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Novel immunotherapies in MM
Table 2. Clinical trial results with T-cell-engaging antibodies.
Study product Study (Registration n.) population
B-cell maturation antigen (BCMA)
Schedule
i.v. n=84 s.c. n=44 QW
i.v. n=45 QW
i.v.; Q2-Q2W
i.v. n=38 Q3W
sc, QW/ Q2W
i.v. n=30 QW
CRS profile
s.c. 50%/i.v. 53% Grade 3/4: 0%
88.2% Grade 3/4: 0%
61% Grade 3/4: 8%
21% Grade 3/4: 0%
90% Grade 3/4: 0%
77% Grade 3/4: 9% Grade 5: 1 death
Neurotoxicity
3% NA
NA NA 20% NA
7/137 G1/2: 4 G3: 3 6/7 with CRS
5%
Response
ORR: 25% CR/sCR: 9/120
ORR: 35,8% CR/sCR: 6/45
ORR: 23,2% CR/sCR: 5/69
ORR: 37% CR/sCR: 3/38
ORR: 40% CRsCR: 5/30
Last cohorts (n) Ref.
ORR: 63.8% (30/47) 29 CR/sCR: 19.5% (9/47)
ORR: 60% 30 NR
ORR: 29,6% (8/27) 33 CR/CRs: 11.1% (3/27)
ORR: 52% (12/23) 32 CR/CRs: 13% (3/23)
80% 34
ORR: 88,8% (8/9) 36 CR/CRs: 44,4% (4/9)
i.v.: ORR: 14/18 39 s.c.: ORR: 8/12
40
Teclistamab (NCT03145181)
REGN 5458 (NCT03761108)
AMG 701 NCT03287908
TNB-38384 (NCT03933735)
PF-3135
CC-932695 (NCT03486067)
Dara/IMID/PI + EMD
Dara/IMID/PI
+ EMD, asecretory included
Dara/IMID/PI - EMD
Dara/IMID/PI +EMD
Dara/IMID/PI + EMD
G-protein coupled receptor family C group 5 member D (GPRC5D)
Talquetatamab1 (NCT03399799)
Fc receptor-homolog 5 (FcRH5)
Cevostamab (prev. BFCR4350A2) (NCT03275103)
i.v. n=102 s.c. n=35
i.v. n=51 QW
i.v.+ s.c.: 47% i.v. Grade 3/4: 8% s.c. Grade 3/4: 0
74.5% Grade 3/4: 2%
TCE: T-cell-engager; CRS: cytokine release syndrome; Dara: daratumumab; IMID: immunomodulatory drug; PI: proteasome inhibitor; EMD: extramedullary disease; i.v.: intra- venous; s.c.: subcutaneous; ORR: overall response rate; CR: complete response, sCR: stringent complete response; QW: once weekly; Q2W: every 2 weeks; Q3W: every 3 weeks; NA: not applicable; NR: not reported; G: grade.
dose, including patients with triple-class and penta-drug RRMM. However, follow-up is limited (median 3.9 months) and it remains to be seen if these responses are durable and if patients with highly proliferative disease or extramedullary involvement have a similar benefit. A phase II study has been initiated.
REGN5458
Another TCE that binds BCMA and CD3, REGN5458, was evaluated in 45 patients in a dose-escalation, phase I study.30 This TCE was administered intravenously on a weekly schedule followed by a maintenance phase in which it was administered every 2 weeks. CRS occurred in 38% of patients, but there were no episodes of grade ≥3 CRS. The ORR increased in a dose-dependent manner and was 62.5% (5/8 patients) at the highest dose level used. Responses were deep and 95% of responders achieved a very good partial response or better. The median duration of follow-up was 2.6 months. The phase II part of the study is currently enrolling patients.
TNB383B
TNB383B is a BCMA x CD3 fully human IgG4 anti- body with improved binding to cell surface BCMA and a half-life of 2-3 weeks.31 It is administered once every 3 weeks and is given intravenously. Decreased affinity to CD3 may be responsible for the lower rate of CRS asso- ciated with this product. The all-grade CRS rate was 45% in the phase I dose escalation study which enrolled 58 patients.32 The ORR was 80% in the highest dose group (n=15). Two patients died from COVID-19 infection.
AMG 701
BiTE® structure resulting in an extended half-life of around 112 hours, making it suitable for once weekly dosing. A total of 82 patients were treated in the dose- escalation phase I study. The ORR was 26% and 83% in the entire study population and in the most recent evalu- able cohort, respectively.33 Extramedullary disease was excluded in subcohorts of this study. AMG 701 was given intravenously on a weekly schedule with a step-up dose during the first cycle to reduce CRS, which was seen in 61% of patients including 7% who experienced grade 3 CRS. Exposure to free drug was affected to some extent by the levels of soluble BCMA, suggesting a possible interaction between the TCE and soluble antigens. The recommended phase II dose has yet to be determined.
PF-06863135
PF-06863135 is a BCMA x CD3 humanized IgG2a anti- body being evaluated in a subcutaneous formulation in an ongoing phase I study. At the 2020 ASH meeting, results from the first 18 patients were presented, indicating an ORR of 33% in the overall population, and 75% in patients receiving the two highest dose levels. The CRS rate was 61% with no CRS grade 3 events.34
CC-93269
This asymmetric, two-arm, humanized IgG BCMA x CD3 antibody is also being evaluated in a phase I study.35 The initial data from 19 patients, presented at the ASH meeting in 2019, indicated an ORR of around 80% at effective dose levels, but also CRS in over 80% of patients including one case that was fatal.36 The recommended phase II dose has yet to be determined and follow-up data are awaited.
AMG 701 is a derivative of AMG 420 with a modified
The specific and consistent expression of BCMA on
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