ORVACABTAGENE AUTOLEUCEL (ORVA-CEL), A B-CELL MATURATION ANTIGEN-DIRECTED CAR T CELL THERAPY FOR PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: UPDATE OF THE PHASE 1/2 EVOLVE STUDY
Author(s): ,
Sham Mailankody
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Andrzej Jakubowiak
Affiliations:
University of Chicago Comprehensive Cancer Center,Chicago,United States
,
Myo Htut
Affiliations:
City of Hope Comprehensive Cancer Center,Duarte,United States
,
Luciano Costa
Affiliations:
University of Alabama at Birmingham School of Medicine,Birmingham,United States
,
Kelvin Lee
Affiliations:
Roswell Park Comprehensive Cancer Center,Buffalo,United States
,
Siddhartha Ganguly
Affiliations:
University of Kansas Medical Center,Westwood,United States
,
Jonathan Kaufman
Affiliations:
Winship Cancer Institute of Emory University,Atlanta,United States
,
David Siegel
Affiliations:
John Theurer Cancer Center ,Hackensack,United States
,
William Bensinger
Affiliations:
Swedish Cancer Institute,Seattle,United States
,
Mariana Cota Stirner
Affiliations:
Juno Therapeutics, a Bristol-Myers Squibb company,Seattle,United States
,
Thomas Doerr
Affiliations:
Juno Therapeutics, a Bristol-Myers Squibb company,Seattle,United States
,
Todd DeVries
Affiliations:
Juno Therapeutics, a Bristol-Myers Squibb company,Seattle,United States
,
Julia Piasecki
Affiliations:
Juno Therapeutics, a Bristol-Myers Squibb company,Seattle,United States
Sandy Wong
Affiliations:
University of California at San Francisco,San Francisco,United States
EHA Library. Mailankody S. 06/12/20; 294844; EP927
Sham Mailankody
Sham Mailankody
Contributions
Abstract

Abstract: EP927

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Orva-cel, an autologous BCMA-directed CAR T cell therapy with a fully human binder, is manufactured using a lentiviral vector and purified CD4 and CD8 T cells to deliver a product enriched in central memory cells. EVOLVE is an open-label, multicenter, phase 1/2 study to determine safety and efficacy of orva-cel in patients (pts) with RRMM. To date, over 100 pts have been treated in EVOLVE phase 1. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). 

Aims
To report safety and efficacy of higher dose levels (DLs) among 51 pts in the ongoing EVOLVE study who received orva-cel manufactured using the process intended to support commercial use.

Methods
Pts with RRMM who had received ≥3 prior regimens (a proteasome inhibitor [PI], an immunomodulatory drug [IMiD], and an anti-CD38 monoclonal antibody [mAb]) were treated with orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide.

Results
Pts had a median age of 61 (range, 33–77) years (y) and a median time from diagnosis of 7.0 (range, 1.7–23.6) y. Pts had a median of 6 (range, 3–18) prior regimens, and 69% had revised ISS stage 2/3. All pts were refractory to the last anti-MM regimen. Overall, 73% of pts were triple refractory (PI, IMiD, and mAb) and 92% were penta-exposed (ie, received 2 PIs, 2 IMiDs, and a mAb). Bridging therapy was received by 61%, and 77% of pts were refractory to it. Two pts had dose-limiting toxicities: 1 pt treated at 300 × 106 CAR+ T cells had a grade (G) 3 neurological event (NE) for >7 days, and 1 pt treated at 450 × 106 CAR+ T cells had G4 neutropenia for >28 days. No G5 adverse events related to orva-cel occurred. Key efficacy and safety outcomes are shown (Table). Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). G≥3 anemia, neutropenia, and thrombocytopenia at 29 days occurred in 21%, 55%, and 44% of pts, respectively (median time to resolution to G≤2 of any cytopenia was ≤2.1 months [mo]). G≥3 infections occurred in 14% of pts. After a median follow-up (F/U) of 5.9 mo, median PFS was not reached. Clinical responses were seen in pts with high baseline sBCMA levels, indicating that sBCMA did not inhibit orva-cel function. Deep declines in sBCMA levels occurred with a median percent change from baseline at nadir in pts sampled at day ≥75 (n=25) of −99.3% (range, −27.0% to −99.9%).

n (%)

300a

450a

600a,b

All DLs

Efficacy

N = 19

N = 18

N = 7

N = 44

ORR (sCR + CR + VGPR + PR)

18 (95)

17 (94)

5 (71)

40 (91)

sCR + CR

5 (26)

9 (50)

3 (43)

17 (39)

VGPR

8 (42)

3 (17)

0

11 (25)

PR

5 (26)

5 (28)

2 (29)

12 (27)

Median F/U, mo (min–max)

6.1 (1.7–9.2)

5.8 (0.9–9.2)

1.7 (0.9–3.0)

5.9 (0.9–9.2)

Safety

N = 19

N = 19

N = 13

N = 51

CRS G≥3

0

1 (5)

0

1 (2)

NE G≥3

1 (5)

1 (5)

0

2 (4)

PR, partial response; VGPR, very good PR. a× 106 CAR+ T cells. bWith additional F/U of 1 mo, 11 pts were efficacy evaluable with an ORR of 100% and CR/sCR of 45%; no G≥3 CRS/NE.

Conclusion
Orva-cel (300, 450, and 600 × 106 CAR+ T cells) demonstrated manageable safety (G≥3 CRS, 2%; G≥3 NEs, 4%) and compelling efficacy (ORR, 91%; CR/stringent CR rate, 39%) in heavily pretreated pts with RRMM. Updated results (MRD, PK, durability of response, and RP2D) will be presented. 

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Cellular therapy, Multiple myeloma, Refractory

Abstract: EP927

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Orva-cel, an autologous BCMA-directed CAR T cell therapy with a fully human binder, is manufactured using a lentiviral vector and purified CD4 and CD8 T cells to deliver a product enriched in central memory cells. EVOLVE is an open-label, multicenter, phase 1/2 study to determine safety and efficacy of orva-cel in patients (pts) with RRMM. To date, over 100 pts have been treated in EVOLVE phase 1. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). 

Aims
To report safety and efficacy of higher dose levels (DLs) among 51 pts in the ongoing EVOLVE study who received orva-cel manufactured using the process intended to support commercial use.

Methods
Pts with RRMM who had received ≥3 prior regimens (a proteasome inhibitor [PI], an immunomodulatory drug [IMiD], and an anti-CD38 monoclonal antibody [mAb]) were treated with orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide.

Results
Pts had a median age of 61 (range, 33–77) years (y) and a median time from diagnosis of 7.0 (range, 1.7–23.6) y. Pts had a median of 6 (range, 3–18) prior regimens, and 69% had revised ISS stage 2/3. All pts were refractory to the last anti-MM regimen. Overall, 73% of pts were triple refractory (PI, IMiD, and mAb) and 92% were penta-exposed (ie, received 2 PIs, 2 IMiDs, and a mAb). Bridging therapy was received by 61%, and 77% of pts were refractory to it. Two pts had dose-limiting toxicities: 1 pt treated at 300 × 106 CAR+ T cells had a grade (G) 3 neurological event (NE) for >7 days, and 1 pt treated at 450 × 106 CAR+ T cells had G4 neutropenia for >28 days. No G5 adverse events related to orva-cel occurred. Key efficacy and safety outcomes are shown (Table). Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). G≥3 anemia, neutropenia, and thrombocytopenia at 29 days occurred in 21%, 55%, and 44% of pts, respectively (median time to resolution to G≤2 of any cytopenia was ≤2.1 months [mo]). G≥3 infections occurred in 14% of pts. After a median follow-up (F/U) of 5.9 mo, median PFS was not reached. Clinical responses were seen in pts with high baseline sBCMA levels, indicating that sBCMA did not inhibit orva-cel function. Deep declines in sBCMA levels occurred with a median percent change from baseline at nadir in pts sampled at day ≥75 (n=25) of −99.3% (range, −27.0% to −99.9%).

n (%)

300a

450a

600a,b

All DLs

Efficacy

N = 19

N = 18

N = 7

N = 44

ORR (sCR + CR + VGPR + PR)

18 (95)

17 (94)

5 (71)

40 (91)

sCR + CR

5 (26)

9 (50)

3 (43)

17 (39)

VGPR

8 (42)

3 (17)

0

11 (25)

PR

5 (26)

5 (28)

2 (29)

12 (27)

Median F/U, mo (min–max)

6.1 (1.7–9.2)

5.8 (0.9–9.2)

1.7 (0.9–3.0)

5.9 (0.9–9.2)

Safety

N = 19

N = 19

N = 13

N = 51

CRS G≥3

0

1 (5)

0

1 (2)

NE G≥3

1 (5)

1 (5)

0

2 (4)

PR, partial response; VGPR, very good PR. a× 106 CAR+ T cells. bWith additional F/U of 1 mo, 11 pts were efficacy evaluable with an ORR of 100% and CR/sCR of 45%; no G≥3 CRS/NE.

Conclusion
Orva-cel (300, 450, and 600 × 106 CAR+ T cells) demonstrated manageable safety (G≥3 CRS, 2%; G≥3 NEs, 4%) and compelling efficacy (ORR, 91%; CR/stringent CR rate, 39%) in heavily pretreated pts with RRMM. Updated results (MRD, PK, durability of response, and RP2D) will be presented. 

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Cellular therapy, Multiple myeloma, Refractory

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