Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy in patients with R/R multiple myeloma

Share :
Published: 6 Jun 2019
Views: 2504
Prof Max Topp - University of Würzburg, Würzburg, Germany

Prof Max Topp talks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the results from a first in-human phase I dose escalation study using the bispecific antibody construct, AMG 420 in patients with relapsed/refractory multiple myeloma.

He explains the use of AMG 420, along with the primary objectives, safety and tolerability of the drug. Secondary endpoints included anti-tumour probabilities of this therapy.

Prof Topp reports that the maximum tolerated dose was reached (800 mg/day) along with the safety and efficacy profile of this treatment.

In the upcoming phase II trial, Prof Topp hopes to consolidate the positive results achieved in this study and believes that AMG 420 may have a potential role in treating MRD-positive myeloma after front-line therapy.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Today’s abstract was a presentation about the first in human study on AMG 420. It’s a bispecific antibody construct utilising as target structure multiple myeloma BCMA. BCMA is a receptor that has been the focus of myeloma and is being now addressed by three different ways, either through immune conjugate, that data that has been presented before with a response rate of about 62-63% in the patients. There is the CAR T-cell field that is also engaging with BCMA CARTs, there has been a New England paper just very recently published showing also response rates of CR as 45% with the majority of the patients end up being MRD negativity. Then the last way of exploiting BCMA expression is by using the bispecific antibody platform, BiTE technology, and now this is a first in human study of a dose escalation, a phase I trial.

The primary objective was to identify the MTD and the safety and tolerability and the secondary endpoints would be, of course, anti-tumour probabilities of this novel concept. The MTD was reached which was at 800μg per day continuous infusion. We saw two patients who classified as having DLT, one had a cytokine release syndrome grade 3 but which resumed very quickly after stopping the drug, within 48 hours back to baseline. The second patient developed a polyneuropathy three or four weeks after initiating treatment which needed also ITG infusions and steroids to be treated but then also returned back to baseline.

In terms of the safety profile what we saw were actually two signals – cytokine release syndrome, the vast majority was just grade 1 treated just with paracetamol. There were two patients with grade 2 cytokine release syndromes which needed then dexamethasone and there was just that one DLT patient who had a cytokine release syndrome of grade 3 by the CTCAE4 criteria. The second signal that we saw was safety, was infectious complications. Particularly we lost two patients on the clinical trial due to infections, one with an aspergillosis on the bottom of an influenza infection and then the second patient due to adenovirus infection of the liver. There were a couple of other patients with chest infections, viral related, and some central venous line infections.

So in terms of the efficacy the first patient that responded on this 3 3 dose escalation design was at 6.5μg per day drug who reached then a very good partial remission. Then as we were escalating we saw at several other dose levels single patients responding. But once we crossed the border at 400μg three patients out of three in the DLT evaluation period had a response. Then once we also went up to 800μg and went back and had a mini expansion cohort we saw an additional four patients responding at 400μg per day. So overall the response rate at the suggested dose of 400μg is seven out of ten patients and what is really meaningful is five of them had an MRD negative CR measured by flow cytometry. The vast majority of those patients are still on continuous response, we’ve only just had two patients who actually have had a relapse in that situation.

So that is one very important point of this trial, that in the dose of 400μg we had seven out of ten responding. The other thing that we also saw which is that there were three patients where we prematurely stopped AMG 420. Two of them had the polyneuropathy so we had to stop treatment in the first cycle and then we had one patient who stopped treatment due to ID problems on cycle 4, they were allowed to get 10 cycles. All those three patients are still in continuous remission with only a really short period of treatment of maybe just three weeks. So we don’t know exactly what that means but this is obviously something that we would like to investigate in the upcoming phase II trial which has already started now and where we hope to really consolidate these very nice results.

In what way do you think the results may impact clinical practice?

It’s an excellent question, of course; the field of myeloma is quite crowded. The current phase II trial is going to be in patients who are double refractory to IMiDs and proteasome inhibitors and also don’t respond anymore to daratumumab. So that is actually quite a sick population. But this is just a registration trial, a single arm trial.

The bigger picture, I feel, AMG 420 may have a role in treating MRD positive myeloma after front line therapy as it applies a different mode of action than the current ways of putting a patient into remission. So that’s one way I would envision it or it could be also sequentially in the consolidation cycles of multiple myeloma after using modern induction regimens like KRD and daratumumab, for example, plus or minus high dose chemotherapy. This could also be another way of actually using consolidation cycles and sequentially using that with KRD and AMG 420. So that’s my personal vision of it, we’ll see what happens down the road.