A phase Ib study of osimertinib and tegavivint as first-line therapy in patients with metastatic EGFR -mutated non–small cell lung cancer (NSCLC).

8648 Background: EGFR TKIs improve clinical outcomes for patients with EGFR-mutated NSCLC. However, they are not curative even when combined with chemotherapy or antibody-based therapies because of slow-cycling, drug-tolerant cells that persist due to transcriptional reprogramming. This inevitably leads to tumor resistance and disease progression. Our preclinical studies showed that EGFR-mutated NSCLC cells enter a persistent state in response to TKIs due to increased transcriptional activity of β-catenin. Treatment of mice bearing EGFR-mutated NSCLC xenografts with an EGFR TKI and a β-catenin inhibitor caused a greater depth and duration of response than treatment with an EGFR TKI alone, which improved overall survival (OS). We also observed that patients with EGFR-mutated NSCLC who had the greatest increase in serum levels of the secreted β-catenin transcriptional target PAI-1 following treatment with a TKI had significantly worse progression free survival (PFS). These data led us to conduct a single-arm phase Ib clinical trial (NCT04780568) that investigated osimertinib in combination with tegavivint, an inhibitor of β-catenin transcriptional activity. Methods: Patients with metastatic EGFR-mutated (exon 19 deletion or L858R) NSCLC who had not received prior treatment with an EGFR TKI were eligible. All participants received osimertinib 80mg daily and were enrolled to escalating dose levels of tegavivint, which was administered weekly IV for 16 weeks. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) of tegavivint. Secondary objectives measured the objective response rate (ORR), median PFS, and OS. Results: Fifteen evaluable patients received treatment on the dose escalation portion of this study, including six patients at the highest dose level of tegavivint (8 mg/kg), which was determined to be the RP2D. No dose limiting toxicities nor drug-related serious adverse events occurred. The adverse events that were observed included hematologic, skin, and GI toxicities, consistent with the known osimertinib toxicity profile. Pharmacokinetic analysis showed a dose-dependent increase in the C max and AUC of tegavivint, and plasma levels of osimertinib were comparable to those seen historically when administered as a single agent. The ORR was 73% with 2 of 15 patients (13%) achieving a complete response. Median PFS was 20.6 months (95% CI: 7-32 months). OS data is still maturing. Conclusions: NCT04780568 showed that the combination of osimertinib and tegavivint was safe and tolerable as first-line therapy in patients with metastatic EGFR-mutated NSCLC. This novel combination has the potential to improve the depth and durability of response to EGFR TKIs, without significantly increasing toxicity, by targeting drug-tolerant persistence. Clinical trial information: NCT04780568 .