Exploration of Targeted Anti-tumor Therapy

Table 1. Summary of pivotal and emerging clinical trials for the management of EGFR-mutant NSCLC.

Trial (Phase)	Study design & regimen	Major outcomes (mPFS/mOS)	Acquired resistance mechanisms	Key toxicities and considerations
FLAURA2 (III) [12]	1L: osimertinib + platinum-pemetrexed vs. osimertinib	PFS: 25.5 vs. 16.7 months; OS: 47.5 vs. 37.6 months		Predominantly C797S and MET alterations; chemotherapy delays but does not change the molecular profile.
MARIPOSA (III) [15, 16]	1L: amivantamab + lazertinib vs. osimertinib	PFS: 23.7 vs. 16.6 months; OS: NR vs. 36.7 months	Significantly reduced MET amp (4.4% vs. 13.6%) and secondary EGFR mutations (0.9% vs. 7.9%).	Infusion-related reactions (IRRs) and dermatological events; utilizes “dual” receptor inhibition.
MARIPOSA-2 (III)	2L (post-osi): amivantamab + chemo ± lazertinib vs. chemo	PFS: 6.3 vs. 4.2 months	Heterogeneous bypass pathway activation.	Managed IRRs; established a new second-line standard.
HARMONi-A (III) [20]	2L: ivonescimab (PD-1/VEGF) + chemo vs. chemo	PFS: 6.8 vs. 4.4 months; OS: 16.8 vs. 14.0 months (trend) + 1	Bypass signaling and RTK/RAS/PI3K pathway modifications.	VEGF-related adverse events (hypertension, proteinuria).
OptiTROP-Lung04 (III) [26]	2L: Sac-TMT (TROP2-ADC) vs. platinum-based chemo	PFS: 8.3 vs. 4.3 months; OS: NR vs. 17.4 months	TROP2 expression remains stable across resistance clones.	Potential for tumor-selective cytotoxicity with reduced systemic toxicity.
TROPION-Lung05 (II) [25]	2L: datopotamab deruxtecan (TROP2-ADC)	PFS: 5.8 months; OS: 18.3 months	Topoisomerase I inhibitor payload engagement.	Stomatitis and ocular toxicities are common to the ADC class.
INSIGHT 2 (II) [24]	2L (MET+): tepotinib + osimertinib	ORR: 54.8% (in MET-amplified)	Targets acquired MET-mediated bypass resistance.	Peripheral edema is a known class effect of MET inhibitors.

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This table provides a comparative overview of frontline (1L) and second-line (2L) regimens, highlighting efficacy outcomes (mPFS, mOS), mechanisms of acquired resistance suppressed or observed, and primary safety considerations to guide clinical stratification. ADC: antibody-drug conjugate; EGFR: epidermal growth factor receptor; IRR: infusion-related reaction; MET: MET proto-oncogene; mOS: median overall survival; mPFS: median progression-free survival; NR: not reached; NSCLC: non-small cell lung cancer; ORR: objective response rate; PD-1: programmed cell death protein 1; RTK: receptor tyrosine kinase; Sac-TMT: sacituzumab tirumotecan; TROP2: trophoblast cell-surface antigen 2; VEGF: vascular endothelial growth factor.

Declarations

Author contributions

CMDC: Conceptualization, Investigation, Data curation, Formal analysis, Writing—original draft, Writing—review & editing. CDR: Data curation, Formal analysis, Visualization, Writing—review & editing. FUH: Data curation, Formal analysis, Visualization, Writing—review & editing. FM: Conceptualization, Writing—review & editing, Supervision, Project administration, Resources, Funding acquisition. All authors read and approved the final manuscript.

Conflicts of interest

Floriana Morgillo received honoraria or consultation fees for speaker, consultancy, or advisory roles from Roche, Servier, Incyte, ESMO, and MSD. Carminia Maria Della Corte reported receiving honoraria or consultation fees for speaker, consultancy, or advisory roles from AstraZeneca, Pfizer, Regeneron, Roche, Genentech, Merck, Novartis, BMS, MSD, Amgen, and Takeda, as well as a travel grant from Daiichi Sankyo, Amgen, MSD, Novartis, and AstraZeneca outside the submitted work. Caterina De Rosa and Faiz Ul Haq declare no conflict of interest. Carminia Maria Della Corte and Caterina De Rosa, who are the Guest Editors of Exploration of Targeted Anti-tumor Therapy, and Floriana Morgillo, who is the Editorial Board Member and Guest Editor of Exploration of Targeted Anti-tumor Therapy, had no involvement in the decision-making or the review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by Fondazione AIRC (MFAG Project Number: 26237) to CMDC and by Progetti di Rilevante Interesse Nazionale (PRIN Project Number: P2022P7439) to FM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

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