Envisaging Sequencing Considerations in EGFR-Mutated Lung Cancer

In light of a multitude of treatment regimens emerging in the EGFR-mutated lung cancer space, including osimertinib (Tagrisso) plus pemetrexed in the phase 3 FLAURA2 trial (NCT04035486), amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) in the phase 3 MARIPOSA trial (NCT04487080), and osimertinib alone in the phase 3 FLAURA trial (NCT02296125), a greater emphasis is placed on effective sequencing for patients.^1-3

In an interview with CancerNetwork® at the Georgia Cancer Center, Girindra Raval, MD, an associate professor of the Department of Medicine: Hematology and Oncology at the Medical College of Georgia at Augusta University, discussed future considerations for optimizing treatment outcomes among patients with EGFR-mutated disease.

In addition to the aforementioned regimens, Raval also highlighted positive data from the TROPION-Lung studies, which displayed a progression-free survival (PFS) advantage with datopotamab deruxtecan-dlnk (Datroway; dato-DXd), and the HARMONi trials, which are evaluating ivonescimab and chemotherapy in patients with metastatic non–small cell lung cancer (NSCLC).^4,5 In addition, he highlighted data presented at the 2025 European Society for Medical Oncology Congress (ESMO), which is evaluating sacituzumab govitecan-hziy (Trodelvy) in patients with EGFR-mutated disease.

Furthermore, Raval expressed an emergent problem with such a multitude of treatment options, which may complicate how patients are treated in the frontline setting. By extension, he suggested that sequencing therapies has emerged as a key consideration, with escalation and de-escalation strategies slated for assessment in future clinical trials.

Transcript:

Thankfully…we have many treatments that have come to the forefront that have shown OS data. We have the [FLAURA2, MARIPOSA, and FLAURA1 regimens]. We have the PFS data from the TROPION-Lung studies [with] datopotamab deruxtecan, and we have some other ongoing trials, like the HARMONi [trials] looking at patients who had bispecific VEGF and PD-L1 inhibition to see if those will be impactful in patients with EGFR-mutated lung cancer. We also have some data that was read out at ESMO this year about patients who received sacituzumab govitecan [for] lung cancer.

We have a problem of plenty, in some ways. We have many trials in this space that are vying for attention, and it’s [quite] difficult to then figure out on which niche should these patients be treated or which patient should be treated with which frontline treatment. The bigger question now that I can see in the field is about sequencing: “What would you start with? Who do you escalate the treatment in?” More specifically, “In who do you deescalate, where you see that there is no advantage of adding the other component of the therapy?” The future in EGFR-mutated lung cancer would be about sequencing, and in what sequence you start and what sequence you would give treatment to these patients.

References

1. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. Published October 17, 2025. doi:10.1056/NEJMoa2510308
2. Yang J, Lu S, Hayashi H, et al. Overall survival with amivantamab–lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681-1693. doi:10.1056/NEJMoa2503001
3. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
4. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed December 2, 2025. https://tinyurl.com/mvtyhnjf
5. Ivonescimab plus chemotherapy demonstrates consistent global benefit: HARMONi data update shows OS HR=0.78, nominal P=0.0332. News release. Akeso, Inc. September 7, 2025. Accessed December 2, 2025. https://tinyurl.com/32msamur