Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study

Abstract

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

“…An example of trimeric forms of the TRAIL protein is SCB-313, which was tested in Phase I clinical trials for peritoneal malignancies (NCT03443674 and NCT04051112) [102]. Furthermore, ABBV-621 (Eftozanermin) is a hexavalent TRAIL-Fc fusion protein that has shown antitumor activity with acceptable toxicity in Phase I clinical trials in solid tumors (NCT03082209) [103]. Currently, ABBV-621 is being studied in Phase II clinical trials for multiple myeloma (NCT04570631).…”

Therapeutic targeting of TRAIL death receptors

“…Thus, Eftozanermin alfa clearly improves upon the agonistic ability and pharmacokinetic profile of first-generation TRAIL therapeutics and has consequently progressed into clinical trials ( Table 1 ). A first-in-human study showed Eftozanermin alfa was well-tolerated in patients with advanced solid tumors and hematological malignancies alone and in combination with venetoclax or chemotherapeutics [ 55 , 56 ] (NCT03082209). The results of dose-escalation and dose-optimization cohorts of patients with advanced solid tumors receiving Eftozanermin alfa monotherapy showed partial responses according to RECIST in three patients (two with CRC and one with pancreatic cancer) among the 105 patients participating in the clinical trial (PMID 35467243).…”

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

“…9 The results of the doseescalation portion of the study with eftoza monotherapy in solid tumors have been previously published. 24 Patients with an AML diagnosis and with histologically confirmed R/R disease were eligible to enroll in the AML dose-optimization cohort, which we report herein, and received treatment with eftoza as monotherapy or in combination with venetoclax. Key eligibility criteria are in Supplemental Table 2.…”