Presentation of the pharmacological action of PAI-1 inhibitor RS5614 in non-small cell lung cancer at the 2024 World Conference on Lung Cancer (WCLC) in San Diego

We are pleased to announce that a novel pharmacological action of our PAI-1 inhibitor RS5614 in non-small cell lung cancer was presented by Dr. Masuda et al. of Hiroshima University Hospital at the 2024 World Conference on Lung Cancer (WCLC), to be held in San Diego, USA from September 7 to 10, 2024.

The prognosis of non-small cell lung cancer has improved with molecular target drugs such as osimertinib*1 and immune checkpoint inhibitors (ICIs) such as nivolumab*3, but many patients are not cured because cancer cells surviving in the tumor acquire resistance after molecular target drug or ICIs treatment. Dr. Masuda et al. previously published a paper showing that plasminogen activator inhibitor-1 (PAI-1) is involved in the acquisition of resistance to osimertinib in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations (Cancers 2023; 15: 1092). In the present study, they further investigated cancer cell resistance during ICIs treatment, and in a mouse subcutaneous tumor model of non-small cell lung cancer, they confirmed that the combination of ICI and the PAI-1 inhibitor RS5614 reduced the expression of immune checkpoint molecules, the number of tumor-infiltrating macrophages, and angiogenesis in resistant cancer cells, and increased the number of tumor-infiltrating lymphocytes, thereby attenuating the resistance of cancer cells and inhibiting their proliferation. These findings indicate that PAI-1 is involved in the acquisition of resistance to molecular target drugs and ICIs in non-small cell lung cancer, and that this is improved by RS5614, suggesting that combination therapy of molecular target drugs or ICIs with RS5614 may be a new treatment for non-small cell lung cancer.

For first-line treatment of progressive non-small cell lung cancer without mutations in the driver gene*5, chemotherapy with platinum combination drugs and ICIs such as nivolumab are used, but few cases are cured, and chemotherapy with docetaxel and other drugs is used as second-line treatment. However, the progression-free survival period is extremely short at 3 months, making third-line treatment necessary. Re-administration of nivolumab is also an option for third-line treatment, but its effectiveness is limited in patients with a history of nivolumab treatment. Therefore, development of therapeutic drugs that enhance anti-tumor immunity to enhance the action of nivolumab is being carried out, but they are accompanied by severe immune-related side effects. In fact, in recent clinical trials of chemotherapy and nivolumab/ipilimumab combination therapy in non-small cell lung cancer, the trial was discontinued due to the high number of deaths. Therefore, a combination drug with fewer side effects and that increases the response rate of nivolumab is eagerly awaited.

Since September 2023, we have been conducting a Phase II investigator-initiated clinical trial to investigate the efficacy and safety of combining nivolumab with RS5614 in 39 patients (third-line treatment patients) with unresectable, advanced or recurrent non-small cell lung cancer who have a history of multiple anti-cancer drug treatments at six medical institutions: Hiroshima University Hospital, Okayama University Hospital, Shimane University Hospital, Tottori University Hospital, Shikoku Cancer Center, and Hiroshima City Hospital. This presentation at the World Conference on Lung Cancer reveals a new pharmacological action of RS5614 against non-small cell lung cancer, and provides a rationale that supports the scientific basis for the combination therapy of ICIs and RS5614.