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

Phase 2Not Yet RecruitingNCT07776717

Fudan University30 enrolled

Overview

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.

TACTIC-RCC is an investigator-initiated, prospective, open-label, single-center, single-arm Phase 2 clinical and translational study in treatment-naive patients with synchronous metastatic renal cell carcinoma containing a clear-cell component, an intact primary renal tumor, at least one measurable extracorporeal metastatic lesion by RECIST v1.1, and biopsy-detectable tertiary lymphoid structures (bdTLS) in the primary tumor. All formally enrolled participants receive induction treatment with toripalimab 240 mg intravenously every 3 weeks plus axitinib 5 mg orally twice daily for approximately 12 weeks (four planned toripalimab cycles). Imaging is mandatory at Weeks 6 and 12. In addition to conventional RECIST v1.1 assessment, the study maintains lesion-level measurements that separate the primary renal tumor from individual metastatic lesions. At Week 12, a multidisciplinary team that is independent of the translational results determines whether selective deferred cytoreductive nephrectomy (DCN) is clinically appropriate. The decision considers systemic treatment benefit, IMDC risk, performance status, anesthetic and surgical risk, primary-tumor burden, metastatic burden, technical resectability, the potential harm of systemic-treatment interruption, and participant preference. DCN is not mandatory and must not be performed solely to obtain research tissue. Participants who do not undergo surgery remain in the intention-to-treat clinical cohort and continue systemic management and follow-up according to clinical need. For participants undergoing DCN, the last preoperative imaging assessment, preferably within 14 days before surgery, serves as the reference for residual metastatic disease. A postoperative confirmation scan is obtained approximately 4-6 weeks after surgery. Imaging is then performed every 8 weeks during the first 24 postoperative weeks and every 12 weeks thereafter. The surgery date is the landmark for postoperative time-to-event outcomes. In participants without progression or unacceptable toxicity, toripalimab plus axitinib is generally resumed after adequate postoperative recovery. Toripalimab may continue for approximately 2 years in total, while axitinib may continue until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. For non-surgical participants, systemic therapy is continued or changed according to the same clinical principles. The primary clinical endpoint is the 24-week progression-free survival rate from DCN (DCN-PFS) in the postoperative residual-metastasis primary analysis set. The primary translational endpoint is the association between a participant-level TLS Functional State Score (TLS-FSS), derived from post-treatment primary-tumor pathology and multiregional immune features, and 24-week DCN-PFS. A key mechanistic analysis evaluates a TLS-to-blood Clonal Persistence Index (TLS-CPI), which quantifies persistence of spatially localized TLS-associated T-cell or B-cell receptor clonotypes in serial blood after nephrectomy. The translational program uses a tissue-to-blood-to-outcome framework. Baseline core biopsy establishes TLS eligibility. When available, nephrectomy tissue undergoes panoramic and multiregional pathology, multiplex immunofluorescence, TCR/BCR profiling, single-cell or single-nucleus transcriptomics, and spatial profiling. Serial peripheral blood mononuclear cells and plasma/serum are collected before and during induction, on the day of surgery, and after surgery to track immune clonotypes and systemic immune states. The study is designed to estimate clinical and biomarker effect sizes rather than to prove that nephrectomy improves survival or that the primary renal tumor is required to maintain systemic anti-tumor immunity. Because surgery is selected after treatment according to clinical benefit and MDT judgment, analyses comparing surgical and non-surgical participants are descriptive or sensitivity analyses and are not intended as causal comparisons.

Interventions

ToripalimabDRUG

Toripalimab 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.

AxitinibDRUG

Axitinib 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 NephrectomyPROCEDURE

Selective 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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: From the date of deferred cytoreductive nephrectomy to the first documented disease progression or death from any cause, whichever occurs first, assessed up to 24 months after surgery.

Secondary Outcomes

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.

Time frame: From the date of surgery through 24 weeks after surgery; blood samples include postoperative Day 28, Week 12, and Week 24.

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.

Time frame: From the last preoperative reference scan through 24 weeks after deferred cytoreductive nephrectomy.

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.

Time frame: Assessed on postoperative imaging through at least 24 weeks after deferred cytoreductive nephrectomy.

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.

Time frame: At the Week 12 multidisciplinary assessment.

12-month DCN-PFS rate

DCN-PFS is defined as the time from the date of deferred cytoreductive nephrectomy to the first radiographically documented disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. Participants without an event will be censored at the date of the last adequate tumor assessment. This outcome will be analyzed among participants who undergo deferred cytoreductive nephrectomy.

Time frame: From the date of deferred cytoreductive nephrectomy to the first documented disease progression or death from any cause, whichever occurs first, assessed up to 12 months after surgery.