Preliminary Safety and Efficacy Results Observed for AMG 160 in mCRPC

Matthew Rettig, MD

The bispecific T‐cell engager (BiTE), AMG 160, demonstrated a manageable safety profile and preliminary evidence of efficacy in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a 2-part, phase 1 open-label study (NCT03792841), presented during the 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat, October 20-23, 2020.

“There is a need for new treatments that can broadly benefit the mCRPC population,” said lead author of the study Matthew Rettig, MD. “AMG 160 is an off-the-shelf therapy that does not require preparation or manipulation of the patient’s T-cells as is required by CAR (chimeric antigen receptor) T-cell therapy.” BiTE immune therapy redirects T cells to kill tumor cells by binding to the prostate specific membrane antigen (PSMA) on tumor cells and CD3 on T cells. Currently, the only bispecific immunotherapy approved worldwide is blinatumomab (Blincyto).

A key safety risk associated with BiTE technology is cytokine release syndrome (CRS), so part 1 is a dose exploration study that will estimate the MTD (maximum tolerated dose) or RP2D (recommended phase 2 dose) using Bayesian logistic regression modeling. The dose expansion portion will assess safety, efficacy, pharmacokinetics, and pharmacodynamics of the selected dose and provide further safety and efficacy data.

Part 2 (n = 3-4 per dose cohort) will evaluate the agent in combination with pembrolizumab (Keytruda). The primary objectives were to evaluate the safety and tolerability of AMG 160. Secondary objectives were to characterize pharmacokinetic properties and to evaluate preliminary antitumor activity.

In the presentation during the conference, Rettig, a professor in the Department of Medicine and Department of Urology, and medical director, Prostate Cancer Program of the Institute of Urologic Oncology, at the University of California, Los Angeles, spotlighted results from part 1.

Patients were pretreated with dexamethasone before short-term IV infusion of AMG 160 every 2 weeks after the target dose was reached. Patients were eligible if they were histologically or cytologically confirmed with a diagnosis of mCRPC refractory to novel hormonal therapy and failed 1-2 taxane regimens; or patients were deemed unsuitable for or refused treatment with taxanes. Patients were excluded if they had active autoimmune disease or required immunosuppressive therapy, received prior PSMA–targeted therapy, or had central nervous system metastases, leptomeningeal disease, or spinal cord compression.

As of the data cut off of July 20 2020, 43 patients have been enrolled. The median age at baseline was 66.0 years, and more than 60% of patients have received 4 or more lines of therapy, said Rettig. The median PSA at baseline was 79.2 μg/L (range, 0.1-4035.0).

Regarding adverse effects, 41 patients (95.3%) experienced treatment-emergent adverse effects (TRAEs), and 19 patients (44.2%) remained on therapy at the time of data analysis. Forty-one patients (95.3%) experienced treatment-related adverse effects (TRAEs), but there were no grade 5 events reported and no treatment discontinuations. Rettig reported that there were 3 patients who experienced reversible dose-limiting toxicities (DLTs), with 2 patients who who experienced grade 3 rash and 1 patient experienced grade 1 gastrointestinal hemorrhage.

Antidrug antibodies (ADAs) with the ability to impact drug exposure between cycles 1 and 10 wee obxeved in 6 patients (20.0%), but no AEs were associated with these ADAs.

CRS was the most common reported all-grade TRAE (90.7%), followed by fatigue (44.2%), vomiting (44.2%), nausea (39.5%), and pyrexia (37.2%). The most common reported grade 3 TRAEs were CRS (25.6%), hypotension (11.6%), hypophosphatemia (9.3%), and rash (9.3%).

CRS is related to the release of cytokines that primarily occurs during the first cycle of treatment, said Rettig. “CRS was reversible, manageable, and as expected, most severe in cycle 1,” he said. CRS presentation varied across patients and was commonly associated with fever, hypotension, transient nausea, vomiting, and diarrhea. Further, “there were no grade 4 or 5 CRS events. There were no treatment discontinuations due to CRS,” Rettig said.

Twenty-six patients (60.5%) experienced grade 2 CRS, manifesting as hypotension in 15 patients (34.9%) and transaminitis in 13 patients (30.2%). Eleven patients (25.6%) experienced grade 3 CRS, manifesting as hypotension in 6 patients (14.0%) and transaminitis in10 patients (23.3%). The transaminitis in both grades of CRS improved to grade 1 within 1 to 2 days without intervention, reported Rettig.

A number of prophylactic mitigation strategies were employed in the part 1 cohort, including dose priming, involving a lower run-in dose before maintenance target dose; dexamethasone premedication, involving 8 mg orally and 8 mg IV before administering the AMG 160 dose; and prophylactic IV hydration, involving 1 liter of normal saline given after the AMG 160 dose.

“These mitigation strategies appear to be effective in minimizing the risk of grade 3 CRS,” Rettig said.

Reduction in prostate-specific antigen (PSA) levels demonstrated preliminary evidence of safety, according to Rettig. Among patients with a PSA/CTC (circulating tumor cell) response (n = 13-35), 8 patents (27.6%) had a confirmed PSA response and 4 patients (11.4%) had an unconfirmed PSA response. Three patients (23.1%) had a CTC0 response. Among 15 patients with RECIST (response evaluation criteria in solid tumors) response, 2 (13.3%) had a confirmed partial response, 1 (6.7%) had an unconfirmed partial response, and 8 patients (53.3%) had stable disease.

In evaluable patients, PSA reductions (best response) were dose dependent and occurred in 24 of 35 patients (68.6%). PSA reductions greater than 50% were reported in 12 of 35 patients (34.3%).

These preliminary results show that the agent has a manageable safety profile. PSA reductions have been observed in 69% of patients across all monotherapy cohorts, with 34% of patients having reductions of at least 50%. Among the 15 patients with measurable disease, three partial responses have been observed. Nineteen of the 43 patients remain on AMG 160.

“The study has recently opened its dose-expansion phase investigation of AMG 160 in combination with pembrolizumab and findings will be reported separately,” concluded Rettig.

_REFERENCE:

_{Rettig M. Interim results from a phase 1 study of AMG 160, a half-life extended (HLE) PSMA bispecific T-cell engager (BiTE) immunotherapy for metastatic castration-resistance prostate cancer (mCRPC). Presented at: 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat. October 20-23, 2020.}