Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase III trial (AENEAS).

Abstract

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p < 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P < 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study

“…13 In the AENEAS study, aumolertinib had significantly longer CNS PFS compared with gefitinib in patients with EGFRmutated, treatment-naive NSCLC (29.0 mo [95% CI: 12.3-not applicable] with aumolertinib versus 8.3 mo [95% CI: 6.9-9.7] with gefitinib, HR ¼ 0.319 [95% CI: 0.176-0.580], p < 0.0001). 21 These results were all comparing a third-generation EGFR TKI with one or two first-generation EGFR TKIs and whether one third-generation EGFR TKI was superior than another remains to be explored. Nevertheless, the reported CNS PFS rate of osimertinib, aumolertinib, and furmonertinib was similar in these studies at 6, 12, and 18 months (FLAURA: 87%, 77%, 58%; AENEAS: 86%, 73%, 60%; FURLONG: 91%, 77%, 63%, respectively).…”

“…Nevertheless, the reported CNS PFS rate of osimertinib, aumolertinib, and furmonertinib was similar in these studies at 6, 12, and 18 months (FLAURA: 87%, 77%, 58%; AENEAS: 86%, 73%, 60%; FURLONG: 91%, 77%, 63%, respectively). 13,21 On the basis of the hypothesis that a higher dose of EGFR TKIs may result in a higher exposure of drugs in the CNS, several studies investigated increased dose or dose elevation of osimertinib or furmonertinib in treating CNS metastases. Park et al 22 reported that the median PFS and median OS were 7.6 months and 16.9 months in patients with EGFR T790M-mutated brain metastatic NSCLC treated with osimertinib 160 mg once daily.…”

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial

“… 5 , 6 , 7 The prespecified analysis of the AURA3 and other phase III studies revealed encouraging results in patients with CNS metastasis. 8 , 9 , 10 The approved EGFR-TKIs have limited ability to cross the blood–brain barrier (BBB), with K puu values (the ratio of cerebrospinal fluid [CSF] to plasma concentration) ranging from 0.066 to 0.29. 11 Therefore, novel molecular targeted agents with improved K puu values may offer improved CNS disease control, and are thus a clinical priority.…”

Results of the phase IIa study to evaluate the efficacy and safety of rezivertinib (BPI-7711) for the first-line treatment of locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation from a phase I/IIa study

“…In the FLAURA study, osimertinib reduced the risk of CNS progression or death while compared with the first-generation EGFR TKI gefitinib/erlotinib with an HR of 0.48 (95% CI: 0.26–0.86; p = 0.014) in the CNS full analysis set (cFAS) [ 28 ]. In the AENEAS study, almonertinib achieved longer median CNS-PFS over gefitinib in cFAS [29.0 vs 8.3 months; HR: 0.323 (95% CI: 0.181–0.576); p < 0.0001] [ 29 ]. Furmonertinib achieved a median CNS-PFS of 11.6 (95% CI: 8.3–13.8) months for EGFR T790M mutated patients in its phase IIb study for the cFAS and further prolonged the median CNS-PFS while compared with gefitinib in cFAS (20.8 vs 9.8 months; HR: 0.40 [95% CI: 0.23–0.71]; p = 0.0011) in the FURLONG study [ 15 , 30 ].…”