Phase 1 Study of ATRA Plus a PD-1 Inhibitor in EGFR-Mutant NSCLC After Third-Generation EGFR-TKI Resistance

Prior treatment

• A history of a Grade 3 or higher immune-related adverse event following treatment with an immune checkpoint inhibitor, or permanent discontinuation of immunotherapy because of immune-related toxicity.
• An unstable thrombotic or bleeding event requiring therapeutic intervention within 6 months before screening.
• Previous or current benign intracranial hypertension or pseudotumor cerebri.
• Current treatment with a tetracycline that cannot be discontinued.
• Current treatment with another anticancer therapy or investigational product without completion of the protocol-required washout period.

Other illness

• History of another malignancy, except for a malignancy that has been clinically cured and is considered by the investigator to have a low risk of recurrence.
• Histologic transformation, such as transformation to small cell lung cancer.
• Uncontrolled acute or chronic infection, or an active infection requiring systemic anti-infective treatment.
• Active tuberculosis.
• Positive human immunodeficiency virus antibody test, active hepatitis B, or active hepatitis C.
• Active autoimmune disease, or a history of autoimmune disease requiring systemic immunosuppressive treatment.
• Severe or uncontrolled cardiovascular or cerebrovascular disease.
• Uncontrolled Grade 2 or higher hepatic dysfunction, or underlying liver disease that may substantially increase the risk of ATRA-related hepatotoxicity, as determined by the investigator.
• History of a severe hypersensitivity reaction to all-trans retinoic acid, another retinoid, tislelizumab, or any component of these products.
• Any other condition that, in the investigator's opinion, makes the individual unsuitable for participation in the clinical trial.

Other

• Uncontrolled brain metastases, leptomeningeal metastases, or a central nervous system lesion requiring urgent local treatment.
• Clinically significant uncontrolled hyperlipidemia, particularly markedly elevated triglycerides, that may increase the risks associated with all-trans retinoic acid treatment, as determined by the investigator.
• Pregnant or breastfeeding, or planning pregnancy or conception during the study.

• Voluntarily provides written informed consent and agrees to comply with the study requirements.
• Aged 18 years or older, with no restriction based on sex.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants with an ECOG performance status of 2 may be enrolled at the investigator's discretion.
• Histologically or pathologically confirmed primary non-small cell lung cancer (NSCLC).
• Stage IV disease according to the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control TNM staging system, or recurrent or metastatic NSCLC that is not suitable for curative local treatment.
• A confirmed sensitizing EGFR mutation, including but not limited to an exon 19 deletion or an exon 21 L858R mutation.
• Previous treatment with a third-generation EGFR tyrosine kinase inhibitor, including but not limited to osimertinib, almonertinib, or furmonertinib, followed by radiographically confirmed disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
• Disease progression after at least one standard systemic treatment following resistance to a third-generation EGFR tyrosine kinase inhibitor, or inability to tolerate or unsuitability for currently available standard treatment, as determined by the investigator.
• No clearly available and appropriate standard targeted therapy option, as determined by the investigator.
• At least one measurable lesion according to RECIST v1.1.
• Adequate major organ function to receive the study treatment, as determined by the investigator.
• Female participants of childbearing potential must have a negative pregnancy test and agree to use effective contraception during study treatment and for at least 1 month after the last dose of all-trans retinoic acid.
• Able to understand and comply with the study requirements, as determined by the investigator.