{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:18:30Z","timestamp":1787807910481,"version":"build-2784847793"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>This case report illustrates the use of amivantamab in combination with pemetrexed-based chemotherapy for the treatment of a 60-year-old man with refractory metastatic upper tract urothelial carcinoma (UTUC) with epidermal growth factor receptor (EGFR) exon 20 insertion (D770_N771insGF) and methylthioadenosine phosphorylase (MTAP) loss identified in both the primary left nephroureterectomy tissue and lung metastasis biopsy. The patient, who had progressed on five prior lines of therapy including platinum-based chemotherapy, immunotherapy, and antibody-drug conjugates, attained a sustained partial response with favourable tolerability before eventual disease progression with brain metastasis. This case is unique because of the uncommon molecular profile, with an EGFR exon 20 insertion observed in only 0.7% of urothelial carcinomas, which highlights the potential for repurposing targeted therapies developed for other malignancies in biomarker-defined subgroups of UTUC. This case report highlights the significance of next-generation sequencing in uncovering rare therapeutic targets, the potential of synthetic lethality approaches in MTAP-deficient tumours, and supports further research to explore molecular-based cancer classification and treatment strategies in precision oncology.<\/jats:p>","DOI":"10.3389\/fonc.2026.1928596","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:26:57Z","timestamp":1787804817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Targeting EGFR exon 20 insertion and MTAP loss in refractory metastatic upper tract urothelial carcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Karen Hoi Lam","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland Ching Yu","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Yau","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]},{"name":"Centre of Cancer Medicine, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua Jing Xi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine Wing Yan","family":"Tsang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny Wai Yan","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry Gin Wai","family":"Kwok","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey Sum Lung","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin Hoi Wai","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan Cho Wing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, Queen Mary Hospital, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]},{"name":"Centre of Cancer Medicine, The University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17152467","article-title":"Diagnosis and management of upper tract urothelial carcinoma: a review","volume":"17","author":"Escobar","year":"2025","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000534858","article-title":"Metastatic squamous cell carcinoma of the urinary bladder: urgent call for new therapies","volume":"108","author":"Banek","year":"2024","journal-title":"Urol Int"},{"key":"B3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41571-025-01095-x","article-title":"Towards biomarker-driven therapies for urothelial carcinoma","volume":"23","author":"Coca Membribes","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1016\/j.ccell.2023.09.005","article-title":"Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance","volume":"41","author":"Gjuka","year":"2023","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29397-z","article-title":"MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers","volume":"13","author":"Alhalabi","year":"2022","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/bju.15006","article-title":"Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions","volume":"125","author":"Madison","year":"2020","journal-title":"BJU Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2306441","article-title":"Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions","volume":"389","author":"Zhou","year":"2023","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.00662","article-title":"Amivantamab in EGFR exon 20 insertion\u2013mutated non\u2013small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study","volume":"39","author":"Park","year":"2021","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2011.37.3571","article-title":"Randomized phase II\/III trial assessing gemcitabine\/carboplatin and methotrexate\/carboplatin\/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986","volume":"30","author":"De Santis","year":"2012","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1613683","article-title":"Pembrolizumab as second-line therapy for advanced urothelial carcinoma","volume":"376","author":"Bellmunt","year":"2017","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.03489","article-title":"TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors","volume":"39","author":"Tagawa","year":"2021","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(21)00094-2","article-title":"Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial","volume":"22","author":"Yu","year":"2021","journal-title":"Lancet Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.09.012","article-title":"Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: interim results of the open-label, single-arm, phase II PEANUT study","volume":"31","author":"Giannatempo","year":"2020","journal-title":"Ann Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1093\/oncolo\/oyae011","article-title":"Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers","volume":"29","author":"Ngoi","year":"2024","journal-title":"Oncologist"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1264785","article-title":"The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality","volume":"13","author":"Bray","year":"2023","journal-title":"Front Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5214","article-title":"MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells","volume":"351","author":"Kryukov","year":"2016","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2021.10.006","article-title":"Integrative clinical and genomic characterization of MTAP-deficient metastatic urothelial cancer","volume":"6","author":"Alhalabi","year":"2023","journal-title":"Eur Urol Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115631","article-title":"Prospective investigation of biomarker and resistance mechanism using longitudinal cell-free NGS in non-small cell lung cancer with EGFR exon 20 insertion treated with amivantamab","volume":"226","author":"Park","year":"2025","journal-title":"Eur J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.07.014","article-title":"Mechanisms of osimertinib resistance and emerging treatment options","volume":"147","author":"Schmid","year":"2020","journal-title":"Lung Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-20-0071","article-title":"Amivantamab (JNJ-61186372), an Fc enhanced EGFR\/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte\/macrophage trogocytosis","volume":"19","author":"Vijayaraghavan","year":"2020","journal-title":"Mol Cancer Ther"},{"key":"B21","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.annonc.2023.10.117","article-title":"Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study","volume":"35","author":"Passaro","year":"2024","journal-title":"Ann Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1016\/j.cell.2017.11.009","article-title":"Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy","volume":"171","author":"Palmer","year":"2017","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol32040206","article-title":"Unveiling the synergistic potential: bispecific antibodies in conjunction with chemotherapy for advanced non-small-cell lung cancer treatment","volume":"32","author":"Khan","year":"2025","journal-title":"Curr Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14093129","article-title":"EGFR-mutant urothelial carcinoma harboring an Ala750_Ile759delinsGlyGly alteration with a primary resistance to polychemotherapy and a sensitivity to osimertinib: a literature review on EGFR alterations and response to EGFR tyrosine kinase inhibitors in C","volume":"14","author":"Barbe-Richaud","year":"2025","journal-title":"J Clin Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"S1133","DOI":"10.1016\/j.annonc.2024.08.2044","article-title":"1959O BL-B01D1, an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic urothelial carcinoma (UC)","volume":"35","author":"Ye","year":"2024","journal-title":"Ann Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06054-z","article-title":"Pan-cancer whole-genome comparison of primary and metastatic solid tumours","volume":"618","author":"Mart\u00ednez-Jim\u00e9nez","year":"2023","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2026.0022","article-title":"Bladder, cancer version 2.2026, NCCN clinical practice guidelines in oncology","author":"Thomas","year":"2026"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17203367","article-title":"Navigating therapeutic landscapes in urothelial cancer: from chemotherapy to precision immuno-oncology","volume":"17","author":"Somoto","year":"2025","journal-title":"Cancers"},{"key":"B29","doi-asserted-by":"crossref","DOI":"10.1038\/d41586-024-00216-3","article-title":"Forget lung, breast or prostate cancer: why tumour naming needs to change","volume":"626","author":"Andr\u00e9","year":"2024","journal-title":"Nature"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1928596\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:27:05Z","timestamp":1787804825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1928596\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":29,"alternative-id":["10.3389\/fonc.2026.1928596"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1928596","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"article-number":"1928596"}}