Phase I trial of the combination of the pan-ErbB inhibitor neratinib and mTOR inhibitor everolimus in advanced cancer patients with ErbB family gene alterations

Sep 23, 2026

Uploaded by Noah

Phase I dose-escalation study evaluated neratinib, a pan-ErbB inhibitor, combined with everolimus, an mTOR inhibitor, in advanced cancers harboring ErbB family alterations. The trial assessed safety, tolerability, dose-limiting toxicities, and maximum tolerated dose, with secondary endpoints including RECIST v1.1 objective response and pharmacokinetic analyses. Twenty-two patients were enrolled; common treatment-related grade 3 events included diarrhea, anemia, mucositis, and acute kidney injury. The MTD was neratinib 240 mg with everolimus 7.5 mg, with a 19% objective response rate.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Background

Patients and methods

Results

Conclusion

Introduction

ORIGINAL ARTICLE Phase I trial of the combination of the pan-ErbB inhibitor neratinib and mTOR inhibitor everolimus in advanced cancer patients with ErbB family gene alterations S. A. Piha-Paul1􀀁, C. Tseng1, H. T. Tran2, A. Naing1, E. E. Dumbrava1, D. D. Karp1, J. Rodon1, 3, T. A. Yap1 , 3, 4, K. P. Raghav5, S. Damodaran6, X. Le2, P. T. Soliman7, J. Lim8 & F. Meric-Bernstam1, 3 , 9 Departments of 1Investigational Cancer Therapeutics (A Phase I Clinical Trials Program); 2Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston; 3The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston; 4Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston; Departments of 5Gastrointestinal Medical Oncology; 6Breast Medical Oncology; 7Gynecologic Oncology & Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston; 8Pharmacy Clinic Programs, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston; 9Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA Available online xxx Background: The ErbB family of receptor tyrosine kinases are key targets for antitumor therapy. Although neratinib, a pan-ErbB kinase inhibitor, is approved in ErbB2-positive breast cancer, drug resistance is common. Preclinical data suggest that combining neratinib with the mTOR inhibitor everolimus may overcome such resistance. Patients and methods: Our trial evaluated this combination’s safety and efﬁcacy in advanced cancers with ErbB alterations. We conducted a phase I dose-escalation trial of neratinib and everolimus. Primary objectives were to assess safety, tolerability, and dose-limiting toxicities (DLTs) and establish the maximum tolerated dose (MTD) . Secondary objectives included objective response by RECIST v1.1 and pharmacokinetic analyses. Results: Twenty-two patients (median age 61, median of four prior therapies) with ErbB alterations (mutations 63 .6%, ampliﬁcation 36 .3%, or ErbB2-overexpressed by immunohistochemistry 9 . 1%) were enrolled. Common tumor types included breast (31 .8%), colorectal (18 . 2%), cervical (9 . 1%), and endometrial (9 . 1%) cancers. Frequent grade (G) 3 treatment-related adverse events were diarrhea (18.2%), anemia (9.1%), mucositis (9.1%), and acute kidney injury (9 . 1%) . DLTs included G3 mucositis and diarrhea at dose level (DL) 5, and G3 increased creatinine at DL4 . The MTD was DL4: neratinib 240 mg with everolimus 7.5 mg. The objective response rate was 19% with partial response in four patients. Stable disease 􀀃16 weeks was seen in two patients (9 .5%), resulting in a clinical beneﬁt rate of 28 .6% . Conclusion: Pharmacokinetic data indicated reduced neratinib clearance possibly due to CYP3A4 pathway saturation by everolimus. Combination therapy with neratinib and everolimus has a tolerable safety proﬁle and clinical activity in ErbB-altered patients. ErbB family receptors and the PI3K pathway are commonly implicated in oncogenesis. This clinical study of neratinib and everolimus demonstrated favorable clinical activity and tolerability. Key words: neratinib, everolimus, ErbB-2, ErbB-3, ErbB-4, EGFR INTRODUCTION The epidermal growth factor receptor family, consisting of four members including epidermal growth factor receptor (EGFR; ErbB1), human epidermal growth factor receptor (HER)-2/ErbB2, HER-3/ErbB3, and HER-4/ErbB4, collaborate to transmit extracellular signals to regulate fundamental cellular processes such as cell growth, metabolism, *Correspondence to: Prof. Sarina A. Piha-Paul, 1515 Holcombe Blvd, Unit 455, Houston, TX 77030, USA. þ1-713-563-1055 E-mail: [spihapau@mdanderson.org](spihapau@mdanderson.org) (S. A. Piha-Paul). 2059-7029/© 2025 The Authors. Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access art

FAQs

What was the main purpose of combining neratinib and everolimus in this phase I trial?

To evaluate the safety and efficacy of the combination in advanced cancers with ErbB family gene alterations, including determining dose-limiting toxicities and the maximum tolerated dose.

How were patients selected for the trial?

Patients with advanced cancers carrying ErbB family alterations were enrolled, including ErbB mutations, amplifications, or ErbB2 overexpression by immunohistochemistry.

What were the key efficacy and dosing outcomes reported?

The maximum tolerated dose was neratinib 240 mg with everolimus 7.5 mg, and the objective response rate was 19% with partial responses in four patients.

Sep 23, 2026

Uploaded by Noah