First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors

John H. Strickler, Colin D. Weekes, John Nemunaitis, Ramesh K. Ramanathan, Rebecca S. Heist, Daniel Morgensztern, Eric Angevin, Todd M. Bauer, Huibin Yue, Monica Motwani, Apurvasena Parikh, Edward B. Reilly, Daniel Afar, Louie Naumovski, Karen Kelly

Research output: Contribution to journalArticle

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Abstract

Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score $ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade $ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.

Original languageEnglish (US)
Pages (from-to)3298-3306
Number of pages9
JournalJournal of Clinical Oncology
Volume36
Issue number33
DOIs
StatePublished - Nov 20 2018

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Non-Small Cell Lung Carcinoma
Neoplasms
Maximum Tolerated Dose
Safety
Fatigue
Pharmacokinetics
Hypoalbuminemia
Appetite
Constipation
Neutropenia
Dyspnea
Nausea
Disease-Free Survival
Vomiting
Half-Life
Anemia
Diarrhea
Edema
Immunohistochemistry
Monoclonal Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors. / Strickler, John H.; Weekes, Colin D.; Nemunaitis, John; Ramanathan, Ramesh K.; Heist, Rebecca S.; Morgensztern, Daniel; Angevin, Eric; Bauer, Todd M.; Yue, Huibin; Motwani, Monica; Parikh, Apurvasena; Reilly, Edward B.; Afar, Daniel; Naumovski, Louie; Kelly, Karen.

In: Journal of Clinical Oncology, Vol. 36, No. 33, 20.11.2018, p. 3298-3306.

Research output: Contribution to journalArticle

Strickler, JH, Weekes, CD, Nemunaitis, J, Ramanathan, RK, Heist, RS, Morgensztern, D, Angevin, E, Bauer, TM, Yue, H, Motwani, M, Parikh, A, Reilly, EB, Afar, D, Naumovski, L & Kelly, K 2018, 'First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors', Journal of Clinical Oncology, vol. 36, no. 33, pp. 3298-3306. https://doi.org/10.1200/JCO.2018.78.7697
Strickler, John H. ; Weekes, Colin D. ; Nemunaitis, John ; Ramanathan, Ramesh K. ; Heist, Rebecca S. ; Morgensztern, Daniel ; Angevin, Eric ; Bauer, Todd M. ; Yue, Huibin ; Motwani, Monica ; Parikh, Apurvasena ; Reilly, Edward B. ; Afar, Daniel ; Naumovski, Louie ; Kelly, Karen. / First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 33. pp. 3298-3306.
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title = "First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors",
abstract = "Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score $ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4{\%} NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42{\%}), nausea (27{\%}), constipation (27{\%}), decreased appetite (23{\%}), vomiting (21{\%}), dyspnea (21{\%}), diarrhea (19{\%}), peripheral edema (19{\%}), and neuropathy (17{\%}). The most frequent Teliso-V–related grade $ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4{\%} each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60{\%}) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8{\%}; 95{\%} CI, 4.1{\%} to 45.7{\%}) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95{\%} CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.",
author = "Strickler, {John H.} and Weekes, {Colin D.} and John Nemunaitis and Ramanathan, {Ramesh K.} and Heist, {Rebecca S.} and Daniel Morgensztern and Eric Angevin and Bauer, {Todd M.} and Huibin Yue and Monica Motwani and Apurvasena Parikh and Reilly, {Edward B.} and Daniel Afar and Louie Naumovski and Karen Kelly",
year = "2018",
month = "11",
day = "20",
doi = "10.1200/JCO.2018.78.7697",
language = "English (US)",
volume = "36",
pages = "3298--3306",
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TY - JOUR

T1 - First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, in patients with advanced solid tumors

AU - Strickler, John H.

AU - Weekes, Colin D.

AU - Nemunaitis, John

AU - Ramanathan, Ramesh K.

AU - Heist, Rebecca S.

AU - Morgensztern, Daniel

AU - Angevin, Eric

AU - Bauer, Todd M.

AU - Yue, Huibin

AU - Motwani, Monica

AU - Parikh, Apurvasena

AU - Reilly, Edward B.

AU - Afar, Daniel

AU - Naumovski, Louie

AU - Kelly, Karen

PY - 2018/11/20

Y1 - 2018/11/20

N2 - Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score $ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade $ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.

AB - Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score $ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade $ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.

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DO - 10.1200/JCO.2018.78.7697

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SN - 0732-183X

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