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• Osimertinib cannot be used for T790M-negative NSCLC after 1st/2nd generation EGFR-TKI. • This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. • We demonstrated that osimertinib had modest antitumor activity against those patients. Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non–small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer). From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6–42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10–4.30), and the rate of 12-month PFS was 17.3 %. Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Osimertinib is widely employed in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Most EGFR-mutated NSCLC cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Avoiding drug tolerance would maintain the long-term efficacy of osimertinib. We showed that the expression of PAI-1 and mesenchymal genes in EGFR-mutated cancer cell lines was upregulated after developing tolerance to EGFR-TKIs in vitro. In addition, PAI-1 inhibition limited the proliferation and mesenchymal gene expression of EGFR-TKI-tolerant cells. These results indicate that PAI-1 is involved in drug tolerance to EGFR-TKIs via epithelial–mesenchymal transition. Furthermore, we demonstrated that the combination of osimertinib with a PAI-1 inhibitor prevented the regrowth of osimertinib-treated tumors composed of EGFR-mutated cancer cells in in vivo experiments. Based on these observations, PAI-1 may prove to be a potential therapeutic target for overcoming tolerance to osimertinib. Most epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved in chemotherapeutic or radiotherapeutic resistance. The purpose of the present study was to investigate whether PAI-1 is involved in osimertinib tolerance and whether it could be a therapeutic target for overcoming this tolerance. We showed that the PAI-1 mRNA expression levels and mesenchymal gene expression levels were significantly higher in drug-tolerant EGFR-mutated NSCLC cells than in control cells after 7 days of in vitro osimertinib treatment. Additionally, an RNA microarray analysis revealed upregulation of the integrin-induced EMT pathway in osimertinib-tolerant cells. Furthermore, we observed that PAI-1 inhibitors suppressed proliferation and the degree of epithelial–mesenchymal transition (EMT) in tolerant cells. Finally, in a subcutaneous tumor model, we showed that combining osimertinib with a PAI-1 inhibitor prevented the regrowth of tumors comprising EGFR-mutated cancer cells. The present study is the first to show PAI-1 to be involved in tolerance to osimertinib via EMT. [ABSTRACT FROM AUTHOR]