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Review
. 2025 Aug:212:104762.
doi: 10.1016/j.critrevonc.2025.104762. Epub 2025 May 3.

Evolving treatment for advanced non-small cell lung cancer harbouring common EGFR activating mutations

Igor Gomez-Randulfe  1 , Federico Monaca  2 , David Planchard  3 , Emilio Bria  4 , Raffaele Califano  5
Affiliations
Review

Evolving treatment for advanced non-small cell lung cancer harbouring common EGFR activating mutations

Igor Gomez-Randulfe et al. Crit Rev Oncol Hematol. 2025 Aug.

Abstract

A clinically important subgroup of non-small cell lung cancer (NSCLC) is driven by common mutations in the epidermal growth factor receptor (EGFR). Over the past decade, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) have substantially improved clinical outcomes, although acquired resistance inevitably emerges. In particular, the third-generation TKI osimertinib has demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to earlier-generation TKIs in the frontline setting, yet median OS remains approximately three years in pivotal trials. Efforts to extend disease control have led to various upfront intensification strategies, including combining EGFR TKIs with antiangiogenics or chemotherapy (e.g., the FLAURA-2 trial), and pairing novel bispecific antibodies such as amivantamab with third-generation TKIs. Upon progression on third-generation EGFR TKIs, platinum-based chemotherapy remains the standard second-line treatment, albeit with modest response rates. Emerging therapies targeting MET amplification (e.g., savolitinib plus osimertinib), leveraging antibody-drug conjugates (e.g., patritumab deruxtecan), or adding immunotherapy and antiangiogenics have shown preliminary promise in overcoming resistance. Ongoing trials are assessing optimal treatment sequencing and the use of circulating tumor DNA (ctDNA) to guide therapy escalation or de-escalation. Ultimately, the evolving landscape of EGFR-mutant NSCLC underscores the need for refined biomarker-driven approaches and personalized regimens to achieve further gains in survival. In this review, we discuss these strategies in detail, highlighting current evidence and future directions for EGFR-mutant NSCLC treatment.

Keywords: Amivantamab; Antibody-drug conjugates; EGFR; Non-small cell lung cancer; Osimertinib.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Igor Gomez-Randulfe reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. David Planchard reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. David Planchard reports a relationship with AbbVie Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Celgene SL that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Daiichi Sankyo Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Eli Lilly and Company that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Merck & Co Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. David Planchard reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Pfizer Inc that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. David Planchard reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. David Planchard reports a relationship with Pierre Fabre SA that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Takeda Oncology that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with ArriVent Biopharma Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Mirati Therapeutics Inc that includes: consulting or advisory and speaking and lecture fees. David Planchard reports a relationship with Seagen Inc that includes: consulting or advisory and speaking and lecture fees. Emilio Bria reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory, funding grants, and speaking and lecture fees. Emilio Bria reports a relationship with Roche that includes: consulting or advisory, funding grants, and speaking and lecture fees. Emilio Bria reports a relationship with Merck & Co Inc that includes: consulting or advisory and speaking and lecture fees. Emilio Bria reports a relationship with Pfizer Inc that includes: consulting or advisory and speaking and lecture fees. Emilio Bria reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees. Emilio Bria reports a relationship with Bristol-Myers Squibb Co that includes: consulting or advisory and speaking and lecture fees. Emilio Bria reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Emilio Bria reports a relationship with Takeda Oncology that includes: speaking and lecture fees. Emilio Bria reports a relationship with Celltrion, Inc. that includes: consulting or advisory. Raffaele Califano reports a relationship with Roche that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Pharmamar that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Pfizer that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Eli Lilly and Company that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Gilead that includes: funding grants. Raffaele Califano reports a relationship with Merck & Co Inc that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with AbbVie Inc that includes: funding grants. Raffaele Califano reports a relationship with Takeda Oncology that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Arrivent that includes: consulting or advisory and funding grants. Raffaele Califano reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc that includes: consulting or advisory. Raffaele Califano reports a relationship with GSK that includes: consulting or advisory. Raffaele Califano reports a relationship with Biontech that includes: consulting or advisory. Raffaele Califano reports a relationship with Bayer AG that includes: consulting or advisory. Raffaele Califano reports a relationship with The Christie Private Care that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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