Manageable safety profile and preliminary evidence of efficacy of the bispecific T-cell engager AMG 160 in metastatic castration-resistant prostate cancer

ESMO 2020 featured the first results of a phase I study evaluating AMG 160, a half-life extended, PSMA-targeted, bispecific T-cell engager (BiTE^®) in patients with metastatic castration-resistant prostate cancer (mCRPC). Overall, AMG 160 as monotherapy had a manageable safety profile without grade 5 treatment related adverse events or toxicity related treatment discontinuations. In addition, this novel agent showed promising preliminary evidence of efficacy in a heavily pre-treated patient cohort.

Introduction

Over the last decade, a long list of drugs emerged for the treatment of patients with mCRPC. Nevertheless, the medical need for patients with resistance to chemotherapy, hormonal therapy and radiation therapies remains prominent. Despite impressive activity in various other cancer types, to date, immune therapies have offered limited efficacy in mCRPC. In recent years, the prostate-specific membrane antigen (PSMA) was validated as a therapeutic target in prostate cancer. AMG 160 is a targeted half-life extended (HLE) bispecific T-cell engager (BiTE^®), an immune therapy that engages patients’ own T cells to kill prostate cancer cells via binding of CD3 on T cells and PSMA on cancer cells. At ESMO 2020, preliminary results from the dose exploration portion of an ongoing phase I study of AMG 160 in mCRPC were presented.

Eligible patients had mCRPC refractory to prior novel hormonal therapy, previously failed 1–2 taxane regimens (or were deemed unsuitable for or have refused taxanes) and had to have evidence of progressive disease. AMG 160 was administered as a short intravenous infusion once every two weeks at doses of 0.003–0.9 mg. Primary study objectives were to evaluate safety and tolerability of AMG 160 in mCRPC as well as to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The combination of AMG 160 and pembrolizumab will also be evaluated in part 2 of the trial. As of 11 May 2020, 43 patients had received at least one dose of AMG 160 monotherapy at one of the six dose levels. The median age of study participants was 66 years and 60.5% of patients had received at least four prior lines of therapy.

Results

Out of the 43 patients who received at least one dose of AMG 160 monotherapy, 41 patients experienced treatment related adverse events (TRAEs). However, there were no grade 5 events and none of the observed TRAEs resulted in treatment discontinuation. In total, 44.2% of patients were still on AMG 160 at the time of data analysis, of which six patients (14.0%) received treatment for at least six months. In total, three reversible dose-limiting toxicities occurred; two patients reported grade 3 rash and one patient suffered from grade 3 gastrointestinal haemorrhage. Six out of the 30 patients who were evaluated developed antidrug antibodies (ADAs) affecting drug exposure between cycles 1 and 10, but no adverse events associated with ADAs were observed. Cytokine release syndrome (CRS), the most common adverse event (all-grade in 90.7% of patients, grade 3 in 25.6%), associated with fever, nausea/vomiting and/or diarrhoea, transient transaminitis, and hypotension, occurred primarily in cycle 1. No grade 4/5 CRS events or treatment discontinuations occurred while 60.5% of patients had grade 2 CRS and 25.6% had grade 3. The CRS profile was effectively managed with standard mitigation approaches such as dose priming, dexamethasone premedication and prophylactic intravenous hydration.

Overall, 8 out of 29 patients (27.6%) had confirmed PSA responses and 3/13 (23.1%) even obtained a CTC0 response. PSA reductions (best response) were dose dependent and occurred in 24 of the 35 evaluable patients (68.6%). PSA reductions of more than 50% occurred in 12 (34.3%) patients. RECIST 1.1 responses among the 15 patients with measurable disease included two confirmed partial responses, one unconfirmed partial response and eight patients with stable disease. Finally, the MTD has not been reached and dosing optimisation of AMG 160 continues as the study nears RP2D.

Conclusion

AMG160 as monotherapy had a manageable safety profile and showed promising signs of efficacy in heavily pre-treated mCRPC patients. Overall, 68.8% of patients experienced a PSA decline with 34.3% of patients having a PSA reduction of at least 50%. Among the 15 patients with measurable disease, three partial responses (2 confirmed) and eight stable diseases were observed. At the time of data analysis, 44.2% of patients remained on AMG 160, with six patients (14.0%) continuing treatment for at least six months. The maximum tolerated dose has not been reached and dosing optimisation of AMG 160 continues as the study nears the recommended phase II dose. Further investigation of AMG 160 in combination with pembrolizumab is in progress.

Reference

Tran B, Horvath L, Dorff T, 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 ESMO 2020; Abstract 609O.