A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.

Autor: Piha-Paul SA; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA. spihapau@mdanderson.org., Tseng C; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Tran HT; Department of Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gao M; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Karp DD; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Subbiah V; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Tsimberidou AM; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Kawedia JD; Pharmacy Pharmacology Research, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, USA., Fu S; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA., Pant S; Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yap TA; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA.; Department of Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Morris VK; Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kee BK; Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Blum Murphy M; Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lim J; Pharmacy Clinical Programs, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Meric-Bernstam F; Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX, 77030, USA.; Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2023 Aug; Vol. 92 (2), pp. 107-118. Date of Electronic Publication: 2023 Jun 14.
DOI: 10.1007/s00280-023-04545-4
Abstrakt: Purpose: Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.
Methods: Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.
Results: Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.
Conclusion: Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions.
Trial Registration Id: NCT03065387.
(© 2023. The Author(s).)
Databáze: MEDLINE
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