Scientists behind the phase III randomized, controlled AENEAS2 clinical trial said their results point to a new front-line treatment option for patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC).
The trial’s principal investigator, Shun Lu, MD, PhD, said that aumolertinib with platinum-pemetrexed chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to aumolertinib monotherapy for this patient group.
EGFR-TKIs, such as the oral third-generation aumolertinib, are standard first-line treatments for patients with advanced metastatic EGFRm NSCLC. Studies have explored and continue to examine the efficacy of combining EGFR-agents with other therapies for first-line treatment options.
In AENEAS2, the blinded independent central review-assessed median PFS for the aumolertinib plus chemotherapy group was 28.9 months versus 18.9 months for the aumolertinib monotherapy group. PFS per investigator assessment were 28.4 months and 19.7 months, respectively.
Prof. Lu, Director of the Lung Cancer Center at Shanghai Chest Hospital, presented the results at the 2025 Annual Meeting of the American Association for Cancer Research.
The trial included 624 patients from 60 sites across China. Both arms received 110 mg aumolertinib daily. There were no differences in drug exposure or adherence of aumolertinib between the two groups, and chemotherapy did not reduce the use of aumolertinib, Prof. Lu said.
The PFS benefits were found to be consistent across all subgroups: gender, age (under 65 and 65 or older), smoking history, baseline CNS metastases, baseline performance status, and in EGFR mutation subtypes.
The incidence of grade 3 or higher adverse events (AEs) was greater with the combination than with monotherapy, 79.6% versus 34.8%, a difference Prof. Lu said was primarily driven by chemotherapy-related AEs.
In his discussion of the study, Pasi Jänne, MD, PhD, Professor of Medicine at Harvard University and Director of Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, placed the aumolertinib clinical trial in the context of ongoing research. Dr. Jänne said AENEAS2 is the third significant EGFR TKI combination approach trial. It joins FLAURA2 (osimertinib) in pairing the inhibitor with chemotherapy, while the MARIPOSA (lazertinib) trial paired the inhibitor with an EGFR/MET bispecific antibody (amivantamab).
Both the FLAURA2 and the MARIPOSA trials showed that combinations do improve progression free survival, Dr. Jänne said, adding that while there is evidence of overall survival in the MARIPOSA trial, overall survival evidence is immature for both the FLAURA2 trial and the ANEAS2 trial.1,2
While the various combinations present options, Dr. Jänne said they also beg a common question that requires more evidence to answer: Who needs combination therapy and who can be treated with single agent osimertinib?
“So far, analyses from all the trials have not revealed a single clear clinical or molecular feature that provides clear guidance to help choose combination over single agent therapy,” Dr. Jänne said.
He added that a secondary question was establishing the best time to intensify treatment with combination therapy.
“Is it at the start of therapy, where all these trials have been performed?” he asked. “Is it following a maximal response? Or is it at the time of resistance to a third-generation TKI?”
As part of the discussion, Prof. Lu also noted the similarity of aumolertinib to other EGFR inhibitors, however, he pointed out the need for patients to have treatment options given differences faced in regard to access, cost, and toxicity. He mentioned an ongoing study3 examining the suitability of aumolertinib for patients intolerant to osimertinib. He said this study supported the idea that patients benefit by having options among EGFR TKI treatments.
“At the least, patients will have more options,” Prof. Lu said.
References
- 1. Planchard, David et al. New England Journal of Medicine 2023; 389:1935-1948 DOI: 10.1056/NEJMoa2306434.
- 2. Cho, Byoung C. et al New England Journal of Medicine 2024; 391:1486-1498 DOI: 10.1056/NEJMoa2403614.
- 3. Lu., S. Prospective Study of Aumolertinib in NSCLC Patients with EGFR Sensitive Mutations Who Are Intolerant to Osimertinib Treatment, Journal of Thoracic Oncology, Volume 17, Issue 9, Supplement, 2022.
