Evidence map›Paper›PMID 39908697›Full record

ArticleESMO open2025

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-Paul, C Tseng, H T Tran, A Naing, E E Dumbrava, D D Karp, J Rodon, T A Yap, K P Raghav, S Damodaran and 4 more

Abstract readClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in ESMO open, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

S A Piha-PaulDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: spihapau@mdanderson.org.
C TsengDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA.
H T TranDepartment of Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
A NaingDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA.
E E DumbravaDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA.
D D KarpDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA.
J RodonDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, USA.
T A YapDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, USA; Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, USA.
K P RaghavDepartment of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
S DamodaranDepartment of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
X LeDepartment of Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
P T SolimanGynecologic Oncology & Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, USA.
J LimPharmacy Clinic Programs, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, USA.
F Meric-BernstamDepartment of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, USA; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, USA; Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DIANE BODURKA · 1985 to 2026
$290.8M
Convalescent Plasma to Limit Coronavirus Associated ComplicationsUL1TR003167 · NCATS · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI KARP, DANIEL D, MCPHERSON, DAVID D · 2019 to 2023
$45.3M
NCATS NIH HHS UL1 TR003167NCI NIH HHS P30 CA016672
6 · The paper itself

Abstract

backgroundThe 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

methodsOur 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.

resultsTwenty-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%.

conclusionPharmacokinetic 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.

Indexed as

Antineoplastic Combined Chemotherapy ProtocolsEverolimusMTOR InhibitorsNeoplasmsQuinolinesAdultAgedErb-b2 Receptor Tyrosine KinasesErbB ReceptorsFemaleHumansMaleMaximum Tolerated DoseMiddle AgedProtein Kinase InhibitorsTOR Serine-Threonine KinasesErb-b2 Receptor Tyrosine KinasesErbB ReceptorsEverolimusMTOR InhibitorsneratinibProtein Kinase InhibitorsQuinolinesTOR Serine-Threonine KinasesEGFRErbB-2ErbB-3ErbB-4everolimusneratinib

Identifiers

PMID39908697
PMCPMC11847258

What Socratic holds

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LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.