• AMG 757,a half-life extended bispecific t-cell engager (bite (r)) immune therapy against DLL3 in SCLC: phase 1 interim results

      Borghaei, H.; Boyer, M.; Johnson, M.; Govindan, R.; Rodrigues, L. P. A.; Blackhall, Fiona H; Boosman, R.; Champiat, S.; Hummel, H. D.; Lai, W. V.; et al. (2020)
      Background Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) and minimally expressed in normal tissues.1 AMG 757, a half-life extended BiTE® immune therapy, binds to DLL3 on tumor cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. We report initial safety and efficacy from the ongoing phase 1 study of AMG 757 in patients with SCLC. Methods AMG 757 was administered intravenously every two weeks (with/without step dose) at doses of 0.003–3.0 mg. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. The study was approved by the Ethics Board at participating institutions. Results As of 1 June 2020, safety and efficacy data are available for 31 patients enrolled at the first seven dose levels (DL) with median age, 63 (44–74) years; ECOG PS: 0–1, n=30 (96.8%); median prior lines, 2.0 (1–6); and previous PD-1/PD-L1 treatment: n=12 (38.7%). Median treatment duration was 6.1 (0.1–59.4) weeks. Treatment-emergent adverse events (AEs) were reported for 30 (96.8%) patients. AMG 757-related AEs occurred in 25 (80.6%) patients, including 5 (16.1%) that were grade ≥3 and one (3.2%) grade 5 (pneumonitis in DL5 [0.3 mg]). Three AEs (dyspnea, pneumonitis, fatigue) led to treatment discontinuation. The most common AE was cytokine release syndrome (CRS), which was reported in 11 (35.5%) patients. CRS AEs were grade 1–2, consisted mainly of fever with/without hypotension, and occurred mostly within 24 hours of the first or second dose of AMG 757. CRS events were reversible, did not lead to treatment interruption or discontinuation, and were managed with supportive care, corticosteroids, and/or anti-IL 6 therapy. The MTD for AMG 757 has not yet been reached. AMG 757 exhibited dose proportional increase in exposures. Response to AMG 757 is shown (figure 1). Confirmed partial response was reported in 5 (16.1%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7), and stable disease in 8 (25.8%) of all treated patients. Most responses occurred after 8 weeks on treatment. All responders remain on treatment with duration of response ranging from 2.0+ to 7.4 months+.
    • 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 half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in patients with small cell lung cancer (SCLC)

      Owonikoko, T. K.; Borghaei, H.; Champiat, S.; Paz-Ares, L. G.; Govindan, R.; Boyer, M. J.; Johnson, M. L.; Udagawa, H.; Hummel, H. D.; Salgia, R.; et al. (2020)
      Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients.