Aumolertinib significantly prolonged progression-free survival vs gefitinib in treatment-naïve patients with locally advanced or metastatic non–small cell lung cancer harboring EGFR mutations, according to findings from the phase 3 ANEAS trial published in the Journal of Clinical Oncology.
Aumolertinib significantly prolonged progression-free survival (PFS) vs gefitinib (Iressa) in treatment-naïve patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR mutations, according to findings from the phase 3 ANEAS trial (NCT03849768) published in the Journal of Clinical Oncology.
At a median follow-up of 20.5 months (95% CI, 18.0-20.6) for aumolertinib and 20.7 months (95% CI, 19.3-20.8) for gefitinib, the median duration of PFS was 19.3 months (95% CI, 17.8-20.8) and 9.9 months (95% CI, 8.3-12.6), respectively (HR, 0.46; 95% CI, 0.36-0.60; P < .0001). The 1-year PFS rates in the investigative and control arms were 69.5% and 46.3%, respectively; the 2-year rates were 32.5% and 12.9%, respectively.
Moreover, the PFS benefit achieved with aumolertinib proved to be consistent PFS benefit across all prespecified stratification factors, including EGFR mutation type and central nervous system (CNS) metastases status.
“These results suggest the possible use of aumolertinib as first-line treatment for EGFR-mutant NSCLC, particularly given the encouraging low rates of EGFR wild-type–mediated toxicity,” lead study author, Shun Lu, MD, a professor in the Department of Medical Oncology at Shanghai Chest Hospital, Shanghai JiaoTong University, and colleagues, wrote in the paper.
EGFR mutations are common oncogenic drivers of NSCLC. A need remains for third-generation EGFR inhibitors that are both effective in the first line and well tolerated. Aumolertinib is a novel third-generation EGFR TKI that is approved in China for use in patients with NSCLC whose tumors harbor an EGFR T790 mutation.
This randomized, double-blind trial enrolled patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC and an EGFR mutation. Permitted EFGR mutations included sensitizing mutations, such as exon 19 deletions and L858R mutations, as detected by a central laboratory. Patients were required to have at least 1 measurable lesion of at least 10 mm per RECIST v1.1 criteria.
Those with asymptomatic and stable CNS metastases that did not require steroids for at least 2 weeks before the initiation of the study drug were permitted. However, those who had received prior systemic therapy, including prior treatment with an EGFR inhibitor, were excluded. Previous treatment in the adjuvant/neoadjuvant setting was allowed.
A total of 429 patients across 53 sites in China were randomly assigned 1:1 to receive aumolertinib at 110 mg once daily (n = 214) or gefitinib at 250 mg once daily (n = 215). Patients were stratified by type of EGFR mutation (exon 19 deletion vs L858R) and CNS metastases status (with vs without). Patients received treatment with the study drug until disease progression, withdrawal of consent, unacceptable toxicity, or other discontinuation criteria were met.
Treatment with the study drug was permitted beyond disease progression if patients continued to derive clinical benefits per treating investigator assessment. Patients in the gefitinib arm who acquired an EGFR T790M mutation were eligible to cross over to the aumolertinib arm.
Baseline characteristics were well balanced between the 2 arms. The median age of patients was 62 years (range, 25-81); most patients in both arms were female, and all were Asian. In total, 65.4% (n = 140) of those in the aumolertinib arm and 65.6% (n = 141) of those in the gefitinib arm had EGFR exon 19 deletions; 34.6% (n = 74) and 34.4% (n = 74) of patients, respectively, harbored EGFR L858R mutations. Additionally, 26.2% (n = 56) and 27.4% (n = 59) of those in the aumolertinib and gefitinib arms, respectively, had CNS metastases.
The primary end point of the trial was investigator-assessed PFS. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and depth of response.
As of the data cutoff date of January 15, 2021, all randomized patients had received at least 1 dose of study drug. Moreover, 19.1% (n = 41) of patients in the gefitinib arm had crossed over and received at least 1 dose of aumolertinib.
The median duration of total drug exposure was 463.5 days (range, 1-715) for the aumolertinib arm and 254.0 days (range, 1-714) for the gefitinib arm. Medication compliance was seen in 99.3% and 98.5% of those in the aumolertinib and gefitinib arms, respectively. A total of 105 patients in the aumolertinib arm (data maturity of 49.1%) and 158 patients in the gefitinib arm (data maturity of 73.5%) experienced RECIST-defined progression or death. At data cutoff, 43.5% (n = 93) and 15.8% (n = 34) of those in the aumolertinib and gefitinib arms, respectively, were still receiving treatment.
In the subset of patients with an EGFR exon 19 deletion, the median PFS with aumolertinib was 20.8 months (95% CI, 18.1-20.9) vs 12.3 months (95% CI, 9.6-13.8) with gefitinib (HR, 0.39; 95% CI, 0.28-0.54; P <.0001). Among the subset with an EGFR L858R mutation, the median PFS was 13.4 months (95% CI, 7.3-18.0) and 8.3 months (95% CI, 6.8-9.9) in the aumolertinib and gefitinib arms, respectively (HR, 0.60; 95% CI, 0.40-0.89; P = .0102).
The median PFS for patients with CNS metastases was 15.3 months (95% CI, 10.8-20.8) in the aumolertinib arm and 8.2 months (95% CI, 6.5-8.3) in the gefitinib arm (HR, 0.38; 95% CI, 0.24-0.60; P < .0001). Among those without CNS metastases, the median PFS was 19.3 months (95% CI, 17.8–not applicable [NA]) and 12.6 months (95% CI, 9.6-14.0) in the aumolertinib and gefitinib arms, respectively (HR, 0.51; 95% CI, 0.38-0.69; P < .0001).
A preliminary OS analysis conducted at the time of the final PFS analysis revealed that 123 patients had died (data maturity of 28.7%), including 54 patients in the aumolertinib arm and 69 patients in the gefitinib arm (data maturities of 25.2% and 32.1%, respectively).
At data cutoff, the median OS was NA in both the aumolertinib (95% CI, NA-NA) and gefitinib (95% CI, 21.8-NA) arms. The 12-month rates were 86.2% (95% CI, 80.8%-90.2%) and 85.3% (95% CI, 79.8%-89.4%) in the aumolertinib and gefitinib arms, respectively; the 24-month OS rates were NA in both arms.
The ORRs were 73.8% (95% CI, 67.4%-79.6%) and 72.1% (95% CI, 65.6%-78.0%) in the aumolertinib and gefitinib arms, respectively (P = .6939). The DCRs were 93.0% (95% CI, 88.7%-96.0%) and 96.7% (95% CI, 93.4%-98.7%) in the aumolertinib and gefitinib arms, respectively (P = .0884). The median DOR was 18.1 months (95% CI, 15.2-NA) with aumolertinib vs 8.3 months (95% CI, 6.9-11.1) with gefitinib (HR, 0.38; 95% CI, 0.28-0.51; P < .0001).
Regarding safety, 98.8% (n = 424) patients experienced at least 1 adverse effect (AE) during study treatment. The most common AEs in the aumolertinib and gefitinib arms were blood creatine phosphokinase increase (35.5% vs 9.3%), aspartate transaminase increase (29.9% vs 54.0%), alanine aminotransferase increase (29.4% vs 55.8%), rash (23.4% vs 41.4%), and diarrhea (16.4% vs 35.8%).
Although rates of blood creatine phosphokinase increase were common with aumolertinib, only 7% of the patients in this arm had a blood creatine phosphokinase increase of grade 3 or higher. No patients had increases associated with rhabdomyolysis, and blood creatine phosphokinase increase was not observed as a serious AE. Additionally, although increases led to temporary aumolertinib interruption in 5.1% (n = 11) of patients and dose reduction in 2.8% (n = 6) of patients, it caused no instances of aumolertinib discontinuation.
AEs of any cause of grade 3 or higher were noted in 36.4% of the aumolertinib arm and 35.8% of the gefitinib arm.
Additionally, 98.6% (n = 211) and 99.1% (n = 213) patients in the aumolertinib and gefitinib arms, respectively, experienced at least 1 treatment-emergent AE (TEAE). The most common grade 3 or higher TEAEs were alanine aminotransferase increase (2.8% vs 12.1%) and aspartate transaminase increase (1.4% vs 9.3%).
Serious AEs occurred in 22.0% and 21.4% of the aumolertinib and gefitinib arms, respectively. Two patients in the aumolertinib arm and 1 patient in the gefitinib arm had grade 2 interstitial lung disease that was determined by the investigator to be treatment related.
The rate of AEs leading to permanent treatment discontinuation was 3.7% in the aumolertinib arm and 5.1% in the gefitinib arm. A total of 16.8% (n = 36) and 24.7% (n = 53) of patients experienced dose interruptions in the aumolertinib and gefitinib arms, respectively. In addition, 4.2% (n = 9) of patients in the aumolertinib arm and 4.7% (n = 10) of patients in the gefitinib arm experienced AEs that required dose reduction.
In total, 5 patients in the aumolertinib arm and 3 patients in the gefitinib arm experienced AEs that resulted in death between the initiation of study drug and 28 days after their last dose of study drug. In the aumolertinib-treated patients, the AEs leading to death were cardiac arrest (n = 2) cerebral infarction (n = 1), cardiogenic pulmonary edema complication with upper gastrointestinal hemorrhage (n = 1), and unexplained (n = 1), respectively. Investigator assessment determined 4 of those events to be unrelated to the study drug and 1 of those events to be indeterminable.
“This study conducted exclusively in China has findings broadly applicable to this genomically defined, global patient population as the natural history of and approach to evaluation and treatment of patients with EGFR-mutant NSCLC are similar worldwide,” the study authors wrote.
Additional studies of aumolertinib are ongoing. A phase 3 study (NCT04687241) is investigating aumolertinib vs placebo in the adjuvant setting, and another phase 3 study (NCT04923906) is investigating the agent plus chemotherapy in the metastatic setting.
Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non–small-cell lung cancer with EGFR exon 19 deletion or L858R mutations. J Clin Oncol. 2022;40(27):3162-3171. doi:10.1200/JCO.21.02641