June 2025: Strategies and Advances in Non-Small Cell Lung Cancer (NSCLC)

Non–small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Since 2011, the U.S. Food and Drug Administration has approved  over 30 new therapies for advanced NSCLC, primarily tyrosine kinase inhibitors and immune checkpoint inhibitors. Biologic agents, including monoclonal antibodies against PD-1/PD-L1 and antibody-drug conjugates (ADCs), are gaining prominence across  molecular subtypes in drug development. Current therapeutic development is increasingly focused on multi-functional antibodies and biomarker-driven approaches, including bispecifics, trispecifics, and ADCs, which aim to enhance antitumor efficacy through novel mechanisms of action.

Bispecific and Trispecific Antibodies Targeting Immune and Angiogenic Pathways

Recent progress in the clinical development of multispecific antibodies reflects an increasingly sophisticated strategy for overcoming resistance mechanisms and enhancing efficacy in NSCLC. Targeting immune checkpoint and angiogenic pathways simultaneously has emerged as a particularly promising approach.

Instil Bio and ImmuneOnco’s bispecific antibody AXN-2510/IMM2510 (‘2510) continues to progress through clinical development in China. The bispecific targets PD-L1 and VEGF and is currently under investigation in a Phase 2 trial in combination with chemotherapy for first-line NSCLC. Notably, ‘2510 incorporates a VEGF trap capable of binding multiple VEGF ligands beyond VEGF-A, while using PD-L1 as an anchor within the tumor microenvironment (TME). The antibody also has enhanced antibody-dependent cellular cytotoxicity (ADCC) activity.

Similarly, ivonescimab, a PD-1 x VEGF bispecific antibody developed by Summit Therapeutics and Akeso, demonstrates how co-targeting immune suppression and angiogenesis can yield enhanced therapeutic outcomes. In a head-to-head comparison with BeiGene’s PD-1 inhibitor Tevimbra, ivonescimab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in the Phase III HARMONi-6 trial. The mechanism of ivonescimab is blockade of PD-1-mediated immune evasion and VEGF-driven angiogenesis, which appears to confer superior tumor control compared to single-target checkpoint inhibitors.

The emergence of trispecific antibodies offers an expanded therapeutic window by targeting multiple non-redundant pathways simultaneously. TAVO412, a novel trispecific antibody engineered to inhibit EGFR, cMET, and VEGF-A, demonstrated robust anti-tumor activity in preclinical NSCLC models encompassing both wild-type and mutant EGFR contexts. Mechanistically, TAVO412 blocks ligand-induced phosphorylation of EGFR and cMET, promotes receptor degradation, and suppresses VEGF-mediated angiogenesis. Enhanced Fc effector function further augments its cytotoxic potential. These findings support TAVO412’s potential as a broadly active agent in NSCLC, particularly for patients with resistance to EGFR- or cMET-targeted monotherapies.    

ADCs and Biomarker-Driven Therapeutics Continue to Gain Ground

On May 14, 2025, the U.S. FDA granted accelerated approval for telisotuzumab vedotin (Emrelis) for adult patients with locally advanced or metastatic, non-squamous NSCLC exhibiting high c-Met protein overexpression (≥50% tumor cells with 3+ staining by IHC) following prior systemic therapy. Emrelis is the first c-Met-directed ADC to receive regulatory approval in this population, addressing an unmet need in a molecularly defined NSCLC subset with poor prognosis and limited therapeutic options.

Meanwhile, preliminary data from a first-in-human Phase I/IIa trial of DB-1310, a novel ADC, revealed encouraging efficacy in patients with advanced, treatment-refractory solid tumors. Among 62 patients with EGFR-mutant NSCLC, DB-1310 elicited an ORR of 44%, with a median progression-free survival (PFS) of 7 months and a median overall survival (OS) of 18.9 months. These patients had undergone multiple lines of prior therapy, including EGFR tyrosine kinase inhibitors and chemotherapy. DB-1310’s performance in this cohort is exciting, given the limited therapeutic options available after resistance to EGFR-targeted agents.

Furthermore, the HER2-directed ADC trastuzumab deruxtecan (T-DXd; Enhertu) continues to establish its role in NSCLC management, supported by pivotal data from the DESTINY-Lung trials. In DESTINY-Lung01, T-DXd achieved an ORR of 55% and median PFS of 8.2 months in HER2-mutant patients. These findings have led to the inclusion of T-DXd in NCCN guidelines for both HER2-mutant and HER2-overexpressing NSCLC. In contrast, trastuzumab emtansine (T-DM1) demonstrated a shorter PFS of 2.6 months in HER2-positive NSCLC, though it remains guideline-recommended. HER3-targeted therapy is also gaining momentum. Patritumab deruxtecan, evaluated in the HERTHENA-Lung01 trial, demonstrated an ORR of ~30%, median PFS of 5.5 months, and CNS activity in patients with EGFR-mutated NSCLC who progressed on TKIs and chemotherapy. Although HER3 expression was not required for trial enrollment, its high prevalence in EGFR-mutated tumors and role in TKI resistance underscore its emerging relevance.    

Strategies in Checkpoint and Conjugate Therapies

In a recent study, a novel site-selective antibody-drug conjugate (ADC) composed of durvalumab and monomethyl auristatin E (MMAE) demonstrated robust preclinical efficacy in NSCLC models, highlighting the potential of precision conjugation strategies in enhancing immunotherapeutic payload delivery. This construct, with a defined drug-antibody ratio (DAR) of 4, leverages the AbClick Pro linker to achieve stable site-specific conjugation, preserving native antibody function while facilitating controlled cytotoxic payload release. Durvalumab-MMAE is a promising next-generation ADC targeting PD-L1, potentially augmenting checkpoint blockade efficacy by delivering cytotoxic agents directly to PD-L1-expressing tumor cells.    

In contrast, the TIGIT checkpoint inhibitor class has experienced a series of high-profile failures in late-stage trials. Most recently, BeiGene discontinued its Phase 3 trial of ociperlimab, an anti-TIGIT monoclonal antibody, combined with its PD-1 inhibitor Tevimbra in PD-L1–high NSCLC after an independent data monitoring committee concluded the study was unlikely to meet its primary endpoint of overall survival.Ociperlimab's termination follows similar outcomes from other TIGIT candidates, including Roche’s tiragolumab, Merck’s vibostolimab, and Arcus Biosciences’ asset partnered with Gilead. These failures suggest either insufficient therapeutic synergy between TIGIT and PD-1 blockade or patient populations not optimally selected for TIGIT dependency. Despite these setbacks, companies such as GSK continue to invest in TIGIT-based therapeutics, with belrestotug now in Phase 3 development.The TIGIT class's ongoing attrition raises critical questions regarding target validation, biomarker development, and the reliability of preclinical models in predicting clinical outcomes. While PD-1/PD-L1 remains an established axis in NSCLC treatment, the path forward for TIGIT therapies will likely require better-defined biomarkers and patient stratification strategies to justify continued investment.