Efforts to Yield Greater OS Benefit With EGFR TKIs Continue in Early-Stage EGFR+ NSCLC

Although EGFR TKIs have helped move the needle for the treatment of patients with EGFR-mutant advanced and early-stage non–small cell lung cancer (NSCLC) throughout the past 2 decades, there is a pressing unmet need for translating the disease-free survival (DFS) benefit seen with these agents into a more significant overall survival (OS) benefit in the early-stage setting, according to Roy S. Herbst, MD, PhD.¹

“EGFR TKIs have evolved. The first inhibitors were used in the clinic around 1996, and [efforts to target EGFR] mutations were established in 2004,” Herbst said during a presentation at the 26th Annual International Lung Cancer Congress. “Now, we use the new drugs in the adjuvant and the neoadjuvant setting. Of course, we’ll probably move to some of the newer combinations soon, it is just a matter of time.”

During the Congress, Herbst discussed the evolution of targeted agents and antibody-drug conjugates (ADCs) in the neoadjuvant and adjuvant settings, and two phase 3 studies designed to potentially bridge this gap in treatment outcomes for patients with early-stage disease.

Herbst is the deputy director and chief of Medical Oncology and Hematology, as well as the assistant dean of Translational Research at Yale Cancer Center and Smilow Cancer Hospital, in New Haven, Connecticut.

ADAURA Trial

Herbst began his presentation by sharing several phase 3 studies attempting to demonstrate both a DFS and OS benefit with EGFR TKIs in early-stage NSCLC. One such trial was the phase 3 ADAURA study (NCT02511106), in which adjuvant osimertinib (Tagrisso) demonstrated significant DFS and OS benefit compared with placebo in resected EGFR-mutant stage IB to IIIA NSCLC.² Data from the updated DFS analysis revealed a median DFS of 65.8 months (95% CI, 61.7-not calculable) and 28.1 months (95% CI, 22.1-35.0) in the osimertinib vs placebo arms, respectively (HR, 0.27; 95% CI, 0.21-0.34). Furthermore, the DFS outcomes translated into 5-year OS rates of 88% (95% CI, 83-91) and 78% (95% CI, 73-82) in these respective arms (HR, 0.49; 95% CI, 0.34-0.70; P < .001).

“This was a positive result, and [osimertinib] has become the standard of care in most countries,” Herbst said.

The molecular residual disease (MRD) analysis of ADAURA, which was presented at the 2024 ASCO Annual Meeting, showed that DFS and MRD event-free status were maintained for most patients on and after receiving osimertinib.³

Results from the study showed that the majority of patients—regardless of disease stage—were MRD undetected at baseline. However, detectable MRD at baseline was associated with poorer outcomes in patients who were treated with osimertinib vs placebo. Notably, patients treated with osimertinib were more likely to be DFS and MRD event-free compared with placebo. At 24 months, the DFS and MRD event-free rates were 91% (95% CI, 84-95) and 46% (95% CI, 36-55) in the osimertinib (n = 112) vs placebo (n = 108) arms, respectively. At 36 months, these rates were 86% (95% CI, 78-92) and 36% (95% CI, 27-45) in these respective arms (HR, 0.23; 95% CI, 0.15-0.36).

Overall, the analysis helped identify molecular recurrence before DFS events, which emphasized [the] potential [utility of MRD event-free status] in this setting, Herbst noted. These findings further indicated that tumor-informed MRD could be used as a potential biomarker of disease recurrence, as circulating tumor DNA is historically challenging to leverage in early-stage NSCLC in the adjuvant setting, he stated.

“MRD could be helpful. The median time to identify progression was 4.7 months earlier using MRD,” Herbst explained. “[Therefore], if we start to use [tumor-informed] MRD [analysis] in some of these studies, that might help us to figure out who gets treated early.”

ALINA Trial

Herbst then discussed the phase 3 ALINA trial, which assessed adjuvant alectinib (Alecensa) for the treatment of patients with resectable, ALK-positive NSCLC. Findings published in The New England Journal of Medicine showed that, among the patient population with stage II or IIIA disease, the median DFS was not reached (NR) in those treated with alectinib compared with 44.4 months (95% CI, 27.8-not evaluable [NE]) in the chemotherapy arm (HR, 0.24; 95% CI, 0.33-0.45; P < .001).⁴ Similarly, patients in the intention-to-treat population demonstrated a median DFS of NR and 41.3 months (95% CI, 28.5-NE) in the alectinib vs chemotherapy arms, respectively (HR, 0.24; 95% CI, 0.13-0.43; P < .001).

NeoADAURA Trial

Lastly, Herbst circled back to the phase 3 NeoADAURA trial (NCT04351555), which investigated osimertinib with or without chemotherapy compared with chemotherapy alone in the neoadjuvant setting for the treatment of patients with resectable EGFR-mutant NSCLC, findings from which were presented at the 2025 ASCO Annual Meeting. In this trial, the major pathologic response (MPR) rate was statistically significantly higher with osimertinib with or without chemotherapy compared with placebo plus chemotherapy.⁵ Specifically, the MPR rate was 26% (95% CI, 18%-34%) in the osimertinib plus chemotherapy arm (n = 121) and 25% (95% CI, 17%-34%) in the osimertinib monotherapy arm (n = 117) compared with only 2% (95% CI, 0%-6%) in the placebo plus chemotherapy arm (n = 120; odds ratio, 19.3; 99.9% CI, 1.7-217.4; P < .0001). Furthermore, 53% of patients with baseline N2 disease were down-staged at surgery in both the osimertinib plus chemotherapy (n = 47) and osimertinib monotherapy arms. In contrast, 21% of patients in the placebo plus chemotherapy arm were down-staged at surgery. Odds ratios were 4.8 (95% CI, 1.6-14.0) and 4.2 (95% CI, 1.4-12.1) in the osimertinib plus chemotherapy and osimertinib monotherapy arms vs placebo plus chemotherapy arm, respectively.

Following the December 2020 FDA approval of adjuvant osimertinib for the treatment of patients with EGFR-mutant NSCLC, the treatment paradigm in NSCLC has increasingly focused on bringing targeted therapies into earlier disease settings, Herbst emphasized, adding that he hopes to see this trend continue.

“[Isaiah J. Fidler, DVM, PhD, FAACR,] used to always say that it’s metastases that kill patients, and that’s to the point here. Using these targeted therapies in the adjuvant setting can really [help prevent] metastases to the brain, liver, and the bone,” Herbst concluded.

References

1. Herbst RS. Targeted agents and ADCs in early-stage NSCLC—what’s new? Presented at: 26th Annual International Lung Cancer Congress; July 25-26, 2025; Huntington Beach, CA.
2. Herbst RS, Wu YL, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage Ib-IIIa non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186
3. John T, Grohe C, Goldman JW, et al. Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2024;42(suppl 16):8005. doi:10.1200/JCO.2024.42.16_suppl.800
4. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532
5. He J, Tsuboi M, Weder W, et al. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol. Published online June 2, 2025. doi:10.1200/JCO-25-00883