The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: a systematic review and future perspectives
A partir d'une revue systématique de la littérature (36 essais), cette étude analyse l'efficacité des thérapies ciblées chez les patients atteints d'un cancer métastatique de la vessie présentant des amplifications ou des mutations du gène ERBB2
Purpose : HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladdercancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. Methods : This is a systematic review of clinical trials evaluating HER2-targeting (amplifications and mutations) in mUC. We assigned each study to one of the following strategiesHER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dualHER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeuticapproaches. Results : 36 clinical trials (17 with results and 19 ongoing) were included in this systematic review. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy(4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonalantibodies proved active in one trial in pretreated patients. Two studies assessedsingle-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with antibody-drugconjugates (ADCs) in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 otherstudies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category,trastuzumab-deruxtecan and other ADCs are still under investigation for either HER2-amplifiedor mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results),CAR-T cells, and HER2-sensitising vaccines. Conclusions : ERBB2 amplification could become a novel target in mUC, although the magnitude of clinicalbenefit remains to be clarified. To this regard, novel ADCs are the most promisingstrategy. ERBB2 mutations are still at very early stage of clinical study.