Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers Journal Article
| Authors: | Harding, J. J.; Piha-Paul, S. A.; Shah, R. H.; Murphy, J. J.; Cleary, J. M.; Shapiro, G. I.; Quinn, D. I.; Braña, I.; Moreno, V.; Borad, M.; Loi, S.; Spanggaard, I.; Park, H.; Ford, J. M.; Arnedos, M.; Stemmer, S. M.; de la Fouchardiere, C.; Fountzilas, C.; Zhang, J.; DiPrimeo, D.; Savin, C.; Selcuklu, S. D.; Berger, M. F.; Eli, L. D.; Meric-Bernstam, F.; Jhaveri, K.; Solit, D. B.; Abou-Alfa, G. K. |
| Article Title: | Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers |
| Abstract: | HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common HER2 mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored. © 2023, The Author(s). |
| Keywords: | adult; cancer survival; clinical article; controlled study; treatment outcome; aged; cancer surgery; overall survival; somatic mutation; genetics; missense mutation; mutation; constipation; drug tolerability; fatigue; cisplatin; fluorouracil; advanced cancer; ascites; cancer growth; diarrhea; drug safety; drug withdrawal; monotherapy; side effect; systemic therapy; gemcitabine; paclitaxel; cancer radiotherapy; follow up; antineoplastic agent; progression free survival; antineoplastic metal complex; phase 2 clinical trial; anemia; nausea; vomiting; antineoplastic combined chemotherapy protocols; dehydration; epidermal growth factor receptor 2; cohort analysis; antineoplastic activity; breast neoplasms; protein p53; carcinogenesis; irinotecan; abdominal pain; aspartate aminotransferase blood level; asthenia; dizziness; fever; rash; genome analysis; alkaline phosphatase; aspartate aminotransferase; bilirubin; acute kidney failure; hypokalemia; folinic acid; breast tumor; xerostomia; sepsis; open study; receptor, erbb-2; intrahepatic cholangiocarcinoma; bile duct carcinoma; biliary tract surgery; safety; alkaline phosphatase blood level; loperamide; cyclin dependent kinase inhibitor 2a; cancer control; tumor; gallbladder carcinoma; oxaliplatin; k ras protein; gallbladder cancer; fluoropyrimidine; bilirubin blood level; b raf kinase; biliary tract cancer; nonsense mutation; biliary tract neoplasms; fibroblast growth factor receptor 2; fulvestrant; biliary tract tumor; neratinib; vater papilla carcinoma; abdominal distension; molecular pathology; molecularly targeted therapy; decreased appetite; isocitrate dehydrogenase 1; quinolines; antimicrobial activity; quinoline derivative; clinical outcome; hypertransaminasemia; extrahepatic cholangiocarcinoma; body weight loss; cancer prognosis; high throughput sequencing; body weight disorder; cancer; humans; human; male; female; article; patient history of radiotherapy; patient history of surgery; treatment response time |
| Journal Title: | Nature Communications |
| Volume: | 14 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-02-06 |
| Start Page: | 630 |
| Language: | English |
| DOI: | 10.1038/s41467-023-36399-y |
| PUBMED: | 36746967 |
| PROVIDER: | scopus |
| PMCID: | PMC9902444 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK author James J. Harding -- Export Date: 1 March 2023 -- Source: Scopus |
