ESAONA Data Support Asandeutertinib as a Frontline Option in EGFR+ NSCLC With Brain Metastases

Frontline asandeutertinib (TY-9591) led to significant improvements in intracranial objective response rate (iORR) and intracranial progression-free survival (iPFS) compared with osimertinib (Tagrisso) in patients with EGFR-mutated non–small cell lung cancer (NSCLC) and brain metastases, according to results from an interim analysis of the phase 2 ESAONA trial (NCT05948813).¹

The data shared during the 2026 ASCO Annual Meeting showed that the confirmed iORR by blinded independent central review (BICR) was 95.5% (95% CI, 89.8%-98.5%) with asandeutertinib (n = 111) vs 79.6% (95% CI, 71.0%-86.6%) with osimertinib (n = 113), translating to a percentage difference of 15.62% (95% CI, 6.66-24.34; P = .0004). Of those who responded to asandeutertinib, 13.5% achieved a complete response (CR), and 82.0% experienced a partial response (PR); of those who responded to osimertinib, the CR and PR rates were 11.5% and 68.1%, respectively.

The trial also met its co-primary end point of iPFS. At a median follow-up of 15.21 months for asandeutertinib and 17.22 months for osimertinib, the median iPFS was not reached (NR; 95% CI, 22.24-not evaluable [NE]) vs 17.51 months (95% CI, 15.18-NE) with osimertinib (HR, 0.46; 95% CI, 0.28-0.76; P = .0020).

"The efficacy and safety results support asandeutertinib as a potentially superior treatment option for [patients with] advanced EGFR-mutated NSCLC patients with [brain metastases]," lead study author Yuankai Shi, MD, PhD, and coauthors concluded. Shi is affiliated with the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China.

Why do these data matter for EGFR-mutated NSCLC with brain metastases?

Brain metastases are common in EGFR-mutated NSCLC and are associated with worse outcomes, yet no third-generation EGFR TKI has been specifically approved for this setting, Shi said. Osimertinib, a brain-penetrant third-generation EGFR TKI, is the current standard in the first-line setting, but much of its central nervous system activity has been characterized through underpowered subgroup analyses of larger first-line trials rather than dedicated intracranial end points, and intracranial progression remains common.²

Asandeutertinib is a third-generation EGFR TKI designed to retain the activity of osimertinib while reducing production of the active metabolite AZ5104 (TY-9591-D1) through deuteration of key metabolic sites.¹ The agent demonstrated activity and a manageable safety profile in a phase 1 dose-escalation and dose-expansion study (NCT04204473),³ and a single-arm phase 2 study (NCT05146219) evaluated it specifically in patients with EGFR-mutated NSCLC and brain metastases.⁴ ESAONA is the first randomized, comparative study to evaluate the drug against osimertinib in this population, Shi noted.

How was the ESAONA trial designed?

The randomized, open-label, multicenter, pivotal phase 2 study enrolled patients with advanced NSCLC and brain metastases, an EGFR exon 19 deletion or L858R mutation, measurable intracranial lesions, no prior EGFR TKI exposure, no more than 1 prior line of chemotherapy, and an ECOG performance status no higher than 1.¹

Patients (n = 420) were randomly assigned 1:1 to asandeutertinib at 160 mg once daily or osimertinib at 80 mg once daily. They were stratified by EGFR mutation type (exon 19 deletion vs L858R) and number of intracranial lesions (>3 vs ≤ 3). The co-primary end points were BICR-assessed iORR and iPFS per RECIST 1.1 in the full analysis set; this was assessed under a hierarchical gatekeeping procedure in which iPFS was tested only after iORR reached significance.

Key secondary end points comprised ORR and PFS, which were tested only after both primary end points were met. Additional secondary end points included overall survival (OS), intracranial time to tumor response, disease control rate (DCR), duration of response (DOR), depth of response (DepOR), iDCR, iDOR, iDepOR, and safety.

From August 17, 2023, through December 6, 2024, a total of 319 patients were screened and 224 were enrolled and treated. At the time of the data cutoff date of December 15, 2025, 52 patients in the asandeutertinib arm were still on treatment vs 42 patients in the osimertinib arm. The most common reason for discontinuation in both arms was disease progression (n = 38 vs n = 55).

Baseline characteristics were generally balanced between arms, including EGFR mutation type (exon 19 deletions: 54.1% vs 52.2%; L858R: 45.9% vs 47.8%) and number of intracranial lesions (>3 lesions, 58.6% vs 57.5%).

What were the iPFS and additional efficacy outcomes with asandeutertinib?

Intracranial DOR (iDOR) also favored asandeutertinib over osimertinib. At a median follow-up of 13.63 months for asandeutertinib and 14.52 months for osimertinib, the median iDORs were not reached (95% CI, 20.83-NE) vs 16.26 months (95% CI, 13.83-NE), respectively (HR, 0.50; 95% CI, 0.28-0.88; P = .0148).

For the key secondary systemic end points, the confirmed ORR was 89.2% (95% CI, 81.9%-94.3%) with asandeutertinib vs 77.9% (95% CI, 69.1%-85.1%) with osimertinib (unstratified difference, 11.31%; 95% CI, 1.44%-21.38%; P = .0301), and median systemic PFS was not reached (95% CI, 17.22-NE) vs 17.22 months (95% CI, 15.18-19.55), respectively (HR, 0.64; 95% CI, 0.41-1.00; P = .0473).¹

Investigator-assessed outcomes were consistent with the BICR analysis, with a confirmed investigator-assessed iORR of 92.8% (95% CI, 86.3%-96.8%) vs 77.9% (95% CI, 69.1%-85.1%), respectively (stratified difference, 14.75% (95% CI, 5.50%-23.95%; P = .0019). The investigator-assessed iPFS HR was 0.58 (95% CI, 0.36-0.89; P = .0122); the median iPFS was NR (95% CI, 21.45-NE) with asandeutertinib vs 17.51 months (95% CI, 15.38-21.36) with osimertinib.

The iORR and iPFS benefits were generally consistent across prespecified subgroups, including those defined by EGFR mutation type and number of intracranial lesions.

Shi characterized the iPFS and systemic PFS data as immature, but noted that they show favorable trends toward more durable benefit with asandeutertinib pending longer follow-up.

What did the safety analysis show?

In terms of safety, all patients experienced treatment-emergent adverse effects (TEAEs) in the asandeutertinib arm (n = 111) vs 99.1% of those in the osimertinib arm (n = 113); they were grade 3 or higher for 49.5% and 21.2% of patients, respectively. Serious TEAEs were observed in 19.8% of those given asandeutertinib vs 11.5% who received osimertinib. TEAEs led to dose reduction or interruption for 18.0% and 38.7% of those in the asandeutertinib arm; these rates were 0% and 18.6% in the osimertinib arm. TEAEs resulted in discontinuation for 4.5% of those in the asandeutertinib arm vs 4.4% of those in the osimertinib arm; they proved fatal for 3.6% and 1.8% of patients, respectively.

Any-grade treatment-related toxicities occurred in 99.1% of those in the asandeutertinib arm vs 95.6% of those in the osimertinib arm; they were grade 3 or higher for 43.2% and 15.9% of patients, and they were serious for 10.8% and 7.1% of patients. Treatment-related toxicities led to dose reduction or interruption of asandeutertinib for 32.4% and 9.9% of patients, and of osimertinib for 15.0% and 2.7% of patients. These toxicities led to discontinuation for 3.6% and 3.5% of patients in the asandeutertinib and osimertinib arms, respectively; they were. fatal for 0% and 0.9% of patients.

“Most grade 3 or higher AEs were manageable after dose interruption or reduction,” Shi said.

The most common any-grade treatment-related adverse effects (TRAEs) with asandeutertinib were decreased white blood cell count (64.0%), anemia (61.3%), increased blood creatine phosphokinase (54.1%), decreased neutrophil count (52.3%), decreased weight (47.7%), decreased platelet count (46.8%), diarrhea (42.3%), and rash (40.5%).

Shi reported that the types of TRAEs were generally comparable between arms and most TRAEs were grade 1 or 2.

What are the next steps for asandeutertinib?

Analyses of iPFS, systemic PFS, and OS remain immature, and follow-up is ongoing. According to Shi, the conditional new drug application for asandeutertinib has been accepted and granted priority review by China's National Medical Products Administration, and additional studies of the agent as monotherapy and in combination regimens are underway in China.

References

1. Shi Y, Xing L, Zhang Z, et al. Efficacy and safety of asandeutertinib versus osimertinib as first-line treatment in EGFR-mutated NSCLC patients with brain metastases: interim analysis of an open-label, multicenter, randomized, pivotal phase II study (ESAONA). J Clin Oncol. 2026;44(suppl 17):LBA2007. doi:10/1200/JCO.2026.44.17_suppl.LBA2007
2. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018;36(33):3290-3297. doi:10.1200/JCO.2018.78.3118
3. Han B, Liu J, Wu L, et al. Safety, pharmacokinetics, and efficacy of asandeutertinib in advanced EGFR-mutated NSCLC: a phase 1 dose-escalation and dose-expansion study. J Thorac Oncol. 2025;20(6):763-774. doi:10.1016/j.jtho.2025.02.003
4. Xing P, Shi Y, Wu L, et al. A phase II study of asandeutertinib (TY-9591) in advanced NSCLC patients with EGFR-positive mutations and brain metastases. J Clin Oncol. 2025;43(suppl 16):2004. doi:10.1200/JCO.2025.43.16_suppl.2004