• 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.; Blackhall, Fiona H; Boosman, R.; Champiat, S.; Hummel, H.; Lai, W. V.; et al. (2021)
      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.
    • Phase I study of AMG 757, a delta-like ligand 3 (DLL3) targeting, half-life extended bispecific T-cell engager immuno-oncology therapy, in small cell lung cancer (SCLC)

      Paz-Ares, L.; Owonikoko, T. K.; Johnson, M.; Govindan, R.; Izumi, H.; Lai, V.; Borghaei, H.; Boyer, M.; Boosman, R. J.; Hummel, H. D.; et al. (2021)
      Background: AMG 757 simultaneously binds DLL3 on SCLC cells and CD3 on T cells leading to T cell- mediated tumor lysis. Data from an ongoing phase I study of AMG 757 in SCLC are reported. Methods: Safety and efficacy were evaluated in a phase I trial of AMG 757 for patients (pts) with relapsed/refractory SCLC after >= 1 platinum-based regimen (NCT03319940). AMG 757 was administered intravenously (9 dose levels (DLs); dose range: 0.003−30 mg q2w, ± step dosing). Results: As of 03 Nov 2020, 52 pts (median age, 64 [32−80] y; median prior lines of therapy, 2 [1−6]) were enrolled. 79% (41/52) of pts reported treatment (tx)-related adverse events (TRAEs) (Grade [Gr] >= 2, 29/52 [56%], Gr >= 3, 12/52 [23%], Gr >= 4, 4/52 [8%]). TRAEs accounted for 1 tx discontinuation and 1 death (Gr 5 pneumonitis, DL, 0.3 mg). Cytokine release syndrome (CRS; 44%; Lee criteria (2014): Gr 2, 5/52 [10%], Gr 3, 1/52 [2%], no Gr >= 4) was the most common TRAE and typically occurred in cycle 1. Median time to onset of CRS was 9 (3−52) h following an AMG 757 dose; median duration was 60 (3−197) h. Fever (31%), tachycardia (19%), and nausea (14%) were the most common CRS-related symptoms. Significant increases in cytokine (IL-8, MCP-1, IFN-g, IL-10, IL-6, MIP-1a, MIP-1b, TNF-a) levels from baseline in the 24 h following the first AMG 757 dose in cycle 1 were observed in pts experiencing CRS vs. pts who did not experience CRS symptoms. CRS did not result in tx discontinuation or deaths and was managed with supportive care, corticosteroids, and/or anti-IL-6R. 14% (7/51) of pts achieved a confirmed partial response (PR) (modified RECIST 1.1) in 4 DLs (0.3 mg [8% of PR], 1 mg [13%], 3 mg [33%], and 10 mg [20%]). Stable disease was seen in 24% (12/51). Median time to response was 1.8 months; the estimated duration of response was > 6 months in 83% (95% CI: 27%, 98%) of pts with a confirmed PR. An unconfirmed PR was noted in an additional pt (30 mg DL). Conclusions: AMG 757 showed an acceptable safety profile and preliminary evidence for efficacy in pts with SCLC. The most common TRAE—CRS—occurred early in the dosing cycle, did not recur, was typically mild in severity, and manageable. The maximum tolerated dose has not been reached. Dose-finding for monotherapy is ongoing.