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A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients With Small Cell Lung Cancer

2024; American Association for Cancer Research; Volume: 30; Issue: 22 Linguagem: Inglês

10.1158/1078-0432.ccr-24-1547

1557-3265

Daniel Morgensztern, Neal Ready, Melissa L. Johnson, Afshin Dowlati, Noura J. Choudhury, David P. Carbone, Eric Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, Aparna Hegde, Anne C. Chiang, Wade T. Iams, Anthony W. Tolcher, Kaname Nosaki, Toshiyuki Kozuki, Tianhong Li, Rafael Santana‐Davila, Hiroaki Akamatsu, Haruyasu Murakami, Hiroshi Yokouchi, Song Wang, Jiuhong Zha, Rui Li, Randy Robinson, Pooja Hingorani, Edwin E. Jeng, Muhammad Furqan,

Peptidase Inhibition and Analysis

Abstract Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3–2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. Results: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41–79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6–6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5–4.2). Conclusions: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.