Preliminary results of phase I trials on safety and tolerability of bispecific antibodies and BiTEs for RRMM

The Multiple Myeloma Hub previously conducted a review of the bispecific antibodies that are under clinical evaluation to treat patients with relapsed/refractory multiple myeloma (RRMM). A summary of the available data from these clinical studies was published in October 2020 and is available here. The article described the mechanism of bispecific antibodies, bispecific T-cell engagers (BiTEs), and presented the preliminary results (where available) of several clinical trials.

At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, held in December 2020, data on safety and efficacy were presented for four novel treatments, which have been summarized below. Findings from two other phase I trials evaluating the bispecific antibodies talquetamab and teclistamab in RRMM patients, have been recently reported on the hub.

New bispecific antibodies and BiTEs presented at ASH 2020

Two B-cell maturation antigen (BCMA)-targeting bispecific antibodies, REGN5458¹ (NCT03761108) and TNB-383B² (NCT03933735), and one BiTE, AMG 701³ (NCT03287908), were evaluated for safety and efficacy in phase I dose-escalation trials. Additionally, we learned about the initial results of a study with a bispecific antibody targeting a new antigen for MM: the anti-FcRH5 cevostamab (BFCR4350A)⁴ (NCT03275103).

These trials included patients who have progressed after ≥ 3 prior lines, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD®), and an anti-CD38 monoclonal antibody (mAb) therapy. The baseline characteristics (Table 1) for age, gender, and prior lines of therapy in all trials were similar except for TNB-383B, which reported data for the MM subtype and patient ethnicity (21% Black or African American patients).

Table 1. Baseline characteristics (summary of the four trials)^1,2,3,4

BMCA, B-cell maturation antigen; ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; IMiD, immunomodulatory drug; ISS, International Staging System; mAb, monoclonal antibody; MM, multiple myeloma; NR, not reported; PI, proteasome inhibitor; R-ISS, Revised International Staging System.
Characteristic	BCMA-directed therapies			Anti-FcRH5 bsAb
	AMG 701 (N = 85)	REGN5458 (N = 49)	TNB-383B (N = 58)	BFCR4350A (N = 53)
Male/Female, n (%)	44/41 (52/48)	25/24 (51/49)	35/23 (60/40)	31/22 (59/41)
Age, years, median (range)	64 (34–83)	64 (41–81)	66 (37–88)	62 (33–80)
Race
Black or African American, n (%)	NR	NR	12 (21)	NR
White, n (%)	45 (78)
Not reported, n (%)	1 (2)
ECOG performance status, n (%)
0	NR	14 (29)	15 (26)	NR
1	34 (69)	33 (57)
2	1 (2)	9 (16)
ISS or R-ISS, n (%)
I	18 (21)	8 (16)	NR	NR
II	41 (48)	31 (63)	NR
III	22 (26)	10 (20)	19 (33)
unknown	4 (5)	0	NR
Prior lines of therapy, median (range)	6 (2–25)	5 (2–17)	6 (3–15)	6 (2–15)
Triple exposed, n (%) Triple refractory (PI, IMiD, and anti-CD38 mAb), n (%)	79 (93) 53 (62)	NR 49 (100)	58 (100) 37 (64)	NR 38 (72)
Penta-drug exposed, n (%) Penta-refractory, n (%)	NR NR	NR 28 (57)	44 (76) 20 (34)	NR 24 (45)
MM subtype, n (%)
IgG	NR	NR	30 (52)	NR
IgA	12 (21)
Light chain	13 (22)
Other	3 (5)

Safety

Table 2 summarizes the adverse events from the four trials.

AMG 701

Twenty-one patients continued treatment with AMG 701, while the remaining discontinued mainly due to progressive disease (n = 51), and five due to adverse events (AEs). There were four deaths from AEs, none related to AMG 701: sepsis (n = 2), retroperitoneal bleeding (n = 1), and subdural hematoma (n = 1). The most common serious adverse events (SAEs) were infections (17%) and cytokine release syndrome (CRS; 9%). Grade III CRS dose-limiting toxicities (DLTs) were seen in eight patients and non-CRS Grade III/IV in three patients.

REGN5458

The most common Grade ≥ 3 AEs were hematologic. DLTs occurred in two patients but were resolved with supportive care. No Grade ≥ 3 CRS was reported, while Grade I and II CRS were reported in 84% and 16%, respectively. The median duration of CRS onset was 18.7 hours (range, 6–382), and the median duration of CRS was 11.7 hours (range, 0–77). There was no correlation between CRS, dose level, and response to treatment.

TNB-383B

Thirty-three patients discontinued treatment, mainly due to progressive disease (n = 30), DLT (n = 1), and COVID-19 (n = 2). The most common AEs were CRS (45%) and hematologic toxicities (≈20%). Despite the increase in AEs (80%) due to CRS (Grade I and II) at doses ≥ 40 mg, non-CRS AEs, including Grade III/IV, remained stable at any given dose. Grade ≥ 3 treatment-emergent AEs were seen in 57% of patients.

Grade I/II CRS was seen in 26% of patients, with no Grade III CRS being observed. The median onset time of CRS was ≤ 1 day (range, 0–7), and the median duration of CRS was 1 day (range, 1–7).

BFCR4350A

The most common AE was CRS (76%) but of Grade I or II. Infusion-related reactions were observed in 23% of patients. Twenty-eight patients had serious AEs with treatment-related events seen in 13 patients. Five patients had AEs leading to withdrawal, with treatment-related events seen in two patients: pneumonitis and meningitis seen in one patient each. There were no treatment-related Grade V events, and only one patient with DLT of Grade III pneumonia was seen in the 3.6/90 mg group.

Table 2. Adverse events (summary of the four trials )^1,2,3,4

AST, aspartate aminotransferase test; CRS, cytokine release syndrome; NR, not reported; SAEs, serious adverse events.
Event	AMG 701	REGN5458		TNB-383B		BFCR4350A
		Any grade	Grade ≥ 3	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3
CRS grade, n (%)
Grade I	23 (27)	16/19 (84)	NR	NR	0 (0)	18 (34)	NR
Grade II	24 (28)	3/19 (16)	21 (40)
Grade III	8 (9)	0 (0)	1 (2)
Hematologic (%)
Anemia	42	37	22	21	17	28	19
Neutropenia	25	16	14	19	16	17	15
Thrombocytopenia	21	18	6	17	14	32	25
Lymphopenia	NR	18	12	NR	NR	15	15
Nonhematologic (%)
CRS	65	39	0	45	0	76	2
Diarrhea	31	NR	NR	12	0	28	2
Hypophosphatemia	31	NR	NR	NR	NR	19	9
Fatigue	NR	35	6	24	2	17	4
Nausea	NR	31	0	21	0	19	0
Pyrexia	NR	31	2	16	2	74	NR
Back pain	NR	27	4	NR	NR	NR	NR
Headache	NR	NR	NR	22	2	8	NR
Infection	17	47	18	21	14	NR	NR
Vomiting	NR	NR	NR	14	0	NR	NR
Chills	NR	NR	NR	12	0	15	NR
Hypomagnesemia	NR	NR	NR	12	0	28	0
Infusion-related reaction	NR	NR	NR	NR	NR	23	0
Hypokalemia	NR	NR	NR	NR	NR	21	4
AST increased	NR	NR	2	NR	NR	15	2
SAEs (%)	38	NR	NR	33	NR	53	NR

Efficacy

Table 3 summarizes the overall response rate (ORR) from trials with AMG 701, REGN5458, TNB-383B, and BFCR4350A.

AMG 701

Data cutoff: July 2020

Median duration for treatment was 7.6 weeks (range, 4.1–15.1). The ORR to the treatment was highest (83%) in the recent cohort of six patients, with 50% ≥ very good partial response (VGPR). Six out of seven patients were minimal residual disease (MRD)-negative with stringent complete response (sCR; n = 3), complete response (CR; n = 3), and VGPR (n = 1). All six patients have ongoing responses, and the median duration of response in one patient is 22 months.

The median response to treatment was 5.6 months, and the median follow-up time for responding patients was 6.5 months (range 1–27). The study did not assess median duration of response as they are still ongoing in 17/21 patients. AMG 701 indicated a good pharmacokinetics (PK) profile in its target patient population of RRMM, with AMG 701 exposures increasing in a dose-related manner and supporting the once-weekly dosing regimen.

REGN5458

Data cutoff: June 2020

The median duration of follow-up was 2.6 months (range 0.5–13.4). The ORR was 39% with 95% (18/19) of responders achieving VGPR. A CR or sCR was observed in 42% (8/19) of patients. The median duration of response was 6 months (range 1.0–13.1) and 37% of responders have maintained response for ≥ 8 months. 74% of the responders are currently continuing treatment. MRD negativity was achieved in 57% (4/7) patients. Treatment with REGN5458 showed early, consistent, and durable responses in RRMM patients.  

TNB-383B

Data cutoff: October 2020

The ORR was 80% at doses ≥ 40 mg of TNB-383B with 60% of patients attaining VGPR, and 13.3% CR. MRD-negativity was seen in three out of four patients. Response to treatment continued to improve with ongoing treatment in 22/27 patients. Median duration of response was up to 18 weeks.

The PK profile of TNB-383B was proportionate with 5.4 mg onwards, and supportive of doses ≥ 20 mg once every three-week schedule.

BFCR4350A

Data cutoff: April 2020

A 53% ORR was observed in the ≥ 3.6 mg/20 mg group and no response was seen in the ≤ 3.6/10.8 mg group. The median time to first response was 29.5 days (range, 21–105), and to best response was 57.5 days (range, 21–272). MRD-negativity was seen in 6/7 patients, and 32% of patients showed ≥ VGPR in the ≥ 3.6 mg/20 mg group. Median follow-up in patients responding to treatment was 10.3 months (range, 2.7–19.5). Eight patients showed durable response to treatment with a response duration of ≥ 6 months, and four patients continued to respond despite treatment discontinuation. The PK profile with BFCR4350A exposures increased in a dose-related manner and was supportive of the dosing regimen.

Table 3. Overall response rate (summary of the four trials)^1,2,3,4

Therapy	ORR (%)
BiTE, bispecific T-cell engager; DL, dose levels; ORR, overall response rate.
AMG 701
All patients (n = 82)	26
Dose 0.015–1.6 mg (n = 27)	4
Dose 3–18 mg (n = 55)	36
Most recent cohort (n = 6)	83
REGN5458
All patients (N = 49)
DL 1–3 (n = 24)	29.2
DL 4–5 (n = 17)	41.2
DL 6 (n = 8)	62.5
TNB-383B
0.025–1.8 mg (n = 15)	20
5.4–30 mg (n = 28)	43
40–60 mg (n = 15)	80
BFCR4350A
≥ 3.6/20 mg (n = 34)	53
3.6/20 mg–3.6/60 mg (n = 16)	44
3.6/90 mg–3.6/132 mg (n = 18)	61

 Conclusion

The preliminary findings from these clinical trials indicate that AMG 701, REGN5458, TNB-383B, and BFCR4350A have a good safety profile and show a durable efficacy in heavily pretreated RRMM patients. ORRs were encouraging across all patients, and responses improved over time. The dose-escalation studies for all four treatments are ongoing.