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On Sunday 2 June, 2019, Professor Max Topp, University of Würzburg, Würzburg, DE, presented the results of the phase I trial of AMG 420 (BI 836909) in relapsed/refractory multiple myeloma (RRMM), at the annual American Society of Clinical Oncology (ASCO) meeting, in Chicago, US.
AMG 420 is a bispecific T-cell engager (BiTE®) antibody construct that binds to B-cell maturation antigen (BCMA) on tumor/plasma cells, and CD3 on T-cells. This dual action leads to T-cell mediated lysis of BCMA+ cells.
Table 1: Patient characteristics
ECOG, Eastern Cooperative Oncology Group; IMid, immunomodulatory drugs; PI, proteosome inhibitor |
|
|
N= 42 |
---|---|
Median age (year) |
65 (39–79) |
ECOG status (0 vs 1 vs 2) |
57% vs 40% vs 2% |
Cytogenetics (standard vs intermediate vs high) |
55% vs 31% vs 14% |
Median prior lines of therapy |
4 (2–13) |
Prior monoclonal antibody (daratumumab vs elotuzumab) |
26% vs 10% |
Refractory to monoclonal antibody (daratumumab vs elotuzumab) |
21% vs 10% |
Refractory to IMid/PI/IMid and PI |
55% vs 45% vs 31% |
Table 2 shows a summary of the three grade 3 DLTs that occurred. The MTD was determined to be 400μg/day. No anti-AMG 420 antibodies were detected up to 800μg/day.
Table 2: Summary of grade 3 DLTs
|
DLT |
Dose of AMG 420 |
Timing of DLT |
Notes |
---|---|---|---|---|
1 |
CRS |
800μg/day |
1 day after treatment start. Resolved after AMG 420 was discontinued |
Symptoms; fever, hypertension, tachycardia and retrograde amnesia |
2 |
Peripheral PN |
800μg/day |
1 week after treatment start, required hospitalization by day 14
|
M protein decreased by 58% after 15 days of treatment. PN resolved with IV Ig and corticosteroid |
3 |
PN |
400μg/day |
Grade 1 PN developed to grade 3 by day 30 and improved to baseline by day 84 |
M protein decreased by 79% after 28 days of treatment. PN resolved with IV Ig and corticosteroid |
CRS, cytokine relase syndrome; DLT, dose-limiting toxicities; PN, polyneuropathy |
The safety data for CRS, SAEs and treatment-related SAEs is shown in Table 3. Of the two patients who died of infection, one died of aspergillosis/flu and one died of fulminant hepatitis related to adenovirus infection. Neither were deemed to be treatment-related.
Of the 19 patients (45%) experiencing a SAE, 16 were hospitalized, 4 for a prolonged period. No grade 3–4 central nervous system toxicities were observed.
Table 3: CRS, SAEs and treatment-related SAEs grade 1–5 (N= 42)
CRS, cytokine relase syndrome; PN, polyneuropathy; SAEs, serious adverse events | ||||||
Grade |
Total |
1 |
2 |
3 |
4 |
5 |
---|---|---|---|---|---|---|
CRS |
16 (38%) |
13 |
2 |
1 |
- |
- |
SAEs (≥2 patients) |
|
|
|
|
|
|
Infections |
13 (31%) |
- |
3 |
8 |
- |
2 |
PN |
2 (5%) |
- |
- |
2 |
- |
- |
Treatment-related SAEs |
|
|
|
|
|
|
PN |
2 (5%) |
- |
- |
2 |
- |
- |
Edema |
1 (2%) |
- |
- |
1 |
- |
- |
Currently, two patients remain on therapy, with the remainder having discontinued for the following reasons; PD (n= 25, 60%), AEs (n= 7, 17%), death (n= 4, 10%), completion of 10 cycles (n= 3, 7%), and withdrawal of consent (n= 1, 2%). Deaths were attributable to disease progression (n= 2) and AEs (n= 2).
At a dose of 400μg/day (n= 10), 5 MRD negative complete responses (CRs) were seen, with 1 very good partial response (VGPR) and 1 partial response (PR) giving a response rate of 70%, lasting for a median of 9.0 months (5.8–13.6).
In total, 13 patients responded (13/42), with a median time to response of 1 month, lasting for 8.4 months on average (2.5–15.5). MRD negative CRs lasted for a median of 9.6 months (2.8–12.8), with 5 of these patients in the 400μg/day cohort. Aside from the patients whose last response at evaluation was PD (n= 5), all patients were responding.
Responses at doses less than 200μg/day were:
Table 4: Characteristics of responding patients at doses ≥200μg/day
CR, complete response; EOT; end of treatment, N/A; patient received 10 cycles or treatment ongoing as of April 2019 (maximum); MRD, minimum measurable disease; PD, progressive disease; PN, polyneuropathy; PR, partial response; VGPR, very good partial response | |||||
Dose (μg/day) |
Number of cycles to response |
Prior lines of therapy |
Reason for discontinuation |
Best response |
Cycle of best response |
---|---|---|---|---|---|
200 |
4 |
6 |
Port infection |
MRD- CR |
3–4 to 11 months post-treatment |
400 |
7 |
3 |
N/A |
MRD- CR |
3–7 |
400 |
10 |
4 |
N/A |
MRD- CR |
3–10 |
400 |
8 |
6 |
PD |
MRD- CR |
1–7 |
400 |
10 |
2 |
N/A |
MRD- CR |
1–10 |
400 |
5 |
5 |
PD |
MRD- CR |
3–4 |
400 |
1 |
5 |
PN |
VGPR |
From EOT to 7 months post-EOT |
400 |
1 |
5 |
Death |
PR |
1 |
800 400 (dose reduction) |
2 1 |
5 |
Withdrew consent |
VGPR |
2–3 |
800 |
0.5 |
5 |
PN |
PR and CR |
PR in 1, CR 9 months post-EOT |
AMG 420 demonstrates activity in a heavily pre-treated population with RRMM who had received, on average, 4 prior lines of therapy. At the MTD of 400μg/day there was a 70% response rate, with 5 patients achieving MRD negative CR. No major toxicities were reported in the dose escalation portion of the study, subsequently DLTs were experienced by three patients. In addition, 13 (31%) patients experienced infections, 10 of which were grade 3 or above. Professor Topp suggested that future clinical trials of AMG 420 should thoroughly evaluate infection risk in order to best inform AE management guidelines. A phase Ib/II trial is ongoing.
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