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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>\nPatients with actionable somatic mutations or amplifications in <jats:italic>ERBB<\/jats:italic> genes or actionable <jats:italic>KRAS<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>\nTwenty patients were enrolled with a median age of 50.5\u00a0years 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\u00a0mg daily with trametinib 1\u00a0mg, 5\u00a0days on and 2\u00a0days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160\u00a0mg daily with trametinib 1\u00a0mg 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)\u2009\u2265\u20094\u00a0months.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug\u2013drug interactions.<\/jats:p>\n                <jats:p>Trial registration ID: NCT03065387.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-023-04545-4","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T09:02:52Z","timestamp":1686733372000},"page":"107-118","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["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"],"prefix":"10.1007","volume":"92","clinical-trial-number":[{"clinical-trial-number":"nct03065387","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-1660","authenticated-orcid":false,"given":"Sarina A.","family":"Piha-Paul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chieh","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai T.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel D.","family":"Karp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek","family":"Subbiah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apostolia Maria","family":"Tsimberidou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jitesh D.","family":"Kawedia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siqing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubham","family":"Pant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy A.","family":"Yap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Van K.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan K.","family":"Kee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariela","family":"Blum Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JoAnn","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Funda","family":"Meric-Bernstam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"issue":"7","key":"4545_CR1","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nrc2656","volume":"9","author":"J Baselga","year":"2009","unstructured":"Baselga J, Swain SM (2009) Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. 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DDK reports research funding\/grant support for clinical trials from Pfizer, Phoplatin Therapeutic, Symphogen, NIH clinical translation science award, clinical translation NCI grant and consultancy\/advisory board participation for Black Beret Life Science, Affigen and Phosplatin.VS reports research funding\/grant support for clinical trials from AbbVie, Agensys, Inc., Alfasigma, Altum, Amgen, Bayer, BERG Health, Blueprint Medicines Corporation, Boston Biomedical, Inc., Boston Pharmaceuticals, Celgene Corporation, D3 Bio, Inc., Dragonfly Therapeutics, Inc., Exelixis, Fujifilm, GlaxoSmithKline, Idera Pharmaceuticals, Inc., Incyte Corporation, Inhibrx, Loxo Oncology, MedImmune, MultiVir, Inc., NanoCarrier, Co., National Comprehensive Cancer Network, NCI-CTEP, Northwest Biotherapeutics, Novartis, PharmaMar, Pfizer, Relay Therapeutics, Roche\/Genentech, Takeda, Turning Point Therapeutics, UT MD Anderson Cancer Center, and Vegenics Pty Ltd.; travel support from ASCO, ESMO, Helsinn Healthcare, Incyte Corporation, Novartis, and PharmaMar; consultancy\/advisory board participation for Helsinn Healthcare, Jazz Pharmaceuticals, Incyte Corporation, Loxo Oncology\/Eli Lilly, MedImmune, Novartis, QED Therapeutics, Relay Therapeutics, Daiichi-Sankyo, and R-Pharm US; and other relationship with Medscape. AT reports research funding\/grant support for clinical trials from OBI Pharma USA Inc., Baxalta, Bayer, Boston Biomedical, EMD Serono, Parker Institute for Cancer Immunotherapy, Placon Therapeutics, Agenus, Tempus Labs, Tvardi Therapeutics, Karus Therapeutics, Novocure, NIH\/NCI P30CA016672 \u2013 Core Grant (CCSG Shared Resources). AT served as consulting or advisory role for Vincerx, Diaccurate. BrYet, NEX-II, Macrogenics. SQF reports research funding\/grant support for clinical trials from NIH\/NCI P30CA016672 \u2013 Core Grant (CCSG Shared Resources), Abbisko, BeiGene, BioAtla, Boehringer Ingelheim, CUE Biopharma, Eli Lilly & Co., Exelisis, Greenfire Bio, Hookipa Biotech, IMV, Innovent Biologics, K-Group Beta, Lyvgen Biopharm, MacroGenics, MediLink Therapeutics, Millennium Pharmaceuticals, Nerviano Medical Sciences, NeuPharma, NextCure, Ningbo NewBay Technology Development, Novartis, NovoCure, Nykode Therapeutics AS., Parexel International, Pionyr Immunotherapeutics, PureTech Health, Sellas Life Sciences Group, Soricimed Biopharma, SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncology and NCCN; Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience, Virogin Biotech. SP reports clinical trial research funding\/grant support through the institution from Mirati Therapeutics, Merck, Pfizer, Lilly, Xencor, Novartis, Bristol-Myers Squibb, Ipsen, Astellas, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Zymeworks, BioNtech and receives personal fees for advisory\/consulting from Zymeworks, Ipsen,Novartis, Janssen, Boehringer Ingelheim. TAY reports research funding\/grant support for clinical trials from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith, served as a consultant for AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio and a stockholder in Seagen. VKM discloses research funding (to institution) from EMD Serono, Pfizer, Novartis, Bicara Pharmaceuticals, Bristol Myers Squibb, RedX, and BioNTech. BK declares ownership medtronic corporation stock that is less than $10,000. FM-B reports research funding\/grant support for clinical trials from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, Taiho Pharmaceutical. FM-B served as advisory committee for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, personal fees for consulting\/travel related from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, Daiichi Sankyo, DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai Bio, Samsung Bioepis, Seattle Genetics, Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), personal fees for honoraria from Chugai Biopharmaceuticals<b>.<\/b> No potential conflicts of interest were disclosed by the other authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All participants signed the consent form prior to study enrollment. The study was approved by MD Anderson Institutional Review Board (IRB) in accordance with the Declaration of Helsinki, Good Clinical Practice, and all federal, state and local regulatory guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"A signed informed consent was obtained from each participant prior to any study procedure.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}