MANTIS-RCC: Toripalimab-Axitinib Induction in TLS-Positive Advanced Non-Clear Cell and Renal Medullary Carcinomas

MANTIS-RCC is an investigator-initiated, prospective, open-label, single-center, single-arm Phase II clinical and translational study. Candidate participants will undergo image-guided core biopsy of the intact primary renal tumor. Central pathology review will confirm non-clear cell renal cell carcinoma and renal medullary carcinoma, exclude any clear cell component, and confirm biopsy-detectable tertiary lymphoid structures using a prespecified morphologic and immunophenotypic definition.

Enrolled participants will receive toripalimab 240 mg by intravenous infusion every 3 weeks plus axitinib 5 mg orally twice daily for four planned cycles, corresponding to approximately 12 weeks of induction therapy. Imaging is required at baseline, Week 6, and Week 12. In the absence of progression or unacceptable toxicity, systemic therapy may continue after Week 12 and after surgery. Toripalimab may continue for up to approximately 2 years, and axitinib may continue until progression, unacceptable toxicity, withdrawal of consent, or an investigator decision that treatment should stop.

At Week 12, a multidisciplinary team that does not use the translational assay results will determine whether deferred cytoreductive nephrectomy is clinically appropriate. The decision will consider systemic disease control, performance status, operative risk, resectability of the primary tumor, metastatic burden, the clinical purpose of surgery, and participant preference. Surgery will not be performed solely to obtain research tissue. Participants with rapid progression, organ-threatening disease, unacceptable surgical risk, or a need to change systemic therapy will not undergo elective cytoreductive nephrectomy but will remain in the intention-to-treat clinical cohort.

The main postoperative analysis population will include participants who undergo protocol-defined deferred cytoreductive nephrectomy, have at least one measurable metastatic lesion that is not removed or locally treated at surgery, and are expected to resume the same systemic regimen. The surgery date is the landmark for postoperative time-to-event outcomes. Imaging obtained within 14 days before surgery provides the reference metastatic burden; imaging at 4 to 6 weeks after surgery confirms postoperative status but does not restart the progression-free survival clock.

The translational program integrates treated primary-tumor tissue, longitudinal imaging, and immune-repertoire measurements. The postoperative primary tumor will be used to construct a patient-level TLS Functional State Score. TCR sequencing is the primary repertoire analysis and BCR sequencing is supportive. Peripheral blood collected before surgery may include baseline, Week 3, Week 6, Week 12, and the day of surgery. After surgery, peripheral blood for TCR/BCR analysis will be collected only at Month 3, Month 6, and disease progression. The progression sample should be collected before a new systemic or local treatment when clinically feasible. The Month 3 samples will be used to characterize persistence of prespecified TLS-associated clonotypes; the progression sample will characterize loss, re-expansion, and newly detectable clonotypes.

The study is estimation-oriented. Thirty participants are planned. Enrollment may expand to a maximum of 40 only if an independent review confirms acceptable safety and feasibility and fewer than 20 participants are available for the postoperative residual-metastasis primary analysis, with ethics approval before expansion. The study does not test whether cytoreductive nephrectomy improves survival and does not include a TLS-negative comparison group or a randomized no-surgery control.

Inclusion criteria

• Age 18 years or older and able to provide written informed consent before any study-specific procedure.
• Newly diagnosed advanced renal cell carcinoma or renal medullary carcinoma with no prior systemic anticancer therapy for advanced disease and with the primary renal tumor still in place.
• Central pathology review of a core biopsy of the primary renal tumor confirms non-clear cell renal cell carcinoma and renal medullary carcinoma under the 2022 World Health Organization classification and finds no clear cell component. Eligible entities include papillary renal cell carcinoma, chromophobe renal cell carcinoma, TFE3-rearranged or TFEB-altered renal cell carcinoma, fumarate hydratase-deficient renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, ALK-rearranged renal cell carcinoma, and renal cell carcinoma not otherwise specified or unclassified after adequate workup. Sarcomatoid or rhabdoid differentiation is recorded as a feature and is not an independent subtype.
• Clinical Stage IV disease according to the AJCC 8th edition, with synchronous distant metastasis documented by imaging or pathology.
• At least one RECIST version 1.1 measurable metastatic lesion outside the primary renal tumor: longest diameter at least 10 mm for a non-nodal lesion or short axis at least 15 mm for a lymph node.
• If deferred cytoreductive nephrectomy is anticipated, the investigator expects that at least one measurable metastatic lesion can remain for longitudinal observation; clinically necessary local treatment must not be delayed for research purposes.
• Primary-tumor biopsy is adequate for clinical diagnosis, subtype confirmation, required immunohistochemistry or molecular testing, and central TLS assessment, and meets the protocol definition of TLS positivity.
• TLS positivity requires at least one organized lymphoid aggregate in or near viable tumor, with a recognizable CD20-positive B-cell zone adjacent to or surrounded by a CD3-positive T-cell area, and with organization exceeding scattered lymphocytes or a nonspecific small aggregate.
• Eastern Cooperative Oncology Group performance status of 0 or 1 and estimated life expectancy of at least 6 months.
• Adequate hematologic, hepatic, renal, thyroid, and coagulation function according to institutional laboratory requirements and the current prescribing information for the study drugs.
• Blood pressure is controlled with or without medication, and baseline proteinuria is acceptable for axitinib treatment in the investigator's judgment.
• Participants of reproductive potential agree to use effective contraception as required by the current prescribing information and institutional policy.
• Agreement to provide baseline tumor tissue, serial imaging, and protocol-required blood samples. Refusal of an optional early or progression biopsy or optional additional omics testing does not exclude participation.

Exclusion criteria

• Need for immediate surgery or local intervention for uncontrolled bleeding, infection, urinary obstruction, pain, renal failure, or another emergency that prevents safe completion of induction systemic therapy.
• Rapidly life-threatening metastatic disease requiring immediate radiotherapy, surgery, or another local treatment before study treatment.
• Active central nervous system metastases with unstable symptoms. Participants with locally treated, stable disease who are off corticosteroids or receiving a stable physiologic dose may be considered by the multidisciplinary team.
• Prior organ transplantation or active autoimmune disease requiring systemic immunosuppressive therapy. Physiologic hormone replacement or local therapy may be permitted.
• History of life-threatening immune-related toxicity from prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.
• 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.
• Clinically significant proteinuria, uncontrolled thyroid dysfunction, severe hepatic or renal impairment, or another condition that makes toripalimab plus axitinib unacceptably risky.
• Active infection requiring systemic treatment. Known active hepatitis B, hepatitis C, or HIV infection is evaluated according to institutional infectious-disease policy and protocol-defined risk assessment.
• Pregnancy or breastfeeding.
• Another active malignancy within 5 years, except an adequately treated malignancy with very low recurrence risk, such as selected carcinoma in situ or basal or squamous cell skin cancer, as determined by the investigator.
• Severe hypersensitivity to either study drug or its excipients.
• Inability, in the investigator's judgment, to comply with visits, oral treatment, blood-pressure monitoring, or imaging follow-up.
• No reasonable possibility of entering the planned deferred cytoreductive nephrectomy pathway after induction, or a pathologic subtype for which the clinically preferred immediate treatment is clearly incompatible with the study intervention.