Novel BiTE Immuno-Oncology Therapy Appears Safe with Preliminary Efficacy in mCRPC

A novel BiTE immuno-oncology therapy, AMG 160, demonstrated a manageable safety profile, with preliminary evidence of efficacy in men with metastatic castration-resistant prostate cancer (mCRPC) who were heavily pretreated, according to preliminary results from a phase 1 study (NCT03792841) presented at the virtual 2020 ESMO Congress.

“Despite the long list of agents now approved for the treatment of metastatic castration-resistant prostate cancer, there remains an urgent need for treatments that can overcome resistance to hormonal therapies, chemotherapies, and radiation therapies. And despite impressive activity in other cancers, novel immune-based therapies have offered limited efficacy in mCRPC,” Ben Tran, MBBS, FRACP, Peter MacCallum Cancer Centre, Melbourne, Australia, explained during a presentation at the virtual Congress.

Therefore, he and his colleagues evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of AMG 160—a targeted half-life extended BiTE (bispecific T-cell engager) immune therapy that engages patients’ own T cells to kill prostate cancer cells by binding CD3 on T cells and prostate-specific membrane antigen (PSMA) on cancer cells.

In the global, open-label phase 1 study, the investigators will evaluate the safety and tolerability of AMG 160 monotherapy (part 1) or in combination with pembrolizumab (Keytruda; part 2) in men with mCRPC that is refractory to prior novel hormonal therapy and 1 to 2 taxane regimens and evidence of progressive disease.

“The study is nearing completion of the dose exploration phase 1b, followed by those expansion phase armory objectives to evaluate the safety and tolerability of AMG 160 and to determine its recommended phase 2 dose and secondary objectives to characterize pharmacokinetics and evaluate preliminary anti-tumor activity,” Tran said.

AMG 160 was administered as a short IV infusion every 2 weeks at doses of 0.003 mg to 0.9 mg.

Patients were a median age of 66 years (range, 49-78). The majority of patients were white (79.1%) and had 4 or more prior lines of therapy (60.5%). Median PSA at baseline was 79.2 μg/L (range, 0.1-4035.0 μg/L).

Forty-three patients received ≥ 1 dose of AMG 160 monotherapy, of which 41 (95.3%) experienced treatment-emergent adverse events (TEAEs). In addition, 19 patients remained on treatment at the time of data analysis.

Forty-one patients experienced treatment-related AEs (TRAEs), including cytokine release syndrome (CRS; 90.7%), fatigue (44.2%), vomiting (44.2%), nausea (39.5%), pyrexia (37.2%), headache (34.9%), diarrhea (32.6%), dry mouth (30.2%), rash (27.9%), hypophosphatemia (25.6%), hypotension (23.3%), chills (23.3%), dysgeusia (23.3%), and decreased appetite (20.9%). Of note, no grade 5 events occurred and none resulted in treatment discontinuation. In total, 3 reversible dose-limiting toxicities occurred (grade 3 rash, n = 2; grade 3 gastrointestinal hemorrhage, n = 1).

CRS observed in patients was reversible and manageable. The AE was most severe in cycle 1 and was associated with fever, hypotension, transient transaminitis, nausea/vomiting, and/or diarrhea. There were no grade 4/5 CRS events or treatment discontinuations. Grade 2 CRS occurred in 26 patients (60.5%) and grade 3 in 11 patients (25.6%).

Of the 30 patients assessed for antidrug antibodies (ADAs), 6 (20.0%) had ADAs affecting drug exposure between cycles 1 and 10; however, no AEs associated with ADAs occurred.

“A number of mitigation strategies were used to improve the CRS profile of AMG 160,” Tran said. “Prophylactic mitigation was step dosing or dose priming, in which lower running doses were given prior to the maintenance target dose, which is administered every 2 weeks. Free medication with dexamethasone and prophylactic hydration with IV normal saline were also administered. These mitigation strategies appear to be effective in minimizing the risk of grade 3 serious events and serious adverse events.”

In total, 27.6% of patients had a confirmed PSA response to AMG 160. Overall, 68.6% of patients showed any PSA decline across all monotherapy dose cohorts and 34.3% of patients showed ≥ PSA50 reduction.

Among the 15 patients with measurable disease, 3 patients experienced a partial response (2 confirmed) and 8 patients had stable disease. Moreover, 44.2% of patients remained on AMG 160 at the time of data analysis, with 6 (14.0%) patients continuing treatment for ≥ 6 months.

Maximum tolerated dose has not been reached and dosing optimization of AMG 160 continues. Meanwhile, the investigation of AMG 160 in combination with pembrolizumab is in progress.

Reference

1. B. Tran, L. Horvath, T. Dorff, et al. Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 609O.