Phase I study of the aurora kinase A inhibitor alisertib in combination with osimertinib in EGFR-mutant lung cancer.

Abstract

9074 Background: The 3rd generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutant (mt) lung adenocarcinoma (LUAD). However, tumor resistance to osimertinib monotherapy invariably occurs. Activation of Aurora Kinase A (AURKA) drives resistance to osimertinib treatment in preclinical models of EGFR-mutant LUAD and is associated with TKI resistance in patients. Alisertib is a selective AURKA inhibitor with an acceptable safety profile established in early phase clinical trials. Methods: We performed a single institution phase Ia clinical trial of alisertib in combination with the 3rd generation EGFR inhibitor osimertinib in patients with metastatic EGFR-mutant LUAD who had experienced disease progression on osimertinib monotherapy (NCT04085315). The primary objective of the study was to determine the safety and tolerability of alisertib in combination with osimertinib in order to define the maximum tolerated dose (MTD) and to identify a recommended phase 2 dose (RP2D). Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Utilizing a 3+3 trial design, patients receiving osimertinib 80 mg daily were treated with alisertib using an intermittent dosing strategy of 20-50 mg twice daily (BID) oral alisertib on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle. Results: A total of 10 patients were treated with osimertinib 80 mg and received at least one dose of alisertib. 6 patients were treated at the 30 mg BID and 4 patients at the 40 mg BID intermittent dosing schedule of alisertib. The most commonly reported adverse events (AEs) were diarrhea (70%), fatigue (60%), alopecia (50%) and neutropenia (50%). All AEs, except neutropenia, were grade 1 or 2. Two patients (20%) experienced grade 3 or grade 4 neutropenia; both patients were treated at the 40 mg BID intermittent dose of alisertib. Intermittent alisertib 30 mg BID was identified as the MTD and RP2D in combination with osimertinib 80 mg daily. The ORR was 10% (1/10) and DCR 70% (7/10), with the majority of patients, 60% (6/10), achieving stable disease (SD). 30% (3/10) experienced progressive disease (PD) as their best response. The median PFS was 9.4 months (2.0 months - N.R.). Conclusions: Intermittent dosing of alisertib 30 mg BID on d1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily demonstrates an acceptable toxicity profile. Preliminary efficacy analysis suggests that alisertib + osimertinib may result in clinically meaningful disease control in EGFR-mt LUAD patients whose disease is resistant to osimertinib monotherapy. Clinical trial information: NCT04085315.

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“… 130 More recently, alisertib was combined with EGFR tyrosine kinase inhibitor osimertinib in a phase I clinical trial, with preliminary results showing that alisertib may improve disease control in patients with lung adenocarcinomas resistant to osimertinib monotherapy. 131 PP2A, as previously mentioned, promotes c-Myc degradation. There are two endogenous PP2A inhibitors, su(var)3–9, enhancer of zeste, trithorax (SET)/inhibitor 2 of PP2A and cellular inhibitor of PP2A (CIP2A), which are overexpressed in several types of tumors, including lung.…”

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“…In patients with recurrent or metastatic EGFR wild-type NSCLC, the combination of erlotinib and alisertib was tolerable and effective (with one patient was PR >10 cycles and 5 patients were SD) in a phase I/II study ( 78 ). The combination of alisertib and osimertinib was an acceptable safety profile and established 10% (1/10) ORR in patients with advanced EGFR mutated LUAD who experienced progression on osimertinib monotherapy ( 79 ). In a phase 1b study of osimertinib plus alisertib or sapanisertib for osimertinib-resistant EGFR-mutant (EGFRm) NSCLC, osimertinib plus alisertib (n=20) showed median PFS was 1.9 months, ORR (5%) and DCR (40%) ( 80 ).…”

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“…The combination of osimertinib and alisertib (MLN8237), the most clinically advanced AURKA inhibitor, is currently being evaluated in patients with Osimertinib-resistant LUAD (NCT04085315). Early results suggest an acceptable safety profile as well as clinically meaningful efficacy [ 83 ].…”