Frontline Aumolertinib Plus Anlotinib Elicits Responses in EGFR-Mutant NSCLC With Brain Metastases

The addition of the EGFR TKI aumolertinib to the VEGF TKI anlotinib (AL3818) resulted in intracranial efficacy when used in the first-line treatment of patients with EGFR-mutant non–small cell lung cancer (NSCLC) who have brain metastases, according to preliminary findings from a prospective, single-arm, phase II clinical study (NCT04978753).¹

Results from the study, which were presented at the 2023 IASLC World Conference on Lung Cancer, demonstrated that evaluable patients (n = 39) experienced an overall response rate (ORR) of 62.5% (95% CI, 45.8%-77.3%) and disease control rate (DCR) of 97.5% (95% CI, 86.8%-99.9%) at a median follow-up of 8.8 months (range, 3.0-30.2). The intracranial ORR (iORR) was 74.4% (95% CI, 57.9%-87.0%) and the intracranial DCR (iDCR) was 100% (95% CI, 91.0%-100%).

At the data cutoff date of March 28, 2023, median progression-free survival (PFS) and overall survival (OS) were not yet reached. Notably, the median depth of tumor remission for intracranial lesions was 42.86%.

Initial data from a subgroup analysis indicated that patients with multiple brain metastases (n = 31) experienced an iORR of 77.4% (95% CI, 58.90%-90.41%); this was 62.5% (95% CI, 24.5%-91.5%) in those with oligometastasis (n = 8). In those with (n = 15) and without (n = 24) cerebral edema, the iORRs with the regimen were 86.7% (95% CI, 59.5%-98.3%) and 66.7% (95% CI, 44.7%-84.4%), respectively. Patients with EGFR exon 19 deletions (19del; n = 18) experienced an iORR of 88.9% (95% CI, 65.3%-98.6%), and those with EGFR exon 21 (L858R) mutations (21L858R; n = 21) experienced an iORR of 61.9% (95% CI, 38.4%-81.9%). Lastly, the iORR in the comutation group (n = 27), which consisted of patients with TP53 mutations, EGFR and MET amplification, PIK3CA mutations, or CCND1 amplification, was 74.1% (95% CI, 53.7%-88.9%); this was 77.8% (95% CI, 52.4%-93.6%) in patients with TP53 comutation (n = 18). All subgroups experienced an iDCR of 100% with varying confidence intervals.

“Initial subgroup results demonstrated superior activity of aumolertinib plus anlotinib in patients with multiple intracranial metastases, cerebral edema, or EGFR 19del,” said lead study author Jing Chen, a student/trainee at Sun Yat-sen University Cancer Center in Guangzhou, China, in a presentation of the data. “[Despite having] comutations, [patients with] NSCLC and brain metastasis [also may] still benefit from aumolertinib plus anlotinib. However, [these data] still require further verification.”

Approximately 30% to 50% of patients with NSCLC will develop brain metastasis, and this complication is most frequent among those harboring EGFR mutations. As the presence of brain metastases is associated with worse prognosis, the first-line treatment of this population remains a challenge.

Previous research has shown that third-generation EGFR TKI monotherapy has intracranial activity, and their efficacy may be improved with the addition of bevacizumab (Avastin). In both the randomized phase 2 JO25567 study (JapicCTI-111390; JapicCTI-142569) and the phase 3 NEJ026 trial (UMIN000017069), the combination of erlotinib (Tarceva) plus bevacizumab provided a statistically significant PFS benefit compared with erlotinib monotherapy in chemotherapy-naive Japanese patients with EGFR-mutated NSCLC.^2,3

This research supported the initiation of the current phase 2 study, which aimed to elucidate the potential benefits of pairing aumolertinib with anlotinib for patients with NSCLC who develop brain metastasis.

The double-blinded study enrolled patients between the ages of 18 and 75 years of age who were diagnosed with advanced NSCLC and harbored either EGFR 19del or 21L858R mutations. Patients were required to have 3 or more brain lesions, 1 to 2 of which that were not suitable or reluctant for local treatment, and at least 1 measurable intracranial lesion. Other key inclusion criteria included an ECOG performance status of 0 to 2, an estimated survival time longer than 12 weeks, and no prior treatment after brain metastases occurred.

Patients were not eligible to enroll onto the study if they had small cell lung cancer, brain metastases with active intracranial hemorrhage, or did not respond to prior antiangiogenic agents. Other exclusion criteria included existing grade 2 or greater toxicities linked with prior treatment, bone marrow function insufficiency, and an abnormally prolonged QTc interval of at least 470 milliseconds or various factors that may increase the risk of QTc prolongation or arrhythmia events.

All patients were treated with a daily 110-mg dose of oral aumolertinib, as well as a daily dose of oral anlotinib at either 12 mg (BSA ≥ 1.6 m²) or 10 mg (BSA < 1.6 m²) throughout the first 14 days of a 21-day cycle. Patients will continue to be assessed according to RECIST v1.1 criteria every 9 weeks until unacceptable toxicity or disease progression.

The study’s primary end point was intracranial PFS. Key secondary end points included iORR, iDCR, PFS, OS, and quality of life (QOL).

Forty patients were enrolled onto the study with a median age of 61 years (range, 28-75). The majority of patients were female (55%), had an ECOG performance status of 1 (75%), and had adenocarcinoma (95%). EGFR 19del or 21L858R mutations were present in 47.5% and 52.5% of patients, respectively. Regarding the number of intracranial lesions, 80% of patients had 4 or more brain metastases, and 20% had 1 to 3 oligometastases. Moreover, 37.5% of patients had cerebral edema.

Grade 1 or 2 adverse effects (AEs) occurred in 47.5% of patients and 5% experienced grade 3 or higher AEs. Grade 1 to 2 AEs included hypertension (20%), mouth ulceration (17.5%), rash (17.5%), diarrhea (5%), fatigue (5%), and proteinuria (2.5%). The only grade 3 or higher AE was hypertension, which occurred in 5% of patients.

“To our knowledge, this is the first reported prospective study of a third-generation EGFR TKI plus anlotinib in [patients with] NSCLC and brain metastases,” Chen said.

This research supports the continued enrollment of patients onto the trial and warrants further analyses to validate initial findings, he concluded.

References

1. Chen J, Li MC, Yu, H et al. Aumolertinib plus anlotinib in advanced EGFR-mutant NSCLC with brain metastasis: a single-arm, phase II study. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA03.03.
2. Yamamoto N, Seto T, Nishio M, et al. Erlotinib plus bevacizumab vs erlotinib monotherapy as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: Survival follow-up results of the randomized JO25567 study. Lung Cancer. 2021;151:20-24. doi:10.1016/j.lungcan.2020.11.020
3. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):625-635. doi:10.1016/S1470-2045(19)30035-X