Phase I trial of aurora kinase A (AURKA) inhibitor VIC-1911 plus osimertinib for TKI-resistant, EGFR-mutant non-small cell lung cancer (NSCLC).

8077 Background: ARUKA has been implicated in the emergence of resistance to osimertinib. VIC-1911 is a highly selective ARUKA inhibitor that has minimal activity in EGFR-mutant (mt) cell lines as a monotherapy. Preclinical data show synergy of VIC-1911 with osimertinib across in vitro and in vivo osimertinib-resistant models. Sustained tumor control after drug withdrawal is observed in both osimertinib-naïve and -resistant xenograft models. This trial evaluated the safety and efficacy of VIC-1911 plus osimertinib in patients with TKI-resistant, EGFRmt NSCLC (NCT05489731). Methods: This is a phase I trial with a 3+3 dose escalation stage and a dose expansion stage. Eligible patients should have advanced NSCLC with EGFR 19del/L858R and failure after ≥1 lines of EGFR-TKIs. Patients enrolled into the dose escalation stage were treated with VIC-1911 150mg or 200mg BID intermittently (4 days on, 3 days off) plus osimertinib 80 mg QD consecutively. Patients enrolled into the dose expansion stage were treated with VIC-1911 at the recommended phase 2 dose (RP2D) plus osimertinib 80 mg QD. Toxicity was assessed by the NCI CTCAE V5. Efficacy was evaluated per RECIST v1.1. Results: As of 18 December 2023, a total of 24 patients were treated. Median lines of prior treatment were 3 (range,1-8). Seven patients were enrolled during the dose escalation stage (150mg = 4, 200mg = 3). No DLT was observed and 200mg was selected as the RP2D. The most common AEs related to VIC-1911 at RP2D were diarrhea (52.3%), leucopenia (38.1%), neutropenia (33.3%), and thrombocytopenia (28.6%). Efficacy was evaluable in 23 patients. Among them, 10 patients were osimertinib-naïve (T790M-negative = 8,T790M-positive = 2) and 13 were osimertinib-resistant. For osimertinib-naïve patients, confirmed objective response rate (ORR) was 50% (5PRs, T790M-negative = 4, T790M-positive = 1) and disease control rate (DCR) was 80% (3SDs). For osimertinib-resistant patients, ORR was 0% and DCR was 53.8% (7SDs). Among patients with disease control, 66.7% (10/15) stayed on treatment as of data cutoff. The median follow-up duration was 5.5 months. Median duration of response (DOR) was not reached. The 6-month (6m) DOR rate was 50%. Median progression-free survival (PFS) was not reached and 4.3months for osimertinib- naïve and -resistant patients, respectively. The 6m PFS rate was 70.0% and 38.5%, respectively. Updated DOR and PFS data will be presented. Conclusions: VIC-1911 in combination of osimertinib is well-tolerated in previously-treated EGFRmt NSCLC. The combination demonstrates sustained antitumor activity, which indicates the potential of AURKA blockade in delaying the emergence of resistance to osimertinib. Clinical trial information: NCT05489731 .