25 Phase II Trial of Sacituzumab Tirumotecan in Patients with SMARCB1-Deficient Renal Medullary Carcinoma Previously Treated with at Least One Prior Line of Therapy: STaRMC Trial (NCT07438626)

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Abstract Background SMARCB1-deficient renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma (RCC) that predominantly affects young individuals of African descent harboring sickle hemoglobinopathies (Msaouel et al. Clin Cancer Res 2018, PMID: 29440190). All cases are defined by loss of the SMARCB1 tumor suppressors, and most patients present with metastatic disease, with median overall survival of approximately 24 months (Lebenthal et al. Eur Urol Oncol 2025, PMID: 39013742). Unlike other RCCs, RMC is refractory to anti-angiogenic and mTOR-directed therapies as well as immune checkpoint inhibitors (Msaouel P. Future Oncol. 2026, PMID: 41777050). Cytotoxic chemotherapy yields responses in ∼29% of patients which are durable in less than 5% of patients, underscoring the urgent need for novel strategies. Our integrated molecular profiling of RMC tissues identified TROP2 as upregulated at the RNA and protein levels. RMC additionally shows marked upregulation of topoisomerases that buffers the replication stress induced by SMARCB1 loss, providing a distinctive mechanistic rationale for a topoisomerase 1-targeting payload in this disease. Supporting this, we clinically repurposed the first-generation TROP2 antibody-drug conjugate (ADC) sacituzumab govitecan in four heavily pretreated patients with RMC, with one patient achieving a partial response and two patients maintaining stable disease with symptom improvement (Msaouel et al. Cell Rep Med 2025, PMID: 41172996). Sacituzumab tirumotecan is a next-generation ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated via a stable linker to the topoisomerase 1 inhibitor KL610023, with a drug-antibody ratio of 7.4. We hypothesize that sacituzumab tirumotecan will produce a potent and durable antitumor response in patients with RMC who develop progressive disease on at least one prior line of therapy. Methods This is a phase II, single-arm, open-label, investigator-initiated study (NCT07438626). Eligible patients have locally advanced or metastatic SMARCB1-deficient RMC (or unclassified RCC with medullary phenotype) confirmed by expert pathology, progression on ≥ 1 prior line of therapy, ECOG PS 0-1, age ≥18 years, measurable disease per RECIST 1.1, and adequate organ function. Participants receive sacituzumab tirumotecan 4 mg/kg IV on days 1, 15, and 29 of each 42-day cycle until disease progression, unacceptable toxicity, or completion of 78 doses (∼3 years). Figure 1 presents the study schema. Up to 20 patients will be enrolled under a Bayesian framework with simultaneous monitoring of toxicity via the Bayesian Optimal Phase 2 (BOP2) design and of two efficacy endpoints—objective response rate (ORR) at any time and disease control rate (DCR) at 18 weeks per RECIST 1.1—via the time-to-event Bayesian Optimal Phase 2 (TOP) design. The regimen will be deemed promising if ORR is > 15% or DCR at 18 weeks is > 15%, with 71.4% power to detect a true ORR or DCR of 30% at a type I error rate of 15%. Interim safety and futility monitoring will occur after 10 patients. Secondary endpoints include overall survival, progression-free survival, duration of response, and grade ≥3 adverse events (CTCAE v6.0). Exploratory analyses will evaluate baseline tumor TROP2 expression as a potential biomarker of response. Longitudinal blood and optional tumor biopsies will be obtained for cytokine and immune-cell profiling, spatial transcriptomics, and TROP2 IHC to characterize mechanisms of response and resistance. These will be directly compared with analogous datasets from our prior RMC trials and preclinical models to enable cross-trial and cross-species biomarker integration in this rare disease. Results Significance and Vision: STaRMC is the first clinical trial of a TROP2-directed ADC specifically designed for RMC. Clinical and translational signals will (1) validate TROP2 as a therapeutic target in RMC, (2) establish ADCs as a new therapeutic class for this near-uniform fatal disease, and (3) inform combinatorial strategies and expansion to other SMARCB1-deficient malignancies. Conclusions N/A DOD CDMRP Funding Yes