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This review summarizes current systemic treatment strategies for advanced EGFR-mutated non-small cell lung cancer (NSCLC), with a focus on novel first-line regimens and emerging concepts beyond progression.
Methods
Evidence from pivotal phase III trials and recent regulatory developments was analyzed, emphasizing efficacy outcomes, safety profiles, and patient selection factors relevant for routine clinical practice.
Results
Osimertinib has long been the standard first-line therapy, yet resistance inevitably emerges. The two novel combination strategies, osimertinib plus platinum–pemetrexed chemotherapy (FLAURA2) and amivantamab plus lazertinib (MARIPOSA), have shown superior progression-free and overall survival compared with osimertinib monotherapy. These regimens are associated with higher toxicity, treatment burden, and costs, requiring careful patient selection based on comorbidities, risk features, and preferences. After progression, treatment options remain limited. Current postprogression data are almost exclusively derived from patients previously treated with first-line osimertinib monotherapy, and it remains unclear how outcomes will evolve following upfront combination regimens. Platinum-based chemotherapy remains the historical backbone, while continuation of EGFR inhibition with targeted agents or chemotherapy (e.g., MARIPOSA‑2, COMPEL) and the development of antibody–drug conjugates such as datopotamab deruxtecan represent promising strategies, especially in view of the rapidly changing first-line landscape.
Conclusion
Upfront combination regimens have redefined the standard of care in EGFR-mutated advanced NSCLC, but their survival benefit must be weighed against added toxicity, logistical complexity, and financial impact. Expanding therapeutic options make individualized shared decision-making essential to balance efficacy, tolerability, logistics, and patient priorities, aiming to maintain quality of life while extending survival.
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Introduction
EGFR-mutated non-small cell lung cancer (NSCLC) accounts for approximately 15% of lung adenocarcinomas in Western populations and up to 50% in Asian cohorts [1]. Tyrosine kinase inhibitors (TKIs) have dramatically changed the therapeutic landscape, shifting median survival beyond 3 years in selected patients even in the palliative setting [2]. Osimertinib has become the global standard first-line therapy, but resistance inevitably develops, necessitating exploration of novel strategies.
This review aims to provide an overview of current systemic treatment strategies for patients with advanced NSCLC harboring common sensitizing EGFR mutations, focusing on evidence from pivotal phase III studies and the evolving role of combination regimens.
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First-line options
Osimertinib remains the current reference standard in the first-line treatment of EGFR-mutated advanced NSCLC. In the phase III FLAURA trial, osimertinib significantly improved median progression-free survival (PFS, 18.9 vs 10.2 months; hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.37–0.57) and overall survival (OS, 38.6 vs 31.8 months; HR 0.80, 95% CI 0.64–1.00) compared with first-generation TKIs, with landmark OS rates at 12, 24, and 36 months of 89%, 74%, and 54% versus 83%, 59%, and 44% [2, 3]. In regions where first-line osimertinib is not available, a sequencing strategy using second-generation TKIs such as afatinib or dacomitinib in the first line followed by osimertinib upon emergence of a T790M resistance mutation remains a valid alternative [4, 5].
Two large phase III trials have recently demonstrated superior efficacy of upfront combination regimens compared with osimertinib monotherapy (Table 1). In FLAURA2, the addition of chemotherapy to osimertinib improved median PFS to 25.5 versus 16.7 months (HR 0.62, 95% CI 0.49–0.79) and median OS to 47.5 versus 37.6 months (HR 0.77, 95% CI 0.61–0.96), with 3‑ and 4‑year OS rates of 63% and 49% versus 51% and 41% [6, 7].
*Toxicities with amivantamab + lazertinib have been shown to can be reduced significantly with prophylaxis and subcutaneous administration
The MARIPOSA trial established a chemotherapy-free combination of the EGFR/MET bispecific antibody amivantamab and the third-generation TKI lazertinib. This regimen achieved a median PFS of 23.7 versus 16.6 months (HR 0.70, 95% CI 0.58–0.85) and significantly improved OS (not reached vs 36.7 months; HR 0.75, 95% CI 0.61–0.92) compared with osimertinib, with 36-month OS rates of 60% versus 51% [8]. Subcutaneous administration of amivantamab, introduced after MARIPOSA, was shown to markedly reduce infusion-related reactions, improved convenience, and may further lead to improved efficacy due to better tolerability [9]. According to subgroup analyses of both studies, the upfront combinations may be particularly advantageous for patients with high-risk disease biology, high tumor burden or baseline central nervous system (CNS) or liver metastases (Fig. 1). A recent meta-analysis confirmed the superior efficacy of combination regimens over osimertinib alone especially in patients with brain metastases, though at the cost of higher toxicity [10]. Consistently, restricted mean survival time analyses from both trials indicate that treatment intensification confers delayed yet clinically meaningful survival benefits. The early overlap of the survival curves, which begin to separate only after 16.0 months in FLAURA2 and 11.0 months in MARIPOSA, suggests that the benefits of combination therapy emerge late and may not apply to all patients. This underscores the need for refined patient selection and more precise, biology-driven treatment guidance [11].
Fig. 1
Clinical and molecular poor prognostic factors. Progression-free survival (PFS) outcomes are shown for different treatments groups from the MARIPOSA and FLAURA2 trials. This figure combines subgroup and exploratory analyses from two separate clinical studies to provide a comprehensive overview; however, caution is warranted when performing cross-trial comparisons. Ami-laz amivantamab plus lazertinib, HR hazard ratio, NE not estimable; Osi osimertinib, Osi-CT osimertinib plus chemotherapy. Created in BioRender (Maxime Borgeaud, 2025; https://BioRender.com/s16f601). Reproduced from [12], with permission from Wiley, under the Creative Commons Attribution-NonCommercial-NoDerivs License (CC BY-NC-ND 4.0)
The choice between osimertinib monotherapy, osimertinib plus chemotherapy (FLAURA2), or amivantamab plus lazertinib (MARIPOSA) requires careful assessment of patient comorbidities, preferences, and disease characteristics, as the survival benefit of combination strategies comes at the cost of increased toxicity and treatment burden.
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High-risk disease
Patients with TP53 comutations, high tumor burden, or L858R mutation, baseline liver or CNS metastases or circulating tumor DNA are considered at elevated risk for early progression and may benefit from upfront intensification. An overview and indirect comparison of results in patients with those poor prognostic factors are shown in Fig. 1 [12]. In FLAURA2, subgroup analyses showed particularly pronounced benefit in patients with baseline CNS involvement, suggesting this regimen may be favored in this setting [6]. MARIPOSA also demonstrated improved intracranial disease control; however, baseline brain imaging was performed more rigorously and systematically than in FLAURA2, which may partly account for differences in reported CNS outcomes [8]. The presence of MET-driven biology warrants special consideration. MARIPOSA prospectively assessed and reported outcomes in patients with baseline MET overexpression or amplification, and the dual EGFR/MET targeting of amivantamab may be advantageous in this subgroup.
Comorbidities and frailty
Osimertinib monotherapy is the most tolerable regimen, though QTc prolongation and rare cardiomyopathy necessitate caution in patients with pre-existing cardiac disease [5, 13, 14]. Patients with pre-existing cardiac disease may therefore be better suited for lazertinib-based therapy, which appears to carry a lower risk of cardiotoxicity [15]. Conversely, FLAURA2 showed higher rates of myelosuppression and gastrointestinal toxicity, making it less suitable for patients with hematologic frailty or poor chemotherapy tolerance [5].
Dermatologic and infusion-related toxicity
Dermatologic adverse events are a common class effect of EGFR inhibition. Both FLAURA2 and MARIPOSA include a third-generation TKI, but the addition of amivantamab in MARIPOSA further increases the frequency and severity of skin toxicities such as rash, dermatitis, and paronychia. Patients with severe pre-existing dermatologic conditions may find chemotherapy-containing regimens more manageable compared with antibody-driven rash, although the COCOON trial demonstrated that prophylaxis and systematic dermatologic interventions can significantly reduce severity and improve adherence [16]. Infusion-related reactions were frequent with intravenous amivantamab but are largely mitigated by the newer subcutaneous formulation, which shortens administration time and improves convenience [9].
Patient preference, treatment burden, and financial considerations
Beyond toxicity, practical and systemic factors play a crucial role in treatment selection. Combination regimens often require more frequent hospital visits for parenteral therapy, additional laboratory monitoring, and supportive measures, particularly when chemotherapy is involved. This higher treatment burden can negatively affect quality of life and patient autonomy.
Reimbursement policies and national drug approval status further shape real-world practice, with access to amivantamab- or lazertinib-based regimens varying widely between health care systems. A recent cost-effectiveness analysis demonstrated that amivantamab plus lazertinib more than doubled treatment costs compared with osimertinib monotherapy, exceeding commonly accepted willingness-to-pay thresholds in the United States and China, and likely also in the United Kingdom [17, 18]. By contrast, analyses suggest that osimertinib plus chemotherapy represents a comparatively more cost-efficient intensification strategy, although even this combination is unlikely to meet US willingness-to-pay thresholds [19, 20], while the UK estimates it within an acceptable range of cost-effectiveness [21]. It remains an open ethical and health policy question to what extent these findings can or should be extrapolated to European health care systems, where cost structures and reimbursement frameworks differ substantially and formal cost-effective analysis are still lacking.
Summary of first-line therapy
FLAURA2 and MARIPOSA have both demonstrated significant improvements in PFS and OS over osimertinib monotherapy and can be considered new standards of care. Their distinct toxicity profiles, logistical demands, and financial impact, however, require careful patient selection.
In patients with baseline brain metastases, FLAURA2 showed an impressive PFS benefit, which may support its preferential use in this subgroup. However, the corresponding OS benefit was more moderate than expected (HR 0.72, 95% CI 0.52–0.90), suggesting that the magnitude of intracranial PFS improvement does not fully translate into long-term survival benefit. MARIPOSA also demonstrated convincing intracranial efficacy. Notably, its use of more rigorous and systematic baseline CNS imaging likely increased the detection of brain metastases at enrollment, making the observed intracranial outcomes particularly robust.
Patients with tumors harboring MET overexpression or amplification may theoretically particularly benefit from the dual EGFR/MET targeting of amivantamab plus lazertinib, although MARIPOSA did not provide definitive biomarker-based selection data, and validated predictive biomarkers for this regimen remain lacking at present.
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Osimertinib monotherapy remains an appropriate and widely accessible option, particularly for patients in whom combination strategies are not feasible or acceptable. The decision should weigh the expected efficacy gain against added toxicity, treatment burden, and patient preference, with individual risk profiles guiding the choice between oral monotherapy and intensified combination regimens.
Beyond first-line treatment
Only about half of patients with EGFR-mutated advanced NSCLC receive any second-line therapy after progression on first-line osimertinib. In the osimertinib arm of FLAURA2, just 60% of patients proceeded to second-line treatment, which mirrors real-world data from US academic centers (61%) and our own data from the Austrian LALUCA registry [22, 23].
At progression, rebiopsy or liquid biopsy is recommended to identify resistance mechanisms, which are heterogeneous and include MET amplification, secondary EGFR mutations, and histologic transformation [24, 25]. Histologic transformation often requires tissue biopsy for confirmation. Current data are largely derived from cohorts progressing on osimertinib monotherapy. Resistance patterns after combination regimens such as FLAURA2 or MARIPOSA are not yet well defined.
After progression on first-line therapy, platinum–pemetrexed chemotherapy remains the standard backbone, though responses are modest and PFS is usually limited to about 4.5–5.5 months [26, 27]. An overview of potential treatment sequences after different first-line strategies is shown in Fig. 2. Reported PFS values are derived from separate trials and should not be interpreted as direct comparative evidence.
Fig. 2
Overview of potential treatment sequences in advanced EGFR-mutated non-small cell lung cancer (NSCLC). Illustrative overview of possible treatment sequences after different first-line regimens in advanced EGFR-mutated NSCLC. Median progression-free survival (mPFS) from key phase II and III studies or early-phase trials is shown where available. Data are not derived from head-to-head comparisons, and cross-trial comparisons are not appropriate due to differing patient populations, designs, and maturity of follow-up
Multiple trials have shown no benefit in the addition of immunotherapy to chemotherapy in patients with EGFR-mutated NSCLC after EGFR-TKI pretreatment, regardless of PD-L1 status [28]. To improve outcomes after progression on EGFR-TKIs, several studies have evaluated the addition of immunotherapy and VEGF inhibition to chemotherapy. In IMpower150, the quadruplet of atezolizumab, bevacizumab, carboplatin, and paclitaxel prolonged OS in a post hoc analysis of the EGFR-mutant subgroup after prior TKI therapy [29]. Based on these data, the European Medicines Agency (EMA) approved the regimen for use in EGFR-mutated NSCLC after TKI failure, while the regimen has not been approved by the U.S. Food and Drug Administration (FDA), reflecting the post hoc nature and limited robustness of the evidence.
Similarly, ORIENT-31 demonstrated improved PFS with sintilimab plus chemotherapy, with or without bevacizumab, in a predominantly Asian population after EGFR-TKI failure [30]. More recently, the randomized phase III ATTLAS trial reported benefit for ABCP in EGFR- or ALK-positive NSCLC [31], and analogous strategies are being tested in trials such as IMpower151 [32]. However, results across studies have been inconsistent for the EGFR-mutant subgroup. Most enrolled mainly Asian patients, included few or no individuals pretreated with osimertinib, and often reported only exploratory subgroup analyses, limiting their applicability to current practice.
The phase III HARMONi‑A trial evaluated the PD-1/VEGF‑A bispecific antibody ivonescimab plus chemotherapy versus chemotherapy plus placebo in patients progressing after third-generation EGFR-TKI therapy [33]. A benefit in PFS of 6.8 vs. 4.4 (HR 0.52, 95% CI 0.41–0.66) was reported. Recently presented follow-up data showed a trend toward OS benefit (median OS 16.8 months; HR 0.78, 95% CI 0.62–0.98) [34], though this has not reached statistical significance.
Overall, the data for combined immunotherapy and VEGF blockade in EGFR-mutated NSCLC remain inconclusive, with modest and inconsistent efficacy signals and a higher risk of treatment-related toxicity compared with chemotherapy alone, and less convincing than for alternative strategies.
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Strategies with continuation of EGFR blockade
An alternative to switching to chemotherapy alone is to continue EGFR inhibition beyond progression by combining it with additional targeted agents or chemotherapy. This strategy aims to suppress persistent EGFR-driven clones while treating emerging resistant subclones.
The phase III MARIPOSA-2 trial evaluated the combination of amivantamab plus chemotherapy versus chemotherapy alone in patients progressing on first-line osimertinib. The addition of amivantamab significantly improved PFS (median 6.3 vs 4.2 months; HR, 0.48, 95% CI 0.36–0.64) and showed notable intracranial activity [35]. MARIPOSA‑2 had an all-comer design without mandatory rebiopsy, making it a practical option when tissue acquisition is not feasible or declined.
A similar approach was tested in the COMPEL trial, which randomized patients to continue osimertinib plus chemotherapy versus chemotherapy alone. The study was closed early due to evolving standards, but first results showed encouraging activity particularly in patients without CNS progression (median PFS 8.4 vs 4.4 months; HR 0.43, CI95 0.27–0.70; OS 15.9 vs 9.8 months; HR 0.71, 95%CI 0.42–1.23, survival maturity 55%) [36]. This approach is already used off-label in some centers, supported by additional safety data from FLAURA2 and small retrospective series [37].
Targeted therapies and ADCs
Molecular re-assessment at progression can reveal actionable resistance mechanisms and guide individualized treatment strategies. Among these, MET amplification and overexpression represent well-characterized drivers of resistance to osimertinib.
The phase II SAVANNAH trial investigated osimertinib plus the MET inhibitor savolitinib in patients with MET-driven resistance after first-line osimertinib. The regimen achieved an objective response rate (ORR) of 56% and a median duration of response (DOR) of 7.1 months, with manageable toxicity [38]. Similar results were reported in INSIGHT‑2, where osimertinib plus tepotinib showed meaningful activity in MET-amplified disease progressing on osimertinib [39]. These studies support the concept that integrating MET inhibition may be particularly relevant for patients at risk of early MET-driven resistance, although randomized phase III confirmation is lacking and regulatory approval has not yet been granted.
Antibody–drug conjugates (ADCs) have emerged as a rapidly developing treatment class for EGFR-mutated NSCLC after osimertinib [40]. The TROP2-directed ADC datopotamab deruxtecan (Dato-DXd) received accelerated FDA approval in June 2025 for patients with EGFR-mutated NSCLC after EGFR-TKI and platinum chemotherapy, based on a pooled objective response rate (ORR) of 43%, median duration of response (DOR) of 7.0 months and median PFS of 5.8 months (95% CI 5.4–8.2) [41]. To date, no approval has been granted by the EMA for this indication. Recently, data for intracranial response were presented, showing an intracranial ORR of 38% vs. 0% with the docetaxel comparator arm [42]. Dato-DXd is also under investigation in various combination strategies, including osimertinib. Preliminary data on the Dato-DXd-osimertinib combination after progression on first-line osimertinib were presented in 2025, demonstrating encouraging efficacy with a median PFS of up to 11.7 months (95% CI 8.3- not calculable) [43].
Another promising agent is izalontamab brengitecan, a bispecific EGFRxHER3 ADC. The compound received Breakthrough Therapy Designation from the U.S. FDA in August 2025 based on early results showing durable responses with a manageable safety profile in patients with EGFR-mutant NSCLC who had progressed after third-generation EGFR TKIs and platinum-based chemotherapy [44]. In Europe, the agent has not yet been submitted for regulatory evaluation, and EMA approval is pending.
Uncommon mutations
Beyond the common EGFR alterations (exon 19 deletion and L858R), several uncommon EGFR alterations require distinct therapeutic strategies. A substantial subset comprises exon 20 insertions, which are largely insensitive to classical EGFR TKIs. The current standard of care in this setting is the combination of amivantamab, carboplatin, and pemetrexed. In the PAPILLON trial, this triplet regimen demonstrated benefit over chemotherapy alone, with a median PFS of 11.4 months versus 6.7 months (HR 0.40, 95% CI 0.30–0.53) [45]. The previously available exon 20–targeted TKI mobocertinib has been withdrawn from market following the failure of its confirmatory trial to demonstrate OS advantage over platinum-based chemotherapy in the first-line setting [46, 47]. For TKI-sensitive uncommon mutations, including EGFR TKI-sensitive point mutations or duplications in exons 18–21, certain TKI-sensitive exon 20 insertions, and compound mutations combining classical and uncommon sensitizing variants, the most robust evidence supports the use of the second-generation EGFR TKI afatinib [48, 49]. Osimertinib is also a reasonable treatment option in this context, supported by a growing body of clinical evidence [50‐53]. The therapeutic value of combination approaches for these rare genotypes remains to be defined.
Summary beyond first-line
For most patients progressing after first-line osimertinib, the most evidence-based and currently most effective treatment option is the combination of amivantamab plus chemotherapy as established in MARIPOSA‑2. This regimen has demonstrated the clearest survival benefit and is guideline-endorsed in this setting.
The concept of continuing osimertinib with added chemotherapy, as investigated in the COMPEL trial, is appealing because it may prevent overtreatment and preserve CNS control. Early data are encouraging, and the approach is already used in some centers. However, regulatory approval is unlikely, and its use remains off-label at present.
As the landscape of first-line therapy continues to shift toward combination regimens, alternative postprogression strategies will become increasingly important. Among these, antibody–drug conjugates are rapidly emerging, with Dato-DXd already FDA-approved and supported by comparatively mature data, representing a compelling therapeutic option for this patient population.
Conclusion
Upfront combination regimens have established themselves as new standards of care, demonstrating substantial improvements in progression-free and overall survival over osimertinib monotherapy. However, these efficacy gains come at the cost of increased toxicity, greater treatment burden, and markedly higher financial costs. Importantly, osimertinib monotherapy remains a valid and widely accessible standard option, particularly for patients in whom combination strategies are not feasible.
Many key questions remain unanswered, including whether EGFR inhibition should be continued beyond progression, whether biomarker-driven or biomarker-agnostic approaches are preferable, which regimens offer the best intracranial control, what the optimal treatment sequence will be, and which strategies represent sustainable long-term choices for healthcare systems. Biomarker-based stratification will become increasingly important as treatment options expand, but real-world data will be crucial to complement trial evidence and reflect the heterogeneity of daily clinical practice.
The expansion of therapeutic options represents a major step forward in improving survival, but it also creates a responsibility for more thorough and individualized patient counseling. With more available choices, treatment discussions must become more nuanced, balancing efficacy with toxicity, logistics, quality of life, and patient autonomy. Yet terms such as “manageable toxicity” often fail to reflect patient perception, and a recognized gap exists between clinical terminology and patient experience [54]. Careful, transparent communication and explicit discussion of expectations are therefore essential. Incorporating shared decision-making has been shown to improve patient satisfaction, treatment adherence, and quality of life in patients with non-small cell lung cancer [55].
Ultimately, the success of future advances will not only depend on developing more effective therapies, but also on consistently integrating patient priorities, minimizing treatment burden, and maintaining quality of life while extending survival.
Take-home message
Combination regimens have improved survival outcomes in EGFR-mutated advanced non-small cell lung cancer but increase toxicity and treatment burden. Individualized treatment selection and shared decision-making are essential, particularly as postprogression strategies will need to adapt to the evolving first-line landscape.
Acknowledgements
The author thanks David Rosenthaler, B.Ed., for valuable support in the preparation of Fig. 2, and Dr. Maximilian J. Hochmair for critical content proofreading of the manuscript.
Funding
This research did not receive any specific grant from a funding agency in the public, commercial, or not-for-profit sector. Institutional support for publication costs was provided by the Karl Landsteiner Institute for Lung Research and Pulmonary Oncology. The review has not been presented or submitted elsewhere.
Conflict of interest
O. Illini has received speaker fees and/or honoraria for advisory board participation from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Research grants to the institute were received from Amgen, AstraZeneca, and Takeda outside the submitted work.
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