{"doi":"10.1016/j.esmoop.2025.104136","title":"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","abstract":"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.","journal":"ESMO Open","year":2025,"id":537946,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290153,"name":"Chieh Tseng","orcid":null,"position":1,"is_corresponding":false},{"id":247606,"name":"Hai T. 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Yap","orcid":"0000-0002-2154-3309","position":7,"is_corresponding":false},{"id":264370,"name":"Kanwal Raghav","orcid":"0000-0003-1311-4173","position":8,"is_corresponding":false},{"id":495199,"name":"Senthil Damodaran","orcid":"0000-0002-2470-0891","position":9,"is_corresponding":false},{"id":1377232,"name":"Xiao‐Feng Le","orcid":"0000-0002-2381-5929","position":10,"is_corresponding":false},{"id":1424638,"name":"P T Soliman","orcid":null,"position":11,"is_corresponding":false},{"id":1424639,"name":"Jo Ann Lim","orcid":null,"position":12,"is_corresponding":false},{"id":1293102,"name":"F. Meric-Bernstam","orcid":null,"position":13,"is_corresponding":false},{"id":258839,"name":"Sarina A. Piha‐Paul","orcid":"0000-0001-9455-1660","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:52:16.891390Z","pmid":"39908697","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}