POLESTAR Results Show PFS Benefit of Aumolertinib in NSCLC

Photorealistic illustration of lungs with blood vessels

The tyrosine kinase inhibitor (TKI) aumolertinib (formerly almonertinib; HS-10296) improved progression-free survival (PFS) vs placebo in patients with unresectable stage III non–small cell lung cancer (NSCLC), according to data from an interim analysis of the phase 3 POLESTAR trial (NCT04951635).¹

Findings presented at the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer, showed that at a median follow-up of 16.36 months (range, 0-33.2) for the aumolertinib arm (n = 92) and 13.93 months (range, 0-24.8) for the placebo arm (n = 50), aumolertinib reduced the risk of disease progression or death by 80% vs placebo (HR, 0.200; 95% CI, 0.114-0.352; log-rank P < .0001). Aumolertinib elicited a median PFS of 30.4 months (95% CI, 17.2-not reached [NR]) in patients compared with 3.8 months (95% CI, 3.7-5.6) for placebo per blinded independent central review (BICR) assessment.

Per investigator assessment, the median PFS was 30.4 months (95% CI, 22.1-NR) for patients who received aumolertinib vs 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). “These findings demonstrate aumolertinib [is] a novel treatment option for patients with unresectable stage III EGFR-mutated NSCLC after CRT [chemoradiation therapy],” lead study author Xiangjiao Meng, MD, of Shandong Cancer Hospital and Institute at Shandong First Medical University in Jinan, China, said in a presentation of the data.

POLESTAR Design and Study Methods

POLESTAR was a randomized, double- blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of the third-generation EGFR TKI aumolertinib vs placebo in patients 18 years or older with locally advanced, unresectable stage III NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations.^1,2 Patients were required to have an ECOG performance status of 0 or 1, no disease progression following definitive CRT, and an interval between the last dose of CRT and random assignment of no more than 6 weeks.¹

Investigators randomly assigned patients 2:1 to receive 110 mg of aumolertinib once daily or 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 trial’s primary end point was BICR-assessed PFS per RECIST v1.1 criteria, with investigator-assessed PFS serving as a sensitivity analysis. Secondary end points 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, investigators enrolled 147 patients across 43 sites in China in the trial. Ninety-four patients were assigned to the aumolertinib arm, and 53 were included in the placebo arm. A modified intention-to-treat population was established to evaluate efficacy and included 92 patients from the aumolertinib arm and 50 from the placebo arm.

At data cutoff, 73% of patients (n = 69) in the aumolertinib arm had ongoing treatment compared with 32% (n = 17) in the placebo arm. Notably, 52% of evaluable patients (11 of 21) who experienced disease progression in the aumolertinib arm continued receiving the agent after progression. Eighty-five percent of evaluable patients (29 of 34) in the placebo arm who experienced disease progression crossed over to receive aumolertinib.

In the aumolertinib arm, 27% of patients (n = 25) discontinued treatment due to disease progression (n = 17), adverse events (AEs; n = 5), withdrawn consent (n = 1), patient decision (n = 1), or investigator decision (n = 1). Among the 68% of patients (n = 36) who discontinued treatment in the placebo arm, reasons for discontinuation were disease progression (n = 34), AEs (n = 1), or other reason (n = 1).

At baseline, the median age was 59 years (range, 39-76) in the aumolertinib arm vs 58 years (range, 36-77) in the placebo arm. The majority of patients were women (aumolertinib, 54%; placebo, 62%), had never smoked (70%; 72%), had adenocarcinoma (90%; 96%), had an ECOG performance status of 1 (82%; 80%), received concurrent CRT (75%; 72%), and had disease with EGFR exon 21 L858R mutations (59%; 56%).

In the aumolertinib arm, 24% of patients had stage IIIA disease, 60% had stage IIIB disease, and 16% had stage IIIC disease. These respective rates were 22%, 62%, and 16% in the placebo arm. No patients in either arm had a complete response to CRT.

The partial response rates to CRT were 60% for the aumolertinib arm vs 46% for the placebo arm. The rates of stable disease after CRT were 40% and 52%, respectively.

Digging Into Additional Efficacy Data

Aumolertinib elicited an ORR of 57% (95% CI, 46%-67%) in patients compared with 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%) vs 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 vs 7.1 months (95% CI, 1.71-17.51) in the placebo arm (HR, 0.476; 95% CI, 0.168-1.349; P = .1557).

At a median follow-up of 16.6 months (range, 1.5-33.2) for the aumolertinib group and 14.9 months (range, 0.4-31.4) for the placebo group, OS data reached 9.8% maturity for the experimental arm and 6% maturity for the control arm. The median OS was NR in both groups.

The median CNS PFS was NR (95% CI, NR-NR) in both arms (HR, 0.33; 95% CI, 0.12-0.92; P = .0270). The median TTDM was NR (95% CI, NR-NR) in the aumolertinib arm vs NR (95% CI, 3.84-NR) in the placebo arm (HR, 0.21; 95% CI, 0.09-0.49; P < .0001).

New lesions were detected in 20.7% of patients in the experimental arm vs 58% of patients in the placebo arm. New lesions included chest (aumolertinib, 12.0%; placebo, 34.0%), brain (7.6%; 16.0%), distant lymph node (2.2%; 0%), abdomen (1.1%; 8.0%), and bone (1.1%; 8.0%).

Examining the Safety of Aumolertinib in POLESTAR

Regarding safety, any-grade treatment-related AEs (TRAEs) occurred in 84% of patients in the aumolertinib arm (n = 94) and 43.4% of patients in the placebo arm (n = 53). The rates of grade 3 or higher TRAEs were 9.6% and 1.9%, respectively.

Serious TRAEs were reported in 6.4% of patients in the experimental arm vs 1.9% of patients in the control arm.

TRAEs did not lead to death in any patients 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 vs placebo arm, respectively.

The most common any-grade AEs reported in at least 10% of patients included increased blood creatinine phosphokinase levels (aumolertinib, 46%; placebo, 8%), radiation pneumonitis (45%; 30%), decreased white blood cell count (31%; 11%), decreased platelet count (21%; 6%), increased aspartate aminotransferase levels (21%; 19%), upper respiratory tract infection (21%; 9%), increased alanine aminotransferase levels (21%; 15%), cough (17%; 8%), decreased neutrophil count (15%; 9%), increased weight (14%; 8%), anemia (14%; 2%), diarrhea (13%; 0%), increased blood creatinine levels (12%; 2%), rash (12%; 0%), and COVID-19 (6%; 11%).

“Interstitial lung disease [ILD] was not reported for aumolertinib, but it was reported in 1 patient for placebo [who experienced grade 3 ILD],” Meng concluded.

REFERENCES:

1. Meng X, Ge H, Ning F, et al. Aumolertinib after chemoradiotherapy in unresectable stage III non-small-cell lung cancer with EGFR mutation: interim analysis of the phase III POLESTAR study. Abstract presented at: 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL04.13.

2. A phase III study to assess the effects of almonertinib following chemoradiation in patients with stage III unresectable non-small cell lung cancer. ClinicalTrials.gov. Updated June 16, 2022. Accessed September 9, 2024. https://clinicaltrials.gov/study/NCT04951635