{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:22:17Z","timestamp":1783527737718,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR\/MET) and zenocutuzumab (HER2\/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody\u2013drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks.<\/jats:p>","DOI":"10.3390\/cancers18142197","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:40:09Z","timestamp":1783525209000},"page":"2197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Evolving Role of Bispecific Antibodies in Oncogene-Driven NSCLC"],"prefix":"10.3390","volume":"18","author":[{"given":"Jun Chih","family":"Wang","sequence":"first","affiliation":[{"name":"Memorial Healthcare System, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rosas","sequence":"additional","affiliation":[{"name":"Memorial Healthcare System, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5771","authenticated-orcid":false,"given":"Luis E.","family":"Raez","sequence":"additional","affiliation":[{"name":"Memorial Healthcare System, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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