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
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| Název: | 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 |
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| Autoři: | Daniel Morgensztern, Neal Ready, Melissa L. Johnson, Afshin Dowlati, Noura Choudhury, David P. Carbone, Eric Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, Aparna Hegde, Anne C. Chiang, Wade Iams, Anthony Tolcher, Kaname Nosaki, Toshiyuki Kozuki, Tianhong Li, Rafael Santana-Davila, Hiroaki Akamatsu, Haruyasu Murakami, Hiroshi Yokouchi, Song Wang, Jiuhong Zha, Rui Li, Randy R. Robinson, Pooja Hingorani, Edwin E. Jeng, Muhammad Furqan |
| Zdroj: | Clin Cancer Res Clinical Cancer Research, vol 30, iss 22 |
| Informace o vydavateli: | American Association for Cancer Research (AACR), 2024. |
| Rok vydání: | 2024 |
| Témata: | Male, Adult, Lung Neoplasms, Immunoconjugates, Maximum Tolerated Dose, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Clinical sciences, Clinical Trials: Targeted Therapy, Antibodies, Monoclonal, Humanized, Antibodies, Rare Diseases, Clinical Research, Monoclonal, Medicine and Health Sciences, 80 and over, Humans, Oncology & Carcinogenesis, Lung, 6.2 Cellular and gene therapies, Humanized, Cancer, Aged, Aged, 80 and over, Biomedical and Clinical Sciences, Lung Cancer, ICTS (Institute of Clinical and Translational Sciences), Oncology and carcinogenesis, Middle Aged, Small Cell Lung Carcinoma, Orphan Drug, 6.1 Pharmaceuticals, Female |
| Popis: | 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. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-24-1547 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/39287821 https://escholarship.org/uc/item/0188g55d https://escholarship.org/content/qt0188g55d/qt0188g55d.pdf |
| Rights: | CC BY NC ND URL: http://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
| Přístupové číslo: | edsair.doi.dedup.....fa287c56f1370a5680cb99398713b909 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | 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. |
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| ISSN: | 15573265 10780432 |
| DOI: | 10.1158/1078-0432.ccr-24-1547 |