Sacituzumab Tirumotecan vs MMAE-ADCs in Advanced Urothelial Carcinoma (FUSCC-SPARE-UC-01)

Peripheral Neuropathy Progression Rate (PNPR)

The PNPR is defined as the proportion of participants who experience their first occurrence of treatment-emergent peripheral neurotoxicity of Grade 2 or higher from the time of randomization until the end of treatment. Neurotoxicity severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, a 5-point ordinal scale ranging from Grade 1 (mild; asymptomatic or mild symptoms, clinical or diagnostic observations only) to Grade 5 (death related to adverse event). Higher grades indicate worse outcomes (i.e., more severe neurotoxicity). The difference in PNPR between treatment arms will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors specified in the protocol.

Percent Change in NCS Parameters

The NCS percentage change is calculated as the relative change in electrophysiological parameters from baseline to each post-baseline assessment. The formula used is: \[(Post-baseline Value - Baseline Value) / Baseline Value\] × 100%.

Cumulative Neurotoxicity Burden (CNB)

Cumulative Neurotoxicity Burden (CNB) quantifies total peripheral neurotoxicity exposure, incorporating both severity and duration. Neurotoxicity grades are assigned using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, a 5-point ordinal scale ranging from Grade 1 (mild) to Grade 5 (death); higher grades indicate worse outcomes. Two complementary CNB metrics are calculated: 1. Raw CNB: trapezoidal AUC of NCI-CTCAE grades plotted against time from randomization to end of treatment. Unit: grade-months. 2. Time-Standardized CNB (CNB-TS): Raw CNB divided by total observation duration, expressed as mean grade per unit time. CNB-TS = AUC / T(observation). This standardizes burden across participants with differing treatment durations. Higher values of both metrics indicate worse outcomes. Between-arm comparisons will use mixed-effects models adjusted for stratification factors.

Health-Related Quality of Life: EORTC QLQ-C30

Health-related quality of life (HRQoL) is assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), a 30-item validated cancer- specific questionnaire comprising 5 functional scales (physical, role, emotional, cognitive, social functioning), 3 symptom scales (fatigue, nausea/vomiting, pain), 6 single-item symptom assessments, and a global health status/quality of life scale. All scores are linearly transformed to a 0-100 scale. For functional scales and the global health status/QoL scale, higher scores indicate better functioning or better quality of life (better outcomes). For symptom scales and single items, higher scores indicate a higher level of symptom burden (worse outcomes). Mean changes from baseline in EORTC QLQ-C30 subscale scores will be compared between treatment arms using a mixed-effects model for repeated measures (MMRM), adjusted for stratification factors.

Chemotherapy-Induced Peripheral Neuropathy Symptoms: EORTC QLQ-CIPN20

Patient-reported peripheral neuropathy symptoms are assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20-item module (EORTC QLQ-CIPN20), a validated 20-item instrument designed to specifically capture sensory, motor, and autonomic symptoms of chemotherapy-induced peripheral neuropathy. Items are rated on a 4-point Likert scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate a higher level of peripheral neuropathy symptom burden (worse outcomes). Mean changes from baseline in EORTC QLQ-CIPN20 sensory, motor, and autonomic subscale scores will be compared between treatment arms using a mixed-effects model for repeated measures (MMRM), adjusted for stratification factors.

Serum Neurofilament Light Chain (sNfL) Levels

Serum neurofilament light chain (sNfL) is a blood-based biomarker of neuronal axonal injury. Elevated sNfL levels reflect ongoing axonal damage and have been validated as a biomarker for chemotherapy-induced peripheral neuropathy and other neurodegenerative conditions. sNfL concentration is measured in serum using a quantitative single-molecule array (Simoa) immunoassay. Results are reported in picograms per milliliter (pg/mL). Higher sNfL levels indicate greater axonal injury (worse neurological outcomes). Outcomes assessed include: (1) absolute sNfL concentration at each time point, (2) change from baseline in sNfL concentration, and (3) fold change in sNfL from baseline. Between-arm comparisons will be performed using mixed-effects model for repeated measures (MMRM) on log-transformed values.