The half-life extended, DLL3-targeting bispecific T-cell engager AMG 757 demonstrated early signals of efficacy and a favorable safety profile in patients with small cell lung cancer.
The half-life extended, DLL3-targeting bispecific T-cell engager (BiTE) AMG 757 demonstrated early signals of efficacy and a favorable safety profile in patients with small cell lung cancer (SCLC), according to interim first-in-human results of a phase 1 study (NCT03319940) that were presented during the 2021 European Lung Cancer Congress.
Results showed that in the 52-patient trial, the novel agent elicited a confirmed partial response (PR) rate of 14% and an unconfirmed PR in 1 patient; 22% of patients had stable disease, and the disease control rate was 37%. Tumor shrinkage was observed in 40% of patients.
“AMG 757 showed acceptable safety and preliminary evidence of efficacy,” Fiona H. Blackhall, MD, an author on the study and chair in Thoracic Oncology at The University of Manchester, said in a virtual presentation during the meeting. “The maximum dose of this compound has not been reached, dose escalation continues, and dose optimization for monotherapy is ongoing.”
AMG 757 is a novel immuno-oncology compound, defined as a half-life extended BiTE with both anti-CD3 and anti-DLL3 moieties with an Fc domain. BiTE molecules engage in patients’ own T cells designed to attack and eradicate cancer cells.
In the first-in-human, multicenter, open-label, phase 1 study, 52 patients with small cell lung cancer were intravenously (IV) treated with doses of AMG 757 at doses escalating from 0.003 mg to 30 mg, as of the date cutoff date of November 3, 2020, every 2 weeks with or without step dosing. Antitumor activity was assessed using modified RECIST v1.1 criteria every 8 + weeks.
The primary end point was safety and tolerability, as well as to determine the maximum-tolerated dose or recommended phase 2 dose. Secondary end points were pharmacokinetics and preliminary antitumor activity; exploratory objectives were to evaluate immunogenicity, biomarkers, target protein, and outcomes.
The median age was 64 years (range, 32-80) and 69% of patients were former smokers; 15% were current smokers. The majority (98%) of patients had an ECOG performance status of 0 or 1, and 75% of patients had received 1 to 2 prior lines of therapy; the median number of prior therapies was 2 (range, 1-6). Forty-four percent of patients received a prior PD-1/PD-L1 inhibitor. Additionally, 96% of patients had extensive-stage disease at the initial diagnosis, 25% had brain metastases, and 48% had liver metastases.
Additional data showed that 20% have completed 24 weeks of treatment, and 4 patients with confirmed PR are still receiving treatment with an ongoing response. In patients who had a confirmed PR (n = 7), the median time to response was 1.8 months and the estimated duration of response was greater than 6 months in 83% of patients, at a median follow-up of 11.5 months.
Regarding safety, all-grade and grade 3 or higher treatment-related adverse events (TRAEs) occurred in 79% and 23% of patients, respectively. All-grade TRAEs occurring in 10% or more of patients included cytokine release syndrome (CRS; 44%; grade ≥3, 2%), pyrexia (19%), fatigue (14%), anemia (10%; grade ≥3, 2%), and nausea (10%).
Blackwell noted that grade 4 or higher AEs occurred in 8% of patients and were pneumonitis (n = 1) and lymphocytopenia (n = 3); 1 patient died from pneumonitis.
The severity of CRS was typically mild, she added, and was characterized by fever (31%), tachycardia (19%), and nausea (14%). The AE was generally reversible with supportive care, steroids, IV fluids, and/or anti–interleukin (IL)-6 therapy, and CRS was not linked with discontinuation of treatment or deaths.
Investigators also explored the early increase in cytokine levels that were associated with the development of CRS. All cases of CRS occurred in the first cycle of treatment; 2 recurrences were reported in cycles 2 and 3. The median time to onset was 9 hours (range, 3-52) following a dose of AMG 757; the median duration of CRS was 60 hours (range, 3-197).
Additionally, there was significant increases in TNF-α, IL-10, MCP-1, IL-8, IFN-γ, MIP-1β/α, and IFNg levels from baseline in the 24 hours following the first AMG 757 dose in cycle 1 in patients who had CRS vs those who did not.