Aumolertinib (formerly known as almonertinib; HS-10296) has shown a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to placebo in patients with unresectable, stage III non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations, following definitive chemoradiotherapy (CRT). These findings come from an interim analysis of the phase 3 POLESTAR trial (NCT04951635).
The data, presented at the 2024 IASLC World Conference on Lung Cancer, revealed that at a median follow-up of 16.36 months for the aumolertinib arm (n = 92) and 13.93 months for the placebo arm (n = 50), aumolertinib reduced the risk of disease progression or death by 80% compared to placebo (HR, 0.200; 95% CI, 0.114-0.352; log-rank P < .0001). The median PFS was 30.4 months (95% CI, 17.2-NR) in the aumolertinib group versus 3.8 months (95% CI, 3.7-5.6) in the placebo group, according to blinded independent central review (BICR) assessment.
According to investigator assessment, the median PFS was 30.4 months (95% CI, 22.1-NR) for patients receiving aumolertinib versus 3.8 months (95% CI, 3.7-5.6) for those given placebo (HR, 0.150; 95% CI, 0.080-0.284; log-rank P < .0001).
POLESTAR Trial Design and Methods
The POLESTAR trial was a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of aumolertinib, a third-generation EGFR TKI, versus placebo in patients aged 18 years or older with locally advanced, unresectable, stage III NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. Patients were required to have an ECOG performance status of 0 or 1, have no disease progression following definitive CRT, and have an interval between the last dose of CRT and randomization of no more than 6 weeks.
Participants were randomized in a 2:1 ratio to receive either 110 mg of aumolertinib once daily or a matching placebo. Treatment continued until BICR-assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Stratification factors included EGFR mutation status (exon 19 deletion vs exon 21 L858R mutation), stage (IIIA vs IIIB/C), and CRT method (concurrent vs sequential).
The primary endpoint of the trial was BICR-assessed PFS per RECIST 1.1 criteria, with investigator-assessed PFS serving as a sensitivity analysis. Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), duration of response (DOR), central nervous system (CNS) PFS, time to death or distant metastases (TTDM), and safety.
From April 28, 2021, to February 25, 2024, 147 patients were enrolled across 43 sites in China. Ninety-four patients were assigned to the aumolertinib arm, and 53 to the placebo arm. Efficacy was evaluated using a modified intention-to-treat population, including 92 patients in the aumolertinib arm and 50 in the placebo arm.
At data cutoff, 73% of patients (n = 69) in the aumolertinib arm were still receiving treatment, compared to 32% (n = 17) in the placebo arm. Notably, 52% of evaluable patients (n = 11/21) who experienced disease progression in the aumolertinib arm continued treatment after progression. In the placebo arm, 85% of evaluable patients (n = 29/34) who experienced disease progression crossed over to receive aumolertinib.
Additional Efficacy Outcomes
Aumolertinib demonstrated an ORR of 57% (95% CI, 46%-67%) compared to 22% (95% CI, 11%-34%) for placebo (OR, 4.58; 95% CI, 2.07-10.14; P < .0001). The DCRs were 96% (95% CI, 92%-100%) and 74% (95% CI, 62%-86%), respectively (OR, 8.53; 95% CI, 2.54-28.66; P = .0001). The median DOR was 16.59 months (95% CI, 15.05-NR) in the aumolertinib arm versus 7.10 months (95% CI, 1.71-17.51) in the placebo arm (HR, 0.476; 95% CI, 0.168-1.349; P = 0.1557).
At a median follow-up of 16.6 months for the aumolertinib group and 14.9 months for the placebo group, overall survival (OS) data reached 9.8% maturity for the experimental arm and 6.0% maturity for the control arm. The median OS was not reached in either group.
The median CNS PFS was not reached (95% CI, NR-NR) in both arms (HR, 0.33; 95% CI, 0.12-0.92; P = .0270). The median TTDM was not reached (95% CI, NR-NR) in the aumolertinib arm versus not reached (95% CI, 3.84-NR) in the placebo arm (HR, 0.21; 95% CI, 0.09-0.49; P < .0001).
Safety Profile
Regarding safety, any-grade treatment-related adverse events (TRAEs) occurred in 84.0% of patients in the aumolertinib arm and 43.4% of patients in the placebo arm. Grade 3 or higher TRAEs occurred in 9.6% and 1.9% of patients, respectively. Serious TRAEs were reported in 6.4% of patients in the experimental arm versus 1.9% in the control arm.
TRAEs did not lead to death in either arm. TRAEs led to treatment interruption (13.8% vs 0%), treatment reduction (4.3% vs 0%), and treatment discontinuation (2.1% vs 1.9%) in the aumolertinib versus placebo arm, respectively.
