A phase I/Ib study of the aurora kinase A inhibitor alisertib in combination with osimertinib in advanced osimertinib-resistant EGFR-mutated lung cancer.

8572 Background: The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutated lung adenocarcinoma (LUAD), however treatment resistance invariably occurs. We previously identified Aurora Kinase A (AURKA) activation as a mechanism of resistance to osimertinib. Alisertib is an oral, selective, small-molecule inhibitor of AURKA. We evaluated the combination of alisertib with osimertinib in a phase I/Ib study of patients with advanced EGFR-mutated LUAD who experienced disease progression on prior treatment with osimertinib monotherapy. Methods: 21 total patients were treated in an open-label, single-center phase I trial (NCT04085315). 10 patients were treated in a 3+3 dose escalation phase with alisertib using an intermittent dosing strategy of 30 mg (n = 6) or 40 mg (n = 4) twice daily (BID) on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily. 11 additional patients were treated at the 30 mg alisertib intermittent dosing schedule in combination with osimertinib 80 mg daily in a Phase Ib dose expansion. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of the alisertib and osimertinib combination. Secondary endpoints were investigator-assessed objective response rate (ORR) by RECIST 1.1 criteria, depth of response (DoR), disease control rate (DCR) for at least 12 weeks, progression-free survival (PFS) and overall survival (OS). Results: 21 patients with stage IV EGFR-mutated LUAD (76.1% exon 19 deletion; 14.3% L858R; 9.5 % L861Q) who had progressed on osimertinib were enrolled. 10 (47.6%) patients had received only first-line osimertinib, while 11 (52.3%) had received ≥ 2 lines of prior therapy. Common treatment-related adverse events were neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%). 2 patients had dose limiting toxicities from grade 4 neutropenia at the alisertib 40mg BID dose level. 2 patients had serious adverse events related to the study drugs, including grade 3 constipation and grade 4 anemia. There were no treatment-related deaths. Intermittent alisertib 30 mg BID with osimertinib 80 mg daily was the MTD and R2PD. ORR for all enrolled patients was 9.5% (95% CI: 1.2% to 30.4%), DCR was 81% (95% CI: 58.1% to 94.6%), and median DoR was -4 % (95% CI: -15% to 10%). The median PFS was 5.5 months (95% CI: 3.7 – 13.2 months) and median OS was 23.5 months (95% CI: 11.9 months – NR). Conclusions: Intermittent dosing of alisertib 30 mg BID in combination with osimertinib 80 mg daily demonstrated no dose limiting toxicities and was identified as the RP2D. While ORR was 80% and the median PFS was 5.5 months. These results are comparable to other emerging therapies for patients with advanced osimertinib resistant EGFR-mutated LUAD and warrants further exploration. Clinical trial information: NCT04085315 .