TACTIC-RCC: Toripalimab Plus Axitinib Induction With Selective Deferred Cytoreductive Nephrectomy in TLS-Positive Advanced Clear Cell Renal Cell Carcinoma

Toripalimab Plus Axitinib Induction Therapy With Deferred Cytoreductive Nephrectomy in TLS-Positive Advanced Clear Cell Renal Cell Carcinoma: A Prospective, Single-Arm, Phase II Study (TACTIC-RCC)

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.

Inclusion Criteria:

1. Age ≥18 years; able to understand the study and provide written informed consent before any study-specific procedure.
2. Newly diagnosed and previously untreated with systemic anticancer therapy for advanced renal cell carcinoma; the primary renal tumor remains in situ.
3. 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.
4. Clinical Stage IV disease according to the AJCC 8th edition, with synchronous distant metastasis confirmed radiologically or pathologically.
5. At least one RECIST v1.1 measurable metastatic lesion outside the primary renal tumor: non-nodal lesion with longest diameter ≥10 mm or lymph node with short-axis diameter ≥15 mm. If cytoreductive nephrectomy is performed, the investigator anticipates that at least one metastatic lesion can remain available for postoperative longitudinal assessment; clinically necessary local therapy must not be delayed for research purposes.
6. The primary-tumor biopsy meets specimen-quality requirements and is centrally classified as TLS-positive according to the protocol. Operationally, at least one adequate biopsy core must contain at least one organized lymphoid aggregate showing a relatively well-defined lymphoid structure on H&E, an identifiable CD20-positive B-cell domain with an adjacent or surrounding CD3-positive T-cell domain, and organization beyond scattered lymphocytes or a nonspecific small aggregate.
7. ECOG performance status 0-1 and estimated life expectancy ≥6 months.
8. Adequate major-organ function according to the central laboratory and applicable prescribing information, including acceptable hematologic, hepatic, renal, thyroid, and coagulation function.
9. Blood pressure adequately controlled with treatment if necessary; baseline proteinuria within a range considered safe for axitinib by the investigator.
10. Participants of childbearing potential agree to use effective contraception according to applicable prescribing information and institutional requirements.
11. Agreement to baseline tissue collection, serial imaging, and serial blood collection. Refusal of optional early/progression repeat biopsy or additional omics procedures does not make a participant ineligible.

Exclusion Criteria:

1. 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.
2. 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.
3. A rapidly life-threatening metastatic lesion that, in the investigator's judgment, requires immediate radiotherapy, surgery, or another local treatment before study therapy.
4. 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.
5. Prior organ transplantation, or active autoimmune disease requiring systemic immunosuppressive treatment. Physiologic replacement-dose corticosteroids or local therapy may be permitted according to the protocol.
6. History of life-threatening immune-related toxicity caused by prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.
7. Uncontrolled hypertension, clinically significant cardiovascular disease, recent major arterial or venous thrombosis, active bleeding, a lesion with high bleeding risk, or an uncorrectable coagulation abnormality.
8. Clinically significant proteinuria, uncontrolled thyroid dysfunction, severe hepatic or renal dysfunction, or another condition that makes toripalimab plus axitinib treatment unacceptably risky.
9. Active infection requiring systemic treatment. Participants with known active hepatitis B, active hepatitis C, or HIV infection require protocol- and institutional infectious-disease risk assessment. [The protocol wording is not an absolute exclusion for all such infections; confirm the final eligibility rule.]
10. Pregnancy or breastfeeding.
11. Another active malignancy within 5 years, except adequately treated malignancies with very low recurrence risk, such as selected carcinoma in situ or basal/squamous cell skin cancers, which may be considered individually.
12. Severe hypersensitivity to either study drug or any of its excipients.
13. Inability, in the investigator's judgment, to comply with required visits, oral medication, blood-pressure monitoring, or imaging follow-up.
14. Investigator/MDT judgment that there is no reasonable possibility that the participant could enter a planned deferred cytoreductive nephrectomy pathway after induction therapy.