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

Metastatic Non-Clear Cell Renal Cell Carcinoma, Metastatic Renal Medullary Carcinomas

Non-clear cell renal cell carcinoma, metastatic renal cell carcinoma, tertiary lymphoid structures, toripalimab, axitinib, deferred cytoreductive nephrectomy, Metastatic Renal Medullary Carcinomas

This Phase II study will evaluate toripalimab plus axitinib in adults with previously untreated, synchronous metastatic non-clear cell renal cell carcinoma and renal medullary carcinomas whose primary kidney tumor remains in place and whose baseline tumor biopsy contains a tertiary lymphoid structure. All participants will receive toripalimab and axitinib for approximately 12 weeks. At Week 12, an independent multidisciplinary team will review treatment response, overall disease burden, fitness for surgery, technical resectability, and participant preference. Deferred cytoreductive nephrectomy will be performed only when it has an independent clinical indication; it is not mandatory and is not assigned at random. Participants who do not undergo surgery will remain in the study for clinical follow-up. The study will estimate the proportion of eligible surgical participants who remain free of progression or death 24 weeks after surgery and will evaluate whether the functional state of tertiary lymphoid structures in the treated primary tumor is associated with control of residual metastatic disease. Peripheral blood will be used to track T-cell and B-cell receptor clonotypes. Postoperative blood for this purpose will be collected only at 3 months, and disease progression.

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.

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