Clinical Advances in EGFR-Mutated NSCLC: Insights From MARIPOSA and FLAURA2

The treatment landscape of non–small cell lung cancer (NSCLC) harboring EGFR mutations has undergone profound evolution over the past 2 decades. Beginning with the introduction of first-generation EGFR tyrosine kinase inhibitors (TKIs), subsequent therapeutic innovation has brought increasingly effective and precise options, culminating in the current era where third-generation inhibitors and novel combination regimens dominate clinical discussions.¹

At the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, Jessica Menis, MD, a medical oncologist in the Oncology Department of the University Hospital of Verona, Italy, presented an overview of the global prevalence of EGFR mutations, the critical role of molecular testing, and the rapidly expanding treatment strategies shaping first-line care.¹

Global Prevalence and Distribution of EGFR Mutations

EGFR mutations remain among the most clinically actionable alterations in NSCLC, though their frequency varies widely across populations, according to Menis. Geographic and interethnic differences play a central role, influenced by underlying genetic variation, smoking prevalence, and access to molecular diagnostics.¹

Photomicrograph of fine needle aspiration cytology of a pulmonary nodule showing non–small cell carcinoma. Image Credit: © Saiful52 - stock.adobe.com

“The evolution of common EGFR mutation testing is very heterogeneous worldwide, and this also applies to its clinical application. The reasons are potentially related to interethnic genetic variation as well as differences in smoking habits and in the availability of EGFR complex testing,” Menis said during the WCLC session. “All international guidelines consistently and strongly recommend testing for EGFR mutations, either on tissue or plasma, before starting first-line treatment.”¹

While international guidelines strongly recommend EGFR testing on either tissue or plasma samples prior to initiation of first-line therapy, real-world accessibility is not uniform, Menis explained. For example, the European Society for Medical Oncology has documented wide disparities in the availability of single-gene assays and even more limited access to next-generation sequencing (NGS), despite evidence demonstrating its significant benefits and cost-effectiveness.¹

The Key Role of Comprehensive Testing

The use of parallel testing with NGS panels, rather than sequential single-gene assays, allows detection of multiple relevant alterations from limited samples, shortens turnaround times, and facilitates timely initiation of the most effective therapy, according to Menis. Further, she explained that overall survival (OS) is significantly longer in patients whose results are available before starting first-line therapy, compared with those lacking molecular data at baseline.¹

NGS also allows simultaneous identification of resistance mechanisms and co-mutations such as TP53 mutations or MET amplification, which may influence treatment selection or inform future strategies. As such, the shift toward universal adoption of broad-based testing is considered a cornerstone of precision oncology in NSCLC.¹

Changing Treatment Scenarios in EGFR-Mutated NSCLC

Over the past 20 years, clinical development of EGFR-targeted therapies has progressed from first-generation reversible inhibitors such as gefitinib (Iressa; AstraZeneca) and erlotinib (Tarceva; Genentech and OSI) to more potent and selective second-generation agents such as afatinib (Gilotrif; Boehringer Ingelheim) and dacomitinib (Vizimpro; Pfizer). These early drugs improved outcomes compared with chemotherapy but were limited by high toxicity and rapid development of resistance, Menis explained.¹ The third-generation inhibitor osimertinib (osimertinib; AstraZeneca) transformed the treatment paradigm by achieving superior progression-free survival (PFS) and OS, as demonstrated in the pivotal FLAURA trial (NCT02296125).^1,2

Recent years have seen the emergence of combination approaches designed to overcome resistance and extend survival further. Two regimens have generated particular enthusiasm: amivantamab (Rybrevant; Janssen Biotech) combined with lazertinib (Lazcluze; Yuhan Corporation) in the MARIPOSA trial and osimertinib combined with chemotherapy in the FLAURA2 study (NCT04035486).^1,3,4 MARIPOSA demonstrated significant improvements in both PFS and OS compared with osimertinib monotherapy, while FLAURA2 showed significant improvements in PFS and a median OS of 47.5 months, according to Menis.¹

Balancing Efficacy and Toxicity

While both MARIPOSA and FLAURA2 demonstrated substantial gains in PFS and OS, they also revealed marked increases in toxicity, Menis explained. In MARIPOSA, grade 3/4 adverse events (AEs) occurred in 75% of patients receiving amivantamab plus lazertinib, compared with 43% with osimertinib alone. Similarly, in FLAURA2, 64% of patients receiving osimertinib plus chemotherapy experienced grade 3/4 AEs, compared with 27% with osimertinib monotherapy.¹

Further, Menis noted that toxicities varied by regimen in these trials. Osimertinib–chemotherapy combinations primarily led to cytopenias such as anemia, neutropenia, and thrombocytopenia, along with gastrointestinal events. Amivantamab plus lazertinib, on the other hand, was associated with EGFR inhibitor–related dermatologic toxicities such as rash and paronychia, as well as infusion-related reactions and thromboembolic events. Importantly, the majority of toxicities emerged early in treatment, underscoring the need for proactive management strategies, Menis noted.¹

Strategies for Toxicity Mitigation

Several approaches are being explored to improve tolerability of combination regimens, according to Menis. Subcutaneous amivantamab, studied in the PALOMA-3 trial (NCT05388669),⁵ demonstrated reduced infusion-related reactions and fewer thromboembolic events compared with the intravenous formulation.¹ Prophylactic anticoagulation has also been shown to significantly lower venous thromboembolism risk in patients receiving amivantamab.¹

Dermatologic prophylaxis strategies are equally critical; in the COCOON trial (NCT06120140),⁶ a structured regimen including oral antibiotics, emollients, nail care, and moisturizers was shown to significantly reduce the incidence of severe rash and skin-related AEs.¹ Supportive care protocols for chemotherapy-induced toxicities, such as nausea, cytopenias, and diarrhea, remain vital, according to Menis. These measures highlight how combination regimens, while more toxic, can be managed with anticipatory supportive strategies.¹

Choosing Between Monotherapy and Combination Therapy

Given the dual considerations of efficacy and toxicity, treatment selection in practice requires careful balancing of clinical and patient-specific factors, according to Menis. She proposed a decision framework highlighting situations that may favor each approach. For example, combination therapy may be particularly suitable for younger patients with few comorbidities, good performance status, high disease burden including extensive metastases or central nervous system involvement, or the presence of co-mutations such as TP53 or MET alterations. Conversely, monotherapy may be more appropriate for older patients, such as those with significant comorbidities or reduced organ function, and patients for whom financial, toxicity, or logistical concerns outweigh potential incremental efficacy gains.¹

Ultimately, patient preference and quality-of-life considerations remain paramount, particularly given evidence from surveys that physicians may underestimate toxicity severity compared with patients’ perceptions, Menis explained. In one survey, patients and families in China expressed a strong preference for monotherapy, citing toxicity as the major driver of decision-making.¹

Other Third-Generation EGFR TKIs in Development

Beyond osimertinib and lazertinib, several investigational third-generation TKIs are under clinical evaluation. Agents such as aumolertinib (Ameile; Hansoh Pharma) and furmonertinib (Ivesa; Shanghai Allist), already approved in some regions, may further diversify the treatment armamentarium in coming years. The landscape is also evolving with combination strategies involving local therapies. Radiotherapy combined with first- and second-generation TKIs has demonstrated improved efficacy in early research, and ongoing studies are assessing its integration with osimertinib.¹

The Future Role of Liquid Biopsy and ctDNA

Liquid biopsy and circulating tumor DNA (ctDNA) analysis hold considerable promise for guiding real-time treatment decisions in EGFR-mutated (EGFRm) NSCLC, according to Menis. ctDNA can facilitate early detection of resistance mutations, monitor treatment response, and potentially predict toxicity risk. Incorporating ctDNA into clinical algorithms may enable more personalized treatment strategies, ensuring that patients receive combination therapy only when the potential benefits clearly outweigh the risks.¹

Quality of Life and Real-World Data

While trial data provide the backbone of evidence, real-world outcomes and patient-reported experiences will be critical to refining treatment approaches, according to Menis. Academic centers and cooperative groups are uniquely positioned to generate robust real-world datasets capturing safety, efficacy, and quality-of-life outcomes in broader, more heterogeneous patient populations. These data will help clarify the optimal balance between efficacy and toxicity, particularly as combination regimens move into practice, Menis noted.¹

Conclusion

The management of EGFRm NSCLC is entering a new era defined by therapeutic options and complexity. Osimertinib remains a highly effective and well-tolerated standard, but combination strategies with chemotherapy or amivantamab plus lazertinib now offer additional options that extend survival further, albeit with increased toxicity. As Menis noted, treatment decisions must be individualized, incorporating molecular profiling, disease burden, patient comorbidities, and personal preferences. Broader access to NGS, proactive toxicity management, and shared decision-making are essential for optimizing outcomes.¹

“While we continue to gain more options and knowledge in this field, it is clear after that the field is rapidly evolving. Our future directions will be to better understand tumor biology, promote innovative trial designs, and integrate data from both clinical trials and real-world studies,” Menis said. “In this sense, joint efforts among preclinical and clinical researchers, academia, industry, regulators, and patient organizations will be essential—and will surely be successful.”¹

REFERENCES

1. Menis J. Treatment options for common sensitizing EGFR mutant advanced NSCLC. World Conference on Lung Cancer; Barcelona, Spain; September 6-9, 2025.
2. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA). Clinicaltrials.gov. Updated August 11, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT02296125
3. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT04487080
4. A Study of Osimertinib With or Without Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (FLAURA2) (FLAURA2). Clinicaltrials.gov. Updated July 4, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT04035486
5. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 7, 2025. https://www.clinicaltrials.gov/study/NCT05388669
6. Enhanced Dermatological Care to Reduce Rash and Paronychia in Epidermal Growth Factor Receptor (EGRF)-Mutated Non-Small Cell Lung Cancer (NSCLC) Treated First-line With Amivantamab Plus Lazertinib (COCOON). Clinicaltrials.gov. Updated August 26, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06120140