AMG 757 elicits early response and safety in small cell lung cancer

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The results showed that in the trial of 52 patients, the agent caused a confirmed partial response (RP) rate of 14% and an unconfirmed RP rate in 1 patient (TABLE 1), 22% of patients had stable disease and disease control rate was 37%. . Tumor shrinkage was observed in 40% of patients (KEY RESULTS1).

“AMG 757 has shown acceptable safety and preliminary evidence of efficacy,” said Fiona H. Blackhall, PhD, FRCP, study author and chair of thoracic oncology at the University of Manchester in England, during a virtual presentation during the meeting. “The maximum dose of this compound has not been reached, dose escalation is continuing and dose optimization for monotherapy is underway.”

AMG 757 is a novel compound for immuno-oncology, defined as a long-half-life (BiTE) bispecific T-cell initiator with anti-CD3 and anti-DLL3 fragments with an Fc domain.

In the phase 1, open-label, multicenter study, AMG 757 was administered intravenously (IV) at doses ranging from 0.003 to 30 mg every 2 weeks with or without dose in steps. Antitumor activity was assessed using the modified RECIST v1.1 criteria every 8 weeks.

The primary endpoints were safety, tolerability, and determination of the maximum tolerated dose or recommended phase 2 dose. Secondary endpoints were pharmacokinetics and preliminary antitumor activity; the exploratory objectives were to assess immunogenicity, biomarkers, target protein and outcome.

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 index of 0 or 1 and 75% of patients had received 1 to 2 previous lines of treatment; the median number of previous treatments was 2 (range, 1-6). Forty-four percent of the patients had received a prior PD-1 / PD-L1 inhibitor. In addition, 96% of patients were initially diagnosed with extended stage disease, 25% had brain metastases, and 48% had liver metastases.

Additional data showed that 20% completed 24 weeks of treatment and that 4 patients with confirmed RP are still receiving treatment with a continuous response. In patients with confirmed PR (n = 7), the median time to response was 1.8 months, and the estimated time to response was greater than 6 months in 83% of patients with a median follow-up of 11.5 month.

Regarding safety, treatment-related adverse events (TRAE) of all grades and grade 3 or higher occurred in 79% and 23% of patients, respectively. ERTs of all grades 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%).

AEs of grade 4 or greater occurred in 7.6% of patients and were pneumonia (n = 1) and lymphopenia (n = 3); 1 patient died of pneumonia.

The severity of CRS was generally mild, she added, and was characterized by fever (31%), tachycardia (19%) and nausea (14%). The AE was generally reversible with supportive care, steroids, intravenous fluids, and / or anti-IL-6 therapy, and CRS was not related to discontinuation or death.

The researchers also explored the early rise in cytokine levels associated with the development of CRS. All cases of CRS occurred during 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) after a dose of AMG 757; the median duration of CRS was 60 hours (range, 3-197).

In addition, there were significant increases in TNF-α, IL-10, MCP-1, IL-8, IFN-α, MIP-1β / α and IFNγ levels from baseline within 24 hours after the first dose of AMG 757 in cycle 1 in patients who had CRS versus those who did not.

REFERENCE
1. Paz-Ares L, Owonikoko TK, Johnson M, et al. Phase 1 study of AMG 757, a delta 3 ligand (DLL3) targeting bispecific immuno-oncology therapy of extended half-life T cell engagement, in small cell lung cancer. J Thorac Oncol. 2021; 16 (4): S720-S721. doi: 10.1016 / S1556-0864 (21) 01890-6



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