CHICAGO-A dual-targeted immune therapy agent, murlentamab (an anti-Mullerian hormone receptor II (AMRHII) monoclonal antibody), improved outcomes in patients who had been heavily pre-treated for their AMHRII-expressing advanced ovarian, cervical, or endometrial cancers in a phase I first-in-human study reported at the 2019 ASCO Annual Meeting (Abstract 2521).
"We established safety [and the therapy] is extremely well-tolerated. We established the dose that should be used," said Alexandra Leary, MD, PhD, a medical oncologist with the GINECO Group (Groupe d'Investigateurs National des Etudes des Cancers Ovariens et du sein) and the Institut de Cancerologie Gustave Roussyin Villejuif, France.
Study Details
Sixty-eight patients who had received a median of four prior lines of therapy were treated with murlentamab for up to 11 months. Fifty-nine had the drug as a single agent and nine received it together with cisplatin/paclitaxel chemotherapy. No dose-limiting toxicity was reported.
Leary said that when they did "activity signal-seeking" in two expansion cohorts-as a single agent in granulosa cell tumors and in a small cohort of heavily pre-treated ovarian or endometrial cancers-they showed a "nice synergy with chemotherapy."
One partial response was achieved with the new drug as a single agent in a patient with granulosa ovarian cancer. In the group treated together with added chemotherapy, four patients out of nine responded to treatment. One had a complete response and three had partial responses. Overall, 22 out of 67 patients were free of progression at 4 months.
From among 17 patients who were treated for at least 6 months, six out of nine (with granulosa tumors) who were treated with the single agent-and four out of five patients (with endometrium or cervix tumors) who received combination therapy-had longer progression-free survivals than under their previous regimens.
Pharmacodynamic assessment of 25 patients treated with the single agent showed an increase in classical monocytes and T cells, and had neutrophil activation.
Mullerian hormone receptor II (MHRII) in the cell membrane is normally activated only during embryonic development, said Leary. But it was capable of being re-expressed-particularly in gynecological tumors.
"The antibody [murlentamab] has been modified so it has a very enhanced binding capacity for CD16," giving the molecule a dual mechanism of action. "It targets tumor cells and recruits [tumor-associated] macrophages and antigen-presenting cells to result in increased phagocytosis." This process restored anti-tumor phagocytosis leading to cytotoxic T-cell reactivation.
Combination Immunotherapy
Leary noted the drug's mechanism of action suggested it could potentially be used in combination with checkpoint inhibitor immunotherapies.
"On the one [hand], it causes direct cytotoxicity via the target. And [on] the [other], it recruits macrophages to result in [an] immune response," she said.
"In [peripheral blood cells] and paired tumor samples, we also saw that after it activates macrophages the antibody also seems to recruit CD8 cells and activate them." This opened up the possibility of chemotherapy-free drug combinations, Leary noted. "An interesting next step would be to combine this antibody (targeting macrophages) with antibodies targeting CD8s by themselves, such as PD-1 or PD-L1 inhibitors."
"We have focused specifically on difficult-to-treat gynecological tumors such as granulosa cell tumors and endometrial or cervical cancer. And we have seen nice results [with] a single agent in granulosa cell tumors, and in combination with chemotherapy in cancers like cervical cancer," Leary explained.
She regarded cervical cancer as an area of unmet medical need. Activity to checkpoint inhibitor therapies had already been reported, with response rates of around 15 percent, "which is good but not enough." So the next step would be to try novel combinations to enhance benefit.
"Gynecological tumors are not melanoma or lung cancer. And single-agent [anti] PD-1 or PD-L1 will not be the answer. This is a nice opportunity to try to work on several different immune subtypes stimulating macrophages and T cells," Leary said.
It was also an advantage to have AMHRII as a diagnostic biomarker to select patients for therapy with the antibody. "You can think of it a bit as localized immune therapy [that] will only select patients who express the target AMHRII-which is in roughly 60 percent of gynecological tumors."
Peter M. Goodwin is a contributing writer.