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A phase 1 Study of AMG 757, half-life extended bispecific t-cell engager (BiTE (R))immune therapy against DLL3, in SCLC
Owonikoko, T. Boyer, M. Johnson, M. Govindan, R. Rodrigues, L. Boosman, R. Champiat, S. Hummel, H. Lai, W. V.
Owonikoko, T.
Boyer, M.
Johnson, M.
Govindan, R.
Rodrigues, L.
Boosman, R.
Champiat, S.
Hummel, H.
Lai, W. V.
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Abstract
Introduction: Delta-like ligand 3 (DLL3), an inhibitory Notch ligand
that is highly expressed in small cell lung cancer (SCLC) compared to
normal tissues, is a potential therapeutic target.1 AMG 757, a half-life
extended BiTE® immune therapy, binds DLL3 on tumor cells and CD3
on T cells, leading to T cell-dependent killing of tumors. Emerging data
from the ongoing phase 1 study of AMG 757 in SCLC are reported
(NCT03319940). Methods: AMG 757 (0.003e10.0 mg) was administered
intravenously every two weeks with/without step dose. Eligible
patients had SCLC that progressed or recurred following 1 platinumbased
regimen. Antitumor activity was assessed using modified RECIST
1.1. Tumor DLL3 expression was assessed by immunohistochemistry.
T-cell activation and cytokine profiles pre and post AMG 757 treatment
were evaluated. Results: As of 7 August 2020, 40 patients (median age
[range], 64 years [44e80]; ECOG PS: 0-1, n¼39 [97.5%], median prior
lines: 2.0 [1e6]; prior PD-1/PD-L1 treatment: n¼17 [42.5%]) enrolled
at eight dose levels (DL) received 1 AMG 757 dose. Median treatment
duration was 6.1 weeks (0.1e59.4). Adverse events occurred in 39
(97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%)
were treatment-related, including 7 (17.5%) grade 3 and 1 (2.5%)
grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS)
was reported in 18 (45.0%) patients; grade 2 CRS in 5 (12.5%); no
grade 3 CRS. CRS presented mainly as fever ± hypotension, was
reversible, did not lead to treatment interruption or discontinuation,
occurred mostly within 24 hours of the first two doses of AMG 757, and
was managed with supportive care, corticosteroids, and/or anti-IL-6
treatment. AMG 757 showed dose proportional increase in exposures.
Confirmed partial response (PR) was reported for 6 (15.8%) patients
(1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7, and 1/7
[14.3%] in DL8 [Figure]). Stable disease was reported for 11 (28.9%).
One patient has ongoing unconfirmed PR in DL8. Evaluation of DL8 is
ongoing. Patients with confirmed PR had a median of 2 (1e4) prior
lines of therapy and duration of response of 1.9+ to 9.4+ months. DLL3
expression at any level was observed in 31/32 (96.9%) patient tumor
samples, with overall H-score 40e300. Tumor shrinkage occurred
across a wide range of DLL3 expression (H-score, 55e300).
Conclusion: AMG 757 has acceptable safety at doses of up to 10 mg
and shows anti-tumor activity in patients with SCLC. Dose escalation is
ongoing. References: 1. Leonetti A, et al. Cell Oncol (Dordr).
2019;42(3):261-273.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Owonikoko T, Boyer M, Johnson M, Govindan R, Rodrigues L, Blackhall F, et al. OA11.03 A Phase 1 Study of AMG 757, Half-Life Extended Bispecific T-Cell Engager (BiTE®)Immune Therapy Against DLL3, in SCLC. Journal of Thoracic Oncology. 2021 Mar;16(3):S126.