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Bispecific T-cell engager AMG 420 active, safe in heavily pretreated multiple myeloma
CHICAGO — The investigational drug AMG 420 induced encouraging clinical responses among patients with relapsed or refractory multiple myeloma, according to data presented at ASCO Annual Meeting.
Nearly a third of patients responded to treatment in this first-in-human, dose-escalation clinical trial. There was a 70% response rate at the maximum tolerated dose (400 µg/day) evaluated in the study.
AMG 420 (Amgen) is a bispecific T-cell engager that targets the B-cell maturation antigen on multiple myeloma cells and CD3 on T cells.
“In this first-in-human study, AMG 420 — a short half-life bispecific T-cell engager molecule targeting BCMA — demonstrated clinical activity in patients with heavily pretreated multiple myeloma,” Max S. Topp, MD, associate professor of internal medicine, hematology and oncology at University Hospital Würzburg and study co-author, told HemOnc Today.
“With these data, I think it’s clear that we need to extend this study into a phase 2,” he added.
The trial included 42 patients with multiple myeloma (median age, 65 years; median disease duration, 5.2 years) as of Dec. 10, 2018. Patients had received a median of four previous therapies.
“The vast majority of patients in our study had a high tumor burden, reaching up to 80% of bone marrow in some cases,” Topp said.
Doses ranged from 0.2 µg/day to 800 µg/day, administered in 6-week cycles for at least 5 weeks or until disease progression, toxicity or withdrawal of consent. An additional five cycles could be given for benefit.
Patients received a median of 2.5 (standard deviation, 2.6) treatment cycles.
Thirteen of 42 patients responded to AMG 420 therapy, including six complete responses, two very good partial responses and two partial responses; 11 of these patients responded in the first treatment cycle, with a median response time of 1 month.
Seven of 10 patients treated with the AMG 420 dose of 400 µg/day responded to treatment, including five with minimal residual disease-negative complete responses, one very good partial response and one partial response. Treatment responses in this group lasted a median of 9 months (range 5.8-13.6).
“Of the doses tested in this study, 400 µg/day was the maximum tolerated dose, and it is the recommended dose that will be tested in the future,” Topp said.
Twenty-five patients discontinued treatment due to progressive disease; seven patients discontinued due to adverse events, three discontinued after 10 cycles of treatment, one withdrew consent, and four died. Causes of death included disease progression (n = 2) as well as flu-related acute respiratory distress (n = 1) and fulminant hepatitis related to adenovirus infection (n = 1), neither of which was related to the treatment drug.
Half of the study patients (n = 21) experienced a serious adverse event, which included infections in 12 patients. Three patients experienced grade 2 or grade 3 cytokine release syndrome. Other treatment-related adverse events included grade 3 polyneuropathy (n = 2) and edema (n = 1).
“Careful evaluation of infections should be conducted in future clinical trials to enable development of optimal management guidelines,” Topp said. – by Drew Amorosi
Reference:
Topp MS, et al. Abstract 8007. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Topp reports honoraria or research funding from, consultant/advisory or speakers’ bureau roles with, or travel expenses from Affimed Therapeutics, Amgen, Gilead Sciences, Jazz Pharmaceuticals, Regeneron and Roche; patents, royalties and other intellectual property for biomarkers for immunotherapies; and providing expert testimony for Affimed Therapeutics, Amgen, Boehringer Ingelheim and Regeneron Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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There has been a lot of excitement in multiple myeloma about B-cell maturation antigen as a target unique to plasma cells. Although there is a whole series of potential treatments targeting BCMA, CAR T-cell therapy seems to get most of the press.
This study by Topp and colleagues looks at a bispecific antibody construct that targets BCMA — one of two versions of an Amgen product currently being tested. Both are looking at ways to pull the cancer cell and the potential killer of a cancer cell into closer proximity.
The data about AMG 420 being presented at ASCO show that the treatment is certainly capable, at relatively low doses, of killing myeloma with impacts even at the lowest doses administered. At higher dose levels, we are seeing very high levels of activity.
One of the issues with CAR T cells for myeloma is that it takes a long time to construct the cells, and it’s very, very expensive. AMG 420 may be a shortcut or alternative to the same type of benefit seen with CAR T-cell therapy, except using an off-the-shelf product.
There is already a commercially available product that uses the same approach — blinatumomab (Blincyto, Amgen), which is directed at killing lymphoma, chronic lymphocytic leukemia and acute leukemias — and it has been very successful in that space. AMG 420 is an application of the same approach to multiple myeloma and the view of it so far is that it works.
We are getting our first look at the toxicities associated with this treatment, and as one might expect, there are significant ones, such as infections. There are also short-term neurologic toxicities that resolve with discontinuation of the drug.
Nevertheless, we have every reason to be excited about these findings. The results we are seeing with AMG 420 are comparable to what we saw with CAR T-cell therapy, which is being held up as the gold standard of immunotherapy. I’m not sure that the depth of response for AMG 420 is comparable to CAR T, but AMG 420 is something that can be administered continuously.
If we can’t cure myeloma patients with one dose of CAR T cells, then AMG 420 may be a less complex and longer-term intervention that may end up controlling disease for longer periods of time than CAR T cells.
It’s hard to say where AMG 420 might be placed in the strategy to treat multiple myeloma, but if we can continue to push up the dose to higher levels and use it in combination with other therapies, this could be a very important asset in the treatment of this disease.
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B-cell maturation antigen has been identified as a promising new target for treatment of multiple myeloma. CART cells have been manufactured to target this antigen.
However, this technology has several challenges. From a side-effect profile, cytokine release syndrome and central neurological symptoms most likely caused by an overactivation of these modified immune cells are significant. Further, because mostly heavily pretreated patients with advanced and often aggressive disease are enrolled in clinical trials with BCMA-directed CAR T cells, the manufacturing time of more than 3 weeks can become an issue. Therefore, an “off-the-shelf” product with a similar mechanism of action is desirable. Bispecific antibodies such as blinatumomab have already been established in other hematologic malignancies, but not yet in multiple myeloma.
This study reports on early results of using a bispecific antibody, or so-called T-cell engager. AMG420 is a construct that connects the myeloma cell via BCMA on one side with a T cell via CD3 on the other. The study objectives were to find the maximum tolerated dose, assess safety and tolerability, and to show first antimyeloma activity of the compound. Forty-two patients with relapsed or refractory myeloma after two or more lines of therapy were enrolled in this phase I study to receive up to 10 cycles of a 4-weeks-on, 2-weeks-off schedule of continuous infusion of the bispecific antibody.
This is a new treatment approach with some benefits over CAR T cells. However, the data are very limited and further studies are needed to evaluate the side-effect profile and efficacy using the maximum tolerated dose of 400 µg daily. An important challenge of this treatment is the constant infusion over 4 weeks. Further development of bispecific antibodies with longer half-lives is underway.