Aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, has shown efficacy as maintenance therapy for patients with unresectable stage III non–small cell lung cancer (NSCLC) harboring EGFR mutations, according to data presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.¹

The interim results of the phase III POLESTAR study revealed a statistically and clinically significant improvement in progression-free survival compared with placebo in patients who received aumolertinib after chemoradiotherapy. Median progression-free survival was 30.4 months with aumolertinib vs 3.8 months with placebo (hazard ratio [HR] = 0.200, P < .0001).

Xiangjiao Meng, PhD

“These findings demonstrate aumolertinib as a novel treatment option for patients with unresectable stage III EGFR-mutated non–small cell lung cancer after chemoradiotherapy,” said study author Xiangjiao Meng, PhD, of Shandong Cancer Hospital and Institute, Shandong First Medical University, in China. “The substantial improvement in progression-free survival compared to current standards of care represents a significant advancement in the management of this patient population.”

Background and Study Details

As Dr. Meng reported, EGFR mutations occur in approximately 15% to 20% of NSCLC cases in Western populations and up to 40% to 50% in Asian populations. Aumolertinib, which has already demonstrated efficacy in first-line and second-line settings of EGFR-mutated NSCLC, works by selectively inhibiting EGFR-activating mutations and the EGFR T790M resistance mutation while sparing wild-type EGFR.

The POLESTAR study was a randomized, double-blind, placebo-controlled phase III trial conducted across 43 sites in China. The study enrolled 147 patients with unresectable stage III EGFR-mutated (exon 19 deletion or L858R) NSCLC who had not experienced disease progression after definitive chemoradiotherapy. Patients were randomly assigned in a 2:1 ratio to receive either aumolertinib or placebo until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

The primary endpoint was progression-free survival as assessed by blinded independent central review. Secondary endpoints included overall survival, objective response rate, disease control rate, central nervous system (CNS) progression-free survival, time to distant metastasis, and safety.

Aumolertinib Reduces Risk of Disease Progression by 80%

After a median follow-up of 16.4 months for the aumolertinib group and 13.9 months for the placebo group, the median progression-free survival was 30.4 months with aumolertinib compared with 3.8 months for placebo (HR = 0.200, 95% confidence interval = 0.114–0.352, P < .0001), as previously mentioned. This represents an 80% reduction in the risk of disease progression or death. The 12-month progression-free survival rate was 76% with aumolertinib and 21% with placebo, respectively.

As Dr. Meng reported, the progression-free survival benefit favoring aumolertinib was consistent across all predefined subgroups. The objective response rate was also significantly higher in the aumolertinib group at 57%, compared with 22% in the placebo group. Although the median overall survival was not reached in either group at the time of this interim analysis, there were fewer instances of CNS lesions and distant metastases with aumolertinib vs placebo, she said.

In terms of safety, aumolertinib demonstrated a manageable profile with no new safety signals identified. The most common adverse event was an increase in blood creatinine phosphokinase. Radiation pneumonitis was reported in 45% of patients receiving aumolertinib vs 30% in the placebo group, with none being grade 3 or higher. Of note, the rate of adverse events leading to treatment discontinuation was low and similar between the two groups (2.1% with aumolertinib vs 1.9% with placebo).

Further research is ongoing. According to Dr. Meng, long-term follow-up data on overall survival and quality-of-life measures will be crucial in fully establishing the role of aumolertinib in this setting. Additionally, studies exploring potential combinations with other targeted therapies or immunotherapies may further optimize treatment strategies for patients with EGFR-mutated NSCLC.

“The POLESTAR study results are highly encouraging and suggest that aumolertinib could become a valuable addition to our treatment arsenal for stage III EGFR-mutated NSCLC,” Dr. Meng concluded. “The significant progression-free survival improvement, coupled with a tolerable safety profile, positions aumolertinib as a promising maintenance therapy option for these patients.”

EXPERT POINT OF VIEW

Fiona Hegi-Johnson, MD

Abstract discussant of the POLESTAR study, Fiona Hegi-Johnson, MD, a radiation oncologist at the Peter MacCallum Cancer Centre in Victoria and Senior Research Fellow at the University of Melbourne, in Australia, called the POLESTAR study results “impressive” but also highlighted several important considerations when interpreting the data.

POLESTAR vs LAURA

Dr. Hegi-Johnson noted the POLESTAR study design was similar to that of the LAURA study,² both being randomized phase III double-blind trials. However, she pointed out key differences:

• POLESTAR’s analysis was by modified intention to treat, excluding some patients from each arm.
• The POLESTAR study was conducted in China alone, unlike the multinational LAURA study.
• Approximately 25% of patients in the POLESTAR trial received sequential rather than concurrent chemoradiotherapy, compared with 85% to 90% of those in the LAURA trial receiving concurrent treatment.
• A total of 50% of patients in the POLESTAR trial had positron-emission tomography (PET) staging, which could occur up to 6 months prior to chemoradiotherapy.
• Approximately 25% of patients in the POLESTAR trial received less than the standard radical dose of 60 Gy in 30 fractions.

Dr. Hegi-Johnson underscored the importance of proper staging and treatment planning, particularly the role of PET scans. She noted that PET staging was recommended in all major international guidelines, as it improved survival by correctly staging 30% to 40% of patients and ensured proper tumor targeting during radiotherapy.

Comparing the POLESTAR results with other studies, Dr. Hegi-Johnson observed that the chemoradiotherapy outcomes in POLESTAR’s control arm did not reflect those seen in studies such as RTOG 617³ or real-world data sets, where median progression-free survival for chemoradiotherapy alone was typically longer than 12 months.

While acknowledging that the addition of tyrosine kinase inhibitors after chemoradiotherapy improved progression-free survival, she emphasized the need to consider the entire course of treatment, including the quality of radiotherapy delivery.

The Challenge of Mutation Testing

Dr. Hegi-Johnson also highlighted a significant challenge in the field: limited access to mutation testing. According to a recent International Association for the Study of Lung Cancer global biomarker survey, more than 40% of patients started treatment without being tested, and 30% to 40% never accessed testing in their countries.

“As a radiation oncologist, I welcome the advent of effective tyrosine kinase inhibitors. However, it’s important to optimize the entire treatment course, including radiotherapy, and advocate for increased access to mutation testing for all patients,” she concluded.

DISCLOSURE: Dr. Meng reported no conflicts of interest. Dr. Hegi-Johnson reported no conflicts of interest.

REFERENCES

1. Yu J, Meng X, Ge H, et al: Aumolertinib maintenance after chemoradiotherapy in stage III non-small-cell lung cancer: Interim results of the phase III study (POLESTAR). 2024 World Conference on Lung Cancer. Abstract PL04.13. Presented September 9, 2024.

2. Lu S, Kato T, Dong X, et al: Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med 391:585-597, 2024.

3. Bradley JD, Hu C, Komaki RR, et al: Long-term results of NRG Oncology RTOG 0617: Standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. J Clin Oncol 38:706-714, 2020.