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

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.