A phase ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced ormetastatic cancers with mutant KRAS

Christopher H. Lieu, Manuel Hidalgo, Jordan D. Berlin, Andrew H. Ko, Andres Cervantes, Patricia LoRusso, David E. Gerber, J. Paul Eder, S. Gail Eckhardt, Amy V. Kapp, Amy Tsuhako, Bruce McCall, Andrea Pirzkall, Anne Uyei, Josep Tabernero

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background. KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. Methods. Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results. Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion. Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.

Original languageEnglish (US)
JournalOncologist
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2017

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Pharmacokinetics
Safety
Epidermal Growth Factor Receptor
Neoplasms
Mitogen-Activated Protein Kinases
Asthenia
Mitogen-Activated Protein Kinase 3
Hypokalemia
GDC-0973
Dermatitis
Cell Proliferation
Ligands
Inflammation
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced ormetastatic cancers with mutant KRAS. / Lieu, Christopher H.; Hidalgo, Manuel; Berlin, Jordan D.; Ko, Andrew H.; Cervantes, Andres; LoRusso, Patricia; Gerber, David E.; Paul Eder, J.; Gail Eckhardt, S.; Kapp, Amy V.; Tsuhako, Amy; McCall, Bruce; Pirzkall, Andrea; Uyei, Anne; Tabernero, Josep.

In: Oncologist, Vol. 22, No. 9, 01.09.2017.

Research output: Contribution to journalArticle

Lieu, CH, Hidalgo, M, Berlin, JD, Ko, AH, Cervantes, A, LoRusso, P, Gerber, DE, Paul Eder, J, Gail Eckhardt, S, Kapp, AV, Tsuhako, A, McCall, B, Pirzkall, A, Uyei, A & Tabernero, J 2017, 'A phase ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced ormetastatic cancers with mutant KRAS', Oncologist, vol. 22, no. 9. https://doi.org/10.1634/theoncologist.2017-0175
Lieu, Christopher H. ; Hidalgo, Manuel ; Berlin, Jordan D. ; Ko, Andrew H. ; Cervantes, Andres ; LoRusso, Patricia ; Gerber, David E. ; Paul Eder, J. ; Gail Eckhardt, S. ; Kapp, Amy V. ; Tsuhako, Amy ; McCall, Bruce ; Pirzkall, Andrea ; Uyei, Anne ; Tabernero, Josep. / A phase ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced ormetastatic cancers with mutant KRAS. In: Oncologist. 2017 ; Vol. 22, No. 9.
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abstract = "Background. KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. Methods. Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results. Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22{\%}) and 12 (52{\%}) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39{\%}) patients required a cobimetinib dose reduction. Three (13{\%}) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion. Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.",
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AU - Hidalgo, Manuel

AU - Berlin, Jordan D.

AU - Ko, Andrew H.

AU - Cervantes, Andres

AU - LoRusso, Patricia

AU - Gerber, David E.

AU - Paul Eder, J.

AU - Gail Eckhardt, S.

AU - Kapp, Amy V.

AU - Tsuhako, Amy

AU - McCall, Bruce

AU - Pirzkall, Andrea

AU - Uyei, Anne

AU - Tabernero, Josep

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N2 - Background. KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. Methods. Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results. Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion. Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.

AB - Background. KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. Methods. Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. Results. Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. Conclusion. Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment.

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