV as first salvage N=37 Univariate analysis: no differences according to age, sex, disease stage, response to induction, bulky disease, or B symptoms. Best response Best response at cycle 2 Response at cycle 4 or EOT ORR 25/36 (69%) 24/36 (67%) 22/36 (61%) CR 13/36 (36%) 13/36 (36%) 13/36 (36%) PR 12/36 (33%) 11/36 (31%) 9/36 (25%) SD 10/36 (28%) 11/36 (31%) 10/36 (27%) PD 1/36 (3%) 1/36 (3%) 4/36 (11%) Chen R, et al. ASH 2014

17 BV plus chemo as first salvage? BV-bendamustine LaCasce, et al. ASH 2014 BV-ICE Fred Hutch Cancer Center Clinicaltrials.gov: NCT BV-DHAP Netherlands Clinicaltrials.gov: NCT

18 ASH 2014: abstract # 293 Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma Who are Relapsed or Refractory after Front line Therapy Ann LaCasce, R. Gregory Bociek, Jeffrey Matous, Ahmed Sawas, Paolo Caimi, Stephen Ansell, Miguel Islas-Ohlmayer, Eric Cheung, Edward Agura, Caroline Behler, Howland Crosswell, Julie Vose, Neil Josephson, Ranjana Advani

19 Schema and Results Main eligibility: 18 years old, Classical HL, R/R disease after frontline chemotherapy, ECOG performance status patients received median 2 cycles of chemotherapy (1-6) No dose-limiting toxicity was observed in C1

20 Best Response to BV + Bendamustine N=48 n (%) 95% CI Best clinical response* Complete remission (CR) 40 (83) Partial remission (PR) 6 (13) Stable disease (SD) 1 (2) Progressive disease (PD) 1 (2) Objective response rate (ORR [CR + PR]) 46 (96) 85.8, 99.5 *Prior to ASCT Dose of bendamustine selected for combination with BV: 90 mg/m 2 Majority of CRs (34/40) achieved at Cycle 2 restage Successful mobilization in all but 1 pt (32/33) All patients engrafted in <2 weeks

21 Key adverse event: Infusion related reactions Dyspnea (15%), chills (13%) and flushing (13%) were most common symptoms; hypotension requiring vasopressor support also occurred Majority of reactions occurred within 24 hrs of Cycle 2 infusion and were considered related to both agents Decreased incidence with premeds (steroids/antihistamines) Delayed hypersensitivity reactions also occurred, the most common of which was rash (14 patients up to 22 days after infusion)

22 Progression-Free Survival Median PFS not reached 22 o 4 progressions and 1 death subsequent to ASCT (8 events overall) Medians also not yet estimable for response duration

23 Is the depth of response the same with BVbendamustine?

24 Case continued 27 yo woman with stage IVB chl, relapsed 1 year after ABVD with diffuse bone involvement, pancytopenia BV 1.2mg/kg weekly (3 weeks on, 1 week off) x 2 cycles Post-BV: resolution of B Sx, pancytopenia, PET Deauville 4 AugICE x2. PET Deauville 2 CBV/ ASCT Remains in remission nearly 3 years later

25 First salvage treatment of choice: single agent brentuximab vedotin (for now) Novel BV combinations Weekly BV x 2 cycles + PET - Augmented ICE x2 cycles PET - HDT/ASCT + Further treatment according to treating physician