ASCO data for Amgen’s acute leukemia drug disappoint, but path forward remains, experts say

Experts expressed dismay at single-agent data from the Phase I study, which a spokesperson noted was still in dose expansion. However, the drug could have a future in combinations or in patients with minimal disease left over after prior treatment.

Amgen’s booth at the 2019 ASCO conference in Chicago

An immunotherapy approach that has led to promising results in acute lymphoblastic leukemia and multiple myeloma has produced results in another form of leukemia that experts found less impressive, though the drug using it may yet have a path forward.

Phase I data for Thousand Oaks, California-based Amgen’s AMG 330 in patients with relapsed or refractory acute myeloid leukemia were presented at the American Society of Clinical Oncology’s annual meeting, which took place online between Friday and Sunday due to the Covid-19 pandemic.

AMG 330 is a bispecific antibody that works by targeting CD33, an antigen widely expressed on the surface of AML cells, and then using another antigen, CD3, on the surface of T cells, to enable the latter to target the former. Data on 42 patients evaluable for efficacy showed that seven achieved a complete remission with or without complete blood count recovery, yielding what is known as a CR/CRi rate, of 16%. The CR/CRi rate included patients receiving at least the minimal efficacious dose of 120 micrograms per day. Three of the responders treated with at least 600 micrograms remained in response as of the December 10, 2019 cutoff. Dosing up to 720 micrograms per day showed acceptable safety, tolerability and anti-leukemic activity, the study abstract concluded.

In an emailed statement, Amgen spokesperson Trish Rowland noted that survival rates in AML are among the lowest among blood cancers, with 40% of patients alive a year after diagnosis and a survival rate of 5% among those older than 65 after five years, thus necessitating new treatments. “While the AMG 330 Phase I study in patients with relapsed/refractory AML is still in dose expansion, anti-tumor activity was observed in patients including those who were heavily pre-treated and those with averse cytogenetic risk,” she wrote.

Still, interviewed experts expressed disappointment.

“I was not impressed by the efficacy,” University of California Los Angeles professor of hematology-oncology Dr. Gary Schiller said in a phone interview, though he added that it’s possible patients were not dosed high enough. He also pointed to the rate of cytokine release syndrome – a common side effect with bispecific antibodies – as unfavorable.

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“If you had a high response rate, you would not think twice about it,” Schiller said, referring to the rate of CRS. “But here there was not such a high response rate,” Schiller said.

According to the data, CRS occurred in 67% of 55 patients in the safety analysis, 13% of whom experienced it at levels considered severe or worse.

“We have been waiting for the data with the CD33 BiTE for a while now, and it was a little disappointing,” said Dr. Eunice Wang, chief of the leukemia service at the Roswell Park Comprehensive Cancer Center in Buffalo, New York, referring to Amgen’s bispecific antibody development platform.

However, the drug could still have utility in AML, such as in combination with other agents or in the setting of patients who have minimal residual disease, or MRD, which refers to the presence of a small number of cancer cells left over after treatment. There is precedence for this: Wang pointed to the initial approval of Blincyto (blinatumomab), Amgen’s CD19-targeting BiTE antibody, for MRD-positive acute lymphoblastic leukemia, in 2014. That could be especially pertinent given the advancements in recent years in the ability to detect lower and lower levels of MRD.

“The addition of [Blincyto] in that setting has been shown to eradicate MRD, which translates to overall very high long-term response rates,” she said.

Another potential use is in combination with other agents, such as checkpoint inhibitors. Wang noted that one potential limitation of AMG 330 by itself is its mechanism of action: Rather than working directly against cancer cells, it brings the host’s T cells in to kill them. That, in turn, depends on the potency of the patient’s own immune response, which may be diminished in the case of relapsed/refractory AML, thereby reducing the efficacy, she said. That means the drug could also have utility in patients with less heavily pretreated disease, who in turn have higher T-cell counts.

“In summary, I think it’s promising,” Wang said. “It does demonstrate activity and tolerability and proves that a bispecific antibody approach can lead to responses in acute leukemia.”

Photo: Alaric DeArment, MedCity News