Evidence map›Paper›PMID 37314501›Full record

ArticleCancer chemotherapy and pharmacology2023

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.

Sarina A Piha-Paul, Chieh Tseng, Hai T Tran, Meng Gao, Daniel D Karp, Vivek Subbiah, Apostolia Maria Tsimberidou, Jitesh D Kawedia, Siqing Fu, Shubham Pant and 6 more

Registry-linked trialOpen access · hybridAbstract readClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer chemotherapy and pharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03065387 (Phase I Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib, or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation), which is not on this map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
1.8field-weighted citation impact, top 14% of its field
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.

NCT03065387 phase1terminatednot on this map

Phase I Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib, or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation

TypeinterventionalSponsorM.D. Anderson Cancer CenterRan2017 to 2026Enrolled84ConditionsAdvanced Malignant Solid Neoplasm, EGFR Gene Amplification, EGFR Gene Mutation, ERBB2 Gene AmplificationArmsEverolimus, Neratinib, Palbociclib, Trametinib
3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. 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

16 authors at 1 institution in 1 country.

Sarina A Piha-PaulDepartment 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.ORCID 0000-0001-9455-1660
Chieh TsengDepartment 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.
Hai T TranDepartment of Thoracic, Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Meng GaoDepartment 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.
Daniel D KarpDepartment 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.
Vivek SubbiahDepartment 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.
Apostolia Maria TsimberidouDepartment 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.
Jitesh D KawediaPharmacy Pharmacology Research, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, USA.
Siqing FuDepartment 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.
Shubham PantDepartment of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Timothy A YapDepartment 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.
Van K MorrisDepartment of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bryan K KeeDepartment of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mariela Blum MurphyDepartment of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
JoAnn LimPharmacy Clinical Programs, Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Funda Meric-BernstamDepartment 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.
The University of Texas MD Anderson Cancer Center · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

purposeAberrant 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.

methodsPatients 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.

resultsTwenty 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.

conclusionNeratinib 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.

Indexed as

NeoplasmsProto-Oncogene Proteins p21(ras)Antineoplastic Combined Chemotherapy ProtocolsDiarrheaErb-b2 Receptor Tyrosine KinasesErbB ReceptorsGenes, erbBHumansMiddle AgedMitogen-Activated Protein Kinase KinasesMutationNauseaProtein Kinase InhibitorsPyridonesPyrimidinonesQuinolinesEGFR protein, humanErb-b2 Receptor Tyrosine KinasesErbB ReceptorsKRAS protein, humanMitogen-Activated Protein Kinase KinasesneratinibProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)PyridonesPyrimidinonesQuinolinestrametinibEGFRERBB familyKRASNeratinibTrametinib

Identifiers

PMID37314501
PMCPMC10326142
OpenAlexW4380577407

What Socratic holds

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LicenceCC BY
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Registered trials

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.