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

This is a prospective, single-arm, open-label, Phase 1 dose-escalation and dose-expansion clinical trial evaluating all-trans retinoic acid (ATRA) in combination with tislelizumab in participants with advanced EGFR-mutant non-small cell lung cancer (NSCLC). The study population will include participants whose disease has progressed after a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) and at least one standard systemic therapy, as well as participants who are unable to tolerate or are considered unsuitable for currently available standard treatment. Participants must have no clearly available and appropriate standard targeted therapy, as determined by the investigator.

The study is designed to characterize the safety and tolerability of the combination, identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and obtain preliminary evidence of antitumor activity. The study will also explore molecular and immune changes associated with treatment response and toxicity.

Dose Escalation and Dose Expansion

A conventional 3+3 dose-escalation design will be used. Three ATRA dose levels are planned:

• Dose Level 1: ATRA 30 mg orally twice daily
• Dose Level 2: ATRA 40 mg orally twice daily
• Dose Level 3: ATRA 50 mg orally twice daily

At each dose level, ATRA will be administered in combination with tislelizumab 200 mg by intravenous infusion once every 3 weeks. Initially, 3 participants will be enrolled at each dose level. Enrollment may be expanded to 6 participants at a dose level according to the occurrence of dose-limiting toxicities (DLTs) and the prespecified 3+3 dose-escalation rules.

After the RP2D has been selected, approximately 6 additional participants are planned to be enrolled in a dose-expansion cohort at that dose level. The expansion cohort will provide additional information on the safety, tolerability, and preliminary antitumor activity of the combination.

Approximately 15 to 24 participants are expected to be enrolled. The final sample size will depend on the number of DLTs observed and the outcome of dose escalation.

Treatment Plan and DLT Evaluation

Treatment will be administered in 21-day cycles. ATRA will be started 7 days before the first tislelizumab infusion. During this 7-day lead-in period, participants will receive ATRA alone. Beginning on Cycle 1 Day 1, participants will continue oral ATRA and receive tislelizumab 200 mg intravenously every 3 weeks.

The DLT evaluation period will consist of the 7-day ATRA lead-in period plus the first 21-day combination-treatment cycle, for a total of 28 days. Participants who complete the required DLT observation period, or who experience a DLT during that period, will be considered evaluable for DLT assessment.

Treatment may continue according to the protocol until disease progression, unacceptable toxicity, withdrawal of consent, pregnancy, loss to follow-up, initiation of another anticancer treatment, investigator determination that continued treatment is no longer in the participant's best interest, or termination of the study.

If an adverse event considered related to ATRA occurs, supportive treatment, temporary interruption, dose reduction, or permanent discontinuation of ATRA may be used according to the type, severity, duration, and recovery of the toxicity. Dose reduction of tislelizumab is not permitted. Tislelizumab may be interrupted, resumed, or permanently discontinued for immune-related or other clinically significant adverse events in accordance with applicable prescribing information, established toxicity-management guidance, and the investigator's clinical judgment.

Study Assessments

The study includes a screening period, a 7-day ATRA lead-in period, the combination-treatment period, an end-of-treatment visit, safety follow-up, and survival follow-up.

Screening assessments will generally be completed within 28 days before the first study treatment. Assessments will include medical and treatment history, physical examination, vital signs, performance status, concomitant medications, laboratory testing, electrocardiography, baseline tumor imaging, and collection of biological samples.

Safety and treatment suitability will be evaluated before treatment in each 21-day cycle. Assessments will include physical examination, vital signs, body weight, performance status, hematology and blood chemistry testing, lipid testing, concomitant medication review, adverse-event monitoring, and evaluation of adherence to oral ATRA treatment.

During the first year of treatment, tumor imaging will generally be performed every 6 weeks, with an allowed window of 7 days. After the first year, imaging may be performed every 9 weeks, with an allowed window of 7 days. Tumor response and disease progression will be assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

Participants who discontinue all study treatment should complete an end-of-treatment visit within 28 days after the last study treatment, with an allowed window of 7 days, or before starting a new anticancer treatment, whichever occurs first. Adverse events, serious adverse events, and clinically significant laboratory abnormalities that have not resolved at treatment discontinuation will be followed until they return to baseline, improve to Grade 1 or lower, stabilize at a level considered acceptable by the investigator, are determined to be irreversible, or the participant begins a new anticancer treatment.

After completion of safety follow-up, survival status and information about subsequent anticancer treatment will be collected approximately every 3 months, with an allowed window of 7 days, until death, loss to follow-up, withdrawal of consent, or study termination.

Translational and Biomarker Research

Tumor tissue will be collected at baseline and, when specified by the protocol, at disease progression. Peripheral blood will be collected at baseline and at planned time points during treatment. These samples will be used to characterize tumor-associated molecular features and their changes over time.

Single-cell analyses may be used to evaluate the molecular characteristics and longitudinal changes of immune-cell populations in peripheral blood mononuclear cells, including T cells and monocyte/myeloid-cell populations. These exploratory analyses are intended to identify potential biomarkers associated with antitumor activity or treatment-related toxicity and to generate hypotheses regarding possible predictors of treatment response.

Statistical Considerations

No formal statistical hypothesis testing is planned for this Phase 1 dose-finding study. Analyses will primarily be descriptive. Safety findings and DLTs will be summarized overall and by dose level. Selection of the MTD and/or RP2D will be based on the prespecified 3+3 dose-escalation rules together with the overall available safety, tolerability, and clinical data.

Preliminary antitumor activity will be summarized descriptively. Time-to-event measures may be explored using the Kaplan-Meier method if the available data are sufficiently mature. Biomarker analyses will be exploratory and will be conducted in participants with suitable tumor tissue or peripheral blood samples and the corresponding clinical data.