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

被引：0

作者：

Piha-Paul, S. A. ^{[1
]}

Tseng, C. ^{[1
]}

Tran, H. T. ^{[2
]}

Naing, A. ^{[1
]}

Dumbrava, E. E. ^{[1
]}

Karp, D. D. ^{[1
]}

Rodon, J. ^{[1
,3
]}

Yap, T. A. ^{[1
,3
,4
]}

Raghav, K. P. ^{[5
]}

Damodaran, S. ^{[6
]}

Le, X. ^{[2
]}

Soliman, P. T. ^{[7
]}

Lim, J. ^{[8
]}

Meric-Bernstam, F. ^{[1
,3
,9
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, Houston, TX USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA

[3] Univ Texas MD Anderson Canc Ctr, Sheikh Khalifa Bin Zayed Nahyan Inst Personalized, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Therapeut Discovery Div, Houston, TX USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX USA

[8] Univ Texas MD Anderson Canc Ctr, Pharm Clin Programs, Div Pharm, Houston, TX USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX USA

来源：

ESMO OPEN | 2025年 / 10卷 / 02期

关键词：

neratinib; everolimus; ErbB-2; ErbB-3; ErbB-4; EGFR; TYROSINE KINASE INHIBITOR; GROWTH-FACTOR RECEPTOR; BREAST-CANCER; DOUBLE-BLIND; TRASTUZUMAB RESISTANCE; JAPANESE PATIENTS; MUTATIONS; HKI-272; NETWORK; ACTIVATION;

D O I：

10.1016/j.esmoop.2025.104136

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：13

共 44 条

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