Addressing the Most Critical Treatment Questions in EGFR-mutant Advanced NSCLC

Session Overview & Presentation Highlights

Frontline Treatment Options: Combination vs Monotherapy

Dr Yu initiated the discussion by asking faculty to describe when they prefer treating with osimertinib monotherapy and whether combination therapy has become their standard-of-care, frontline option for treating EGFRm advanced NSCLC. Dr Yu then reviewed data from the FLAURA2 and MARIPOSA trials and led a faculty discussion about patient- and disease-specific factors that impact treatment decisions. MARIPOSA explored amivantamab plus lazertinib and FLAURA2 examined osimertinib with chemotherapy.

Balancing Therapeutic Benefit Against Additional Toxicity

Dr Yu gave an overview of efficacy and toxicity from FLAURA, FLAURA2, and MARIPOSA; faculty were asked to share their insights on how they weigh reported overall survival benefits against toxicity, with a specific emphasis on amivantamab-lazertinib therapy.

Treatment Options After First Progression

Efficacy and safety results from clinical trials evaluating second-line management of EGFRm NSCLC were presented, and faculty were asked to share their experiences on how they determine which regimen(s) to use upon disease progression.

Mechanisms of Resistance and Potential Sequencing Strategies

Dr Yu engaged faculty in a discussion about mechanisms of resistance to first-line osimertinib and amivantamab-lazertinib, use of immunohistochemistry (IHC) testing, and adjustment of second-line treatments to target identified resistance.

Discussion Themes/Summary

The majority of faculty reported using osimertinib and/or osimertinib-chemotherapy (FLAURA2 regimen) in the first line, although a shift to combination therapy is occurring as the default with the FLAURA2 favored over amivantamab-lazertinib (MARIPOSA regimen). Risk factors considered when making treatment decisions include frailty, uncommon co-mutations, impaired kidney function, hematologic conditions, and socioeconomic factors, with the threshold for giving combination typically being 2 or more risk factors; brain metastases alone would compel some to use combination therapy. Obstacles that delay the start of MARIPOSA include obtaining infusion slots, procuring drug, and prescribing and discussing supportive medications with the patient. Patient quality of life (QOL) is also a consideration with MARIPOSA.

The COCOON study evaluated a proactive dermatologic management regimen to mitigate skin and nail side effects associated with the amivantamab plus lazertinib combination. With this, dermatologic management was believed to be effective in minimizing amivantamab treatment interruptions due to toxicities and improving QOL, it is also complicated. Faculty described clinical trial nurses spending up to an hour counseling patients on the prophylaxis regimen; time will be a consideration in the future and may be a barrier for community oncologists without dedicated clinical trial staff. To avoid toxicities related to amivantamab, faculty described starting at less than the full dose and administering the drug every 3 weeks instead of every 2 weeks, which improves tolerability.

In the context of second-line treatment, most faculty reported giving FLAURA2; when MARIPOSA2 is given, most do not give the maximum dose of amivantamab. The majority also indicated that if they gave chemotherapy up front, they would still give MARIPOSA2 in the second line with a lower carboplatin dose and a 3-week cycle. Many faculty continue osimertinib following progression; however, if the COMPEL results are negative, some will stop osimertinib if patients have stable or no brain metastases. There was some concern that using ivonescimab or datopotamab deruxtecan in brain metastases would remove EGFR blockade, resulting in rapid withdrawal flares. Some faculty indicated that they would consider using ivonescimab in front of amivantamab. However, others expressed concern about the PD-1 target and whether they could use osimertinib later if there was brain progression. Unfortunately, EGFRm patients who could likely benefit from immunotherapy aren’t receiving it.

MET IHC tissue testing upon progression was believed to be ideal; detection of transformation was identified by 1 faculty member as a rationale for routinely getting tissue upon progression. Generally, if a new fusion or MET amplification is found, it would be treated with MET tyrosine kinase inhibitors.

Treatment of EGFRm NSCLC is evolving, with combination therapy becoming the default first-line therapy. The FLAURA2 regimen is generally preferred in the first line. Managing the toxicities related to amivantamab is an ongoing challenge that is being addressed in part by dose and frequency adjustments; it may be further alleviated when subcutaneous (SC) administration is available. As additional treatment options are available, tolerability and the ability to use biomarkers to predict response will be important in guiding treatment decisions.

Unmet Needs and Recommendations

• Starter packs of lazertinib and SC amivantamab would make MARIPOSA an easier regimen to offer in the first line without delay.
• Biomarkers to help predict those who may be at risk for resistance.

References

1. Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
2. Valdiviezo Lama NI, Okamoto I, Hughes BGM, et al. First-line (1L) osimertinib (osi) ± platinum-pemetrexed in EGFR-mutated (EGFRm) advanced NSCLC: FLAURA2 post-progression outcomes. Ann Oncol. 2024;9(suppl 3):153. doi:10.1016/esmoop/esmoop102569
3. Yang JCH, Kim YJ, Lee SH, et al. Amivantamab plus lazertinib vs osimertinib in first-line (1L) EGFR-mutant (EGFRm) advanced NSCLC: final overall survival (OS) from the phase III MARIPOSA study. Abstract presented at: the European Lung Cancer Congress 2025; March 26-29; 2025; Paris, France. Abstract 4O.
4. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
5. Girard N, Li W, Spira A, et al. Preventing moderate to severe dermatologic adverse events in first-line EGFR-mutant advanced NSCLC treated with amivantamab plus lazertinib: early success of the COCOON trial. Abstract presented at: the 2025 European Lung Cancer Congress; March 27, 2025; Paris, France. Abstract 10MO.
6. Passaro A, Wang J, Wang Y, et al; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117
7. Sequist LV, Peled N, Tufman A, et al. P47.11. COMPEL: chemotherapy with/without osimertinib in patients with EGFRm advanced NSCLC and progression on first-line osimertinib. J Thorac Oncol. 2025; 16(10):S1101. doi:10.1016/j.jtho.2021.08.504