This prospective, open-label, single-arm Phase 2 study is evaluating toripalimab plus axitinib as induction therapy for adults with newly diagnosed metastatic clear cell renal cell carcinoma whose primary kidney tumor remains in place and whose baseline kidney-tumor core biopsy contains a biopsy-detectable tertiary lymphoid structure (TLS). TLS are organized immune-cell structures that may reflect an active anti-tumor immune environment.
Participants will receive approximately 12 weeks of toripalimab 240 mg by intravenous infusion every 3 weeks together with axitinib 5 mg by mouth twice daily. At Week 12, an independent multidisciplinary team will review treatment response, performance status, surgical risk, primary-tumor burden, metastatic burden, and the participant's preference to determine whether deferred cytoreductive nephrectomy is clinically appropriate. Surgery is not mandatory, and participants who do not undergo surgery will remain in the study's clinical follow-up cohort.
For participants who undergo deferred cytoreductive nephrectomy and still have at least one measurable metastatic lesion that has not been locally treated, the main clinical outcome is the proportion who are alive and free from disease progression 24 weeks after surgery. The study will also investigate whether the functional state of TLS in the treated primary kidney tumor and the persistence of TLS-associated T-cell and B-cell clones in blood after surgery are associated with longer control of remaining metastatic disease. Translational analyses may include pathology, multiplex immunofluorescence, T-cell and B-cell receptor sequencing, single-cell or single-nucleus sequencing, spatial transcriptomics, and serial blood sampling.
Age ≥18 years; able to understand the study and provide written informed consent before any study-specific procedure.
Newly diagnosed and previously untreated with systemic anticancer therapy for advanced renal cell carcinoma; the primary renal tumor remains in situ.
Histologically confirmed renal cell carcinoma containing a clear-cell component. Tissue used for diagnosis and TLS screening must be obtained from a core-needle biopsy of the primary renal tumor.
Clinical Stage IV disease according to the AJCC 8th edition, with synchronous distant metastasis confirmed radiologically or pathologically.
Prior systemic treatment for advanced renal cell carcinoma with an immune checkpoint inhibitor, VEGF/VEGFR-targeted therapy, mTOR inhibitor, chemotherapy, or other systemic anticancer therapy.
An urgent clinical indication for immediate surgery or local intervention because of uncontrolled bleeding, infection, urinary obstruction, pain, renal-function crisis, or another emergency that prevents safe completion of induction systemic therapy.
A rapidly life-threatening metastatic lesion that, in the investigator's judgment, requires immediate radiotherapy, surgery, or another local treatment before study therapy.
Active central nervous system metastases causing unstable symptoms. Participants with previously locally treated and stable CNS disease who are off corticosteroids or receiving a stable low physiologic/low dose may be considered individually by the MDT.
Single group
Toripalimab
DrugToripalimab 240 mg by intravenous infusion on Day 1 every 3 weeks, with four planned cycles during the approximately 12-week induction period. Dose reduction is not permitted. Treatment may be withheld or permanently discontinued for immune-related or other unacceptable toxicity. For participants without progression or unacceptable toxicity, toripalimab is generally resumed after adequate postoperative recovery (typically 2-6 weeks after surgery) or continued in non-surgical participants, for a total treatment duration of approximately 2 years.
Axitinib
DrugAxitinib 5 mg orally twice daily, administered continuously during induction. Routine dose escalation is not planned. For intolerance, axitinib may be interrupted and reduced stepwise to 3 mg twice daily and then 2 mg twice daily. For elective surgery, axitinib is stopped at least 2 days before surgery, with 3-5 days preferred depending on bleeding/thrombotic and surgical considerations, and is not restarted until at least 2 weeks after major surgery and adequate wound healing. After recovery, axitinib may continue until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.
Deferred Cytoreductive Nephrectomy
Procedure/SurgerySelective cytoreductive nephrectomy considered after approximately 12 weeks of induction therapy. Core conditions include clear clinical benefit or controlled systemic disease, ECOG 0-1, acceptable anesthetic/perioperative risk, technically resectable primary tumor, a meaningful clinical purpose for surgery, and informed participant preference after MDT discussion. Surgical approach (radical or partial nephrectomy; open, laparoscopic, or robotic; management of venous tumor thrombus and lymph nodes when indicated) is determined by the surgical MDT.
Progression-Free Survival Rate From Deferred Cytoreductive Nephrectomy （24 months DCN-PFS rate）
The proportion of participants in the postoperative residual-metastasis primary analysis set who are alive and have not experienced centrally confirmed disease progression by RECIST v1.1 after deferred cytoreductive nephrectomy. In the primary strategy, initiation of a new systemic therapy or local treatment because of progression or symptoms from residual metastatic disease is counted as an event. iRECIST is used as a supportive assessment.
Association Between TLS-to-Blood Clonal Persistence Index (TLS-CPI) and 24-Week DCN-PFS
TLS-CPI is calculated from prespecified dominant TLS-associated clonotypes identified in the surgical specimen and their detection in postoperative blood. The primary TLS-CPI counts weighted clonotypes detected at at least two of postoperative Day 28, Week 12, and Week 24. Its association with 24-week DCN-PFS will be estimated using the prespecified regression framework.
Best Shrinkage Rate of Residual Metastatic Tumor Burden Within 24 Weeks After Surgery
For measurable metastatic lesions that remain untreated locally after nephrectomy, best shrinkage rate is calculated as: (preoperative reference metastatic burden - lowest metastatic burden within 24 postoperative weeks) / preoperative reference metastatic burden × 100%. The preoperative reference is the last suitable imaging assessment, preferably within 14 days before surgery.
Incidence of Mixed Metastatic Response/Progression After Surgery
Descriptive incidence of heterogeneous lesion-level response after surgery, including patterns in which at least one metastatic lesion shows marked shrinkage while another lesion shows marked growth or a new lesion appears, according to the protocol-defined lesion-level framework.
Rate of MDT Recommendation for Deferred Cytoreductive Nephrectomy
Proportion of formally enrolled participants for whom the Week 12 multidisciplinary team recommends planned deferred cytoreductive nephrectomy.
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