Outlining Historical Standard Therapies for EGFR-Mutant NSCLC

Standard treatment options for patients with locally advanced or metastatic EGFR-mutant non–small cell lung cancer (NSCLC) have created a “complicated conversation,” according to Jacob Sands, MD.

In a conversation with CancerNetwork®, Sands discussed standard therapy options for this patient population, as well as their strengths and limitations, following the accelerated approval of datopotamab deruxtecan-dlnk(dato-DXd; Datroway) in pretreated EGFR-mutant metastatic NSCLC in June 2025.1

Sands, assistant professor of Medicine at Harvard Medical School, thoracic oncologist at the Dana-Farber Cancer Institute, and investigator of the TROPION-Lung01 trial (NCT04656652), which supported the FDA approval of dato-DXd, suggested that multiple new drugs being developed for this patient population have complicated the treatment paradigm.

Although noting that osimertinib (Tagrisso) is a serviceable first-line option for some patients, he highlighted data from the phase 3 MARIPOSA (NCT04487080)and FLAURA2 trials (NCT04035486), evaluating amivantamab-vmjw (Rybrevant) plus lazertinib (Leclaza) and osimertinib (Tagrisso) with platinum-containing chemotherapy, respectively, vs osimertinib alone.2,3 Both regimens exhibited efficacy advantages over osimertinib alone. He further explained that nuances in toxicity have a role in distinguishing the best regimen for patients in the first-line setting.

Sands then outlined treatment in the second-line setting, highlighting the phase 3 MARIPOSA-2 trial (NCT04988295) evaluating amivantamab/chemotherapy vs chemotherapy following resistance to osimertinib, with the combination showing improved progression-free survival (PFS) vs chemotherapy alone.4 He concluded in explaining that considerations for second-line therapy might impact first-line treatment and vice versa.

Transcript

This has become a complicated conversation. Thankfully, that’s a result of multiple new drugs being developed. Historically, there’s first-generation EGFR TKIs, but more recently, we’ve been looking at the third generation. Osimertinib has been the US standard, and globally, in most countries, it has been the standard first-line therapy. More recently, we have FLAURA2 data, which have demonstrated an efficacy advantage over osimertinib; that is a combination of carboplatin, pemetrexed, and osimertinib as first-line therapy. We’ve also seen the MARIPOSA data, which is amivantamab and lazertinib, outperform osimertinib.

Realistically, osimertinib still is a good first-line option for some patients, but we have 2 regimens that have outperformed in efficacy, being the FLAURA2, as well as the MARIPOSA [regimens]. Both of those regimens have more toxicities than osimertinib alone. Of course, as you add in other combinations, that’s going to add in toxicities, but there are nuances to that. Certainly, these are regimens that that need to be discussed as part of sorting out what’s the best treatment for patients in that first-line setting.

In the second-line setting, we also have MARIPOSA-2, which is amivantamab plus chemotherapy after first-line osimertinib alone or EGFR TKI. At progression on first-line treatment with a targeted therapy—not just EGFR, but even beyond—when you have something that’s an actionable genomic alteration and there’s progression on that first-line therapy, it’s important to reevaluate that tumor for another possible target that is the resistance alteration for that first regimen. Upon testing and not identifying another particular alteration that’s targetable, or––there’s a little blend there––maybe some that are then looking at next-line therapy, amivantamab/chemotherapy, is an important consideration.

There are older chemotherapy regimens that are also a part of consideration for multiple regimens that those patients might benefit from. It’s gotten somewhat complicated, and what the physician would consider as second-line [therapy] is going to have implications to what you might choose in the first line. Of course, what you choose in the first line has implications for second-line [therapy] as well.

References

1. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed July 28, 2025. https://tinyurl.com/mtay7ab9
2. Felib E, Chul Cho B, Gutérrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504
3. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
4. Califano R, Passaro A, Tan JL, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after disease progression on osimertinib: outcomes by osimertinib resistance mechanisms in MARIPOSA-2. Presented at the 2025 American Society of Clinical Oncology Annual Meeting, May 30-June 3, 2025; Chicago, IL. doi:10.1200/JCO.2025.43.16_suppl.8639