The goal of this Phase 1 clinical trial is to learn whether all-trans retinoic acid (ATRA) combined with tislelizumab is safe and tolerable in adults with EGFR-mutant non-small cell lung cancer (NSCLC). The study is for people whose cancer has worsened after treatment with a third-generation EGFR tyrosine kinase inhibitor and at least one standard systemic treatment, or who cannot tolerate or are not suitable for currently available standard treatments.
The main questions this study aims to answer are:
* What side effects and dose-limiting toxicities occur with the combination of ATRA and tislelizumab? * What is the highest dose of ATRA that can be given safely with tislelizumab, and what dose should be recommended for future studies?
Researchers will also look for early signs that the combination can shrink or control the cancer and will assess how long participants live without their cancer getting worse and how long they live overall. Tumor tissue and blood samples will be studied to explore changes in the cancer and the immune system and to identify possible markers associated with treatment response or side effects.
All participants will receive ATRA and tislelizumab; there is no comparison or placebo group. Participants will:
* Take ATRA by mouth twice daily, beginning 7 days before the first dose of tislelizumab. The ATRA dose will be assigned according to the dose level being studied. * Receive tislelizumab by intravenous infusion once every 3 weeks. * Undergo regular safety assessments, including physical examinations, blood tests, vital-sign measurements, and monitoring for side effects. * Undergo imaging examinations approximately every 6 weeks during the first year to assess the cancer. * Provide tumor tissue and blood samples for biomarker research. * Attend an end-of-treatment visit, safety follow-up visits, and survival follow-up approximately every 3 months after treatment ends.
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).
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.
Uncontrolled brain metastases, leptomeningeal metastases, or a central nervous system lesion requiring urgent local treatment.
Histologic transformation, such as transformation to small cell lung cancer.
Uncontrolled acute or chronic infection, or an active infection requiring systemic anti-infective treatment.
Single group
All-trans retinoic acid
DrugAll-trans retinoic acid will be administered orally twice daily at an assigned dose level of 30 mg, 40 mg, or 50 mg. ATRA will begin 7 days before the first tislelizumab infusion and will continue during the subsequent 21-day combination-treatment cycles. Dose escalation will follow a conventional 3+3 design. After the recommended dose for further study has been determined, additional participants will receive ATRA at that dose in the dose-expansion cohort. ATRA may be interrupted, reduced, or permanently discontinued according to the type, severity, duration, and recovery of treatment-related toxicity.
Tislelizumab
DrugTislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, will be administered at a dose of 200 mg by intravenous infusion once every 3 weeks. The first dose will be administered after the 7-day ATRA lead-in period, and tislelizumab will then be given in combination with oral ATRA during each 21-day treatment cycle. Dose reduction of tislelizumab is not permitted. Treatment may be interrupted, resumed, or permanently discontinued for immune-related or other clinically significant adverse events according to applicable prescribing information, established toxicity-management guidance, and the investigator's clinical judgment.
Incidence and Severity of Adverse Events
The number and percentage of participants who experience adverse events, serious adverse events, and treatment-related adverse events will be summarized overall and by dose level. Safety will also be evaluated using clinically significant changes in laboratory test results, vital signs, physical examinations, and other safety assessments.
Incidence of Dose-Limiting Toxicities
The number and percentage of DLT-evaluable participants who experience a dose-limiting toxicity (DLT) will be summarized by ATRA dose level. DLTs will be assessed according to the protocol-defined criteria during the 28-day DLT evaluation period.
Maximum Tolerated Dose and/or Recommended Dose for Further Study
The maximum tolerated dose (MTD) and/or recommended dose for further study will be determined using the prespecified 3+3 dose-escalation rules. The determination will be based primarily on the occurrence of DLTs at each ATRA dose level, together with the overall available safety and tolerability data for ATRA in combination with tislelizumab.
Objective Response Rate
Objective response rate (ORR) is defined as the percentage of participants whose best overall response is a confirmed complete response (CR) or partial response (PR), as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
Disease Control Rate
Disease control rate (DCR) is defined as the percentage of participants whose best overall response is a complete response (CR), partial response (PR), or stable disease (SD), as assessed by the investigator according to RECIST v1.1.
Progression-Free Survival
Progression-free survival (PFS) is defined as the time from the first dose of study treatment to the first documented disease progression according to RECIST v1.1 or death from any cause, whichever occurs first.
Overall Survival
Overall survival (OS) is defined as the time from the first dose of study treatment to death from any cause.
Changes in Peripheral Blood Immune-Cell Characteristics
Peripheral blood samples collected at baseline and at protocol-specified time points during treatment will be analyzed to characterize changes in the immune microenvironment. Single-cell analyses will be used to assess the molecular characteristics and longitudinal changes of immune-cell populations in peripheral blood mononuclear cells, including T cells and monocyte/myeloid-cell populations.
Association of Exploratory Biomarkers With Treatment Outcomes
Exploratory tumor tissue and peripheral blood biomarkers will be evaluated for potential associations with antitumor activity and treatment-related toxicity. Antitumor activity may include tumor response and disease control according to RECIST v1.1, while toxicity may include dose-limiting toxicities and other treatment-related adverse events.
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