Efficacy and Beyond

The clinical activity of AMG 420 and the other BCMA-targeted therapies is just one aspect to consider; there’s also manufacturing, administration, and safety differences. For example, compared with CAR-T cell therapies, AMG 420 is easier to manufacture. “The nice thing about BiTEs is they’re off the shelf,” Chris Mehlin, PhD, senior staff scientist at Fred Hutchinson Cancer Research Center, Seattle, Washington, told Cancer Therapy Advisor. As Dr Mehlin, a former employee of Amgen who joined Fred Hutch about 6 years ago, explained, “You don’t have to transfect T cells, and you don’t have all the manufacturing headaches and expense associated with doing that.”

During an interview with Cancer Therapy Advisor, Premal Lulla, MBBS, assistant professor of medicine, Center for Cell and Gene Therapy, Hematology-Oncology, Baylor College of Medicine, Houston, Texas, explained that the off-the-shelf potential also opens BiTEs to a larger patient population compared with CAR-T cell therapies because patients don’t have to wait for the therapy to be manufactured. “Some of the patients on BCMA CAR [T] trials would drop off because of either manufacturing failures or they get too sick and become ineligible to receive them,” Dr Lulla said, who was not involved in the current study.


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The downside to AMG 420 is it must be continuously infused because like most BiTEs —including Amgen’s blinatumomab, the only FDA-approved BiTE to date — AMG 420 has a very short half-life. For the dose-escalation study with AMG 420, patients had to undergo continuous infusion for 28 days.

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The continuous infusion, Dr Lulla said, is a treatment barrier, but one that his institution has managed to overcome for blinatumomab. Patients receive their first infusion in the inpatient setting and are observed for 3 or 4 days, and then they are allowed to go home with periodic checks to ensure that the infusion pump is working. “That has been quite a good strategy for some of our patients,” he said.

In addition, continuous infusion may not even be a permanent fixture of BiTEs. Dr Mehlin explains that it is possible to extend the half-life of BiTEs so that continuous infusion is not required. The most obvious strategies are to combine the BiTE with proteins known to extend half-lives, such as serum albumin, but, he said, “it would be a different molecule and you would have to get that re-approved.” In fact, Amgen is already evaluating a half-life–extended version of AMG 420 — dubbed AMG 701 — in a phase 1 clinical trial and the dosing would be only once-weekly (ClinicalTrials.gov Identifier: NCT03287908).

Another differentiating factor for AMG 420 is its safety profile, which may be reason for concern. Specifically, 2 patients — 1 who received a dose of 400 µg/day and the other 800 µg/day — developed grade 3 peripheral polyneuropathy that was considered a dose-limiting toxicity and directly related to treatment. “With regard to BiTEs, this is the first time, I think, we have seen a BiTE that has a neuropathy as a side effect that’s pretty severe,” said Dr Lulla.

The patient treated at a dose of 800 µg/day required hospitalization and the polyneuropathy was treated and resolved within 1 month. For the patient treated at 400 µg/day, the polyneuropathy was treated and returned to baseline — that is, grade 1 — within 2 months. Dr Lulla said it appears that the polyneuropathy is reversible and not tied to having a response, both of which are good signs, but “more patients are needed to understand the pathophysiology.”

The updated analysis for AMG 420 also showed that 16 patients (38%) had cytokine release syndrome; 13 cases were grade 1, and 13 patients (31%) had infections, 2 of which led to death. One death was the result of fulminant hepatitis related to adenovirus infection, and the other patient died from concurrent influenza and aspergillosis; neither death was deemed related to treatment with AMG 420.

Dr Lulla commented that while these infections are rare in myeloma patients, he felt that the patients’ prior therapies helped explain the infections, agreeing with the study investigators that the infections were not related to treatment. “At the same time,” he added, “we need more numbers to be sure what’s going on with the immune system.”

Given the positive results of the dose-escalation study, a single-arm, open-label phase 1/2 clinical trial is now under way to evaluate AMG 420 at a dose of 400 µg/d or 600 µg/d in patients with relapsed/refractory multiple myeloma (ClinicalTrials.gov Identifier: NCT03836053).

References

  1. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study. Presented at 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 8007.
  2. Cho S-F, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1821.
  3. Trudel S, Lendvai N, Popat R, et al. Antibody–drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37.
  4. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726-1737.
  5. Mailankody S, Htut M, Lee KP, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 957.
  6. Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory multiple myeloma. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 1012.
  7. Topp MS, Duell J, Zugmaier G, et al. Treatment with AMG 420, an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE®) antibody construct, induces minimal residual disease (MRD) negative complete responses in relapsed and/or refractory (R/R) multiple myeloma (MM) patients: results of a first-in-human (FIH) phase I dose escalation study. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 1010.
  8. Amgen. Amgen announces first-in-human data evaluating investigational novel BiTE® immunotherapies AMG 420 and AMG 330 at ASH 2018 [news release]. Thousand Oaks, CA: Amgen, December 3, 2018. Accessed July 5, 2019.