A plain language summary of the TROPiCS-04 study: sacituzumab govitecan use after platinum-based chemotherapy and immunotherapy in people with locally advanced or metastatic cancer of the bladder, urethra, or upper urinary tract

TPS4611 Background: SG is a Trop-2–directed antibody-drug conjugate. In the TROPHY-U-01 study, SG monotherapy showed a 27% objective response rate (ORR) and 10.9 months median overall survival (OS) with an overall manageable safety profile in pts with mUC who received platinum (PT)-containing chemotherapy and a checkpoint inhibitor (CPI), resulting in accelerated FDA approval in this population. PT-based chemotherapy followed by avelumab maintenance is standard 1L therapy in pts with Tx-naïve mUC. Zim (anti–PD-1) is a CPI under clinical investigation for antitumor activity. C4 of TROPHY-U-01 will evaluate safety, tolerability, and clinical activity of SG+cis followed by maintenance avelumab+SG or zim+SG in cis-eligible pts with Tx-naïve mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 study. C4 will evaluate 1L SG in combination with cis in pts with cis-eligible mUC or unresectable locally advanced disease. Eligibility requirements include ECOG PS 0-1; no prior anticancer monoclonal antibody within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic and hepatic function. Pts will be treated with cis at 70 mg/m2 on D1 of 21-D cycles (if creatinine clearance [CrCl] ≥60 mL/min) or at an optional split dose of 35 mg/m2 on D1 and D8 of 21-D cycles (if CrCl 50-59 mL/min), followed by SG (5, 7.5, or 10 mg/kg, based on 10-pt safety lead-in of a 3+3 design) on D1 and D8 of 21-D cycles. Granulocyte colony-stimulating factor support is not allowed in the safety lead-in but was permitted during escalation and expansion. SG+cis will continue for up to 6 cycles, followed by maintenance (4 to 8 wk after last induction dose of SG+cis and when RP2D is determined) in the absence of progression. Dose escalation maintenance consists of avelumab 800 mg q2w, then SG 10 mg/kg on D1 and D8 of 21-D cycles. Dose expansion maintenance consists of zim 360 mg (D1 of a 21-D cycle) and SG 10 mg/kg (D1 and D8 of 21-D cycles) and will begin once safety lead-in of 6-8 pts receiving zim+SG of a 21-D cycle in Cohort 5 is deemed safe and completed. Pts will continue Tx until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per RECIST v1.1 by central review. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per central review and investigator assessment. OS and safety will also be evaluated. All statistical analyses will be performed using a two-sided hypothesis test approach at the overall 5% level of significance. Time to event endpoints will be assessed via the Kaplan-Meier method. Enrollment is ongoing; up to 57 pts expected across ~120 sites in North America and Europe. Clinical trial information: NCT03547973 .

Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment for certain types of advanced or metastatic breast cancer. One common type of breast cancer has at least 1 of 2 hormone receptors (HR positive) and does not have human epidermal growth factor 2 (HER2 negative). The HR and HER2 receptors are known to influence how severe a case of breast cancer is. Certain treatments will only work if a specific receptor is present on breast cancer cells. HR-positive/HER2-negative advanced or metastatic breast cancer can be treated with sacituzumab govitecan. This is a summary of the results of the TROPiCS-02 study. This study compared sacituzumab govitecan with standard chemotherapy in participants with HR-positive/HER2-negative advanced or metastatic breast cancer. The study showed that participants treated with sacituzumab govitecan lived significantly longer without their cancer getting worse than participants treated with chemotherapy. Participants also survived significantly longer and their tumors became significantly smaller in more participants treated with sacituzumab govitecan than with chemotherapy. In general, participants treated with sacituzumab govitecan were more likely to have side effects and had more severe side effects. These side effects included low levels of a type of white blood cell known as neutrophils and diarrhea. Oncologists (doctors that treat cancer) know of these side effects as they are common among people being treated for cancer. Doctors can control these side effects by following standard treatment guidelines and the package insert for sacituzumab govitecan. Participants treated with sacituzumab govitecan maintained their sense of well-being and ability to do daily activities (quality of life) longer than participants treated with chemotherapy. It also took longer for fatigue and other symptoms of cancer to worsen in participants treated with sacituzumab govitecan compared with chemotherapy. Sacituzumab govitecan is more effective than standard chemotherapies for people who have already received multiple treatments for HR-positive/ HER2-negative advanced breast cancer. The side effects from sacituzumab govitecan could generally be managed well by doctors. Although there were more side effects with sacituzumab govitecan than with chemotherapy, they were generally mild to moderate.

SummaryWhat is this summary about?Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan.What are the key takeaways?All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan.What were the main conclusions reported by the researchers?The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1)

667 Background: SG is approved in pts with aUC refractory to platinum-based chemotherapy (PBT) and checkpoint inhibitor therapy (CPI). Data on SG outcomes in pts with subtype/variant histologies (VH) are limited. We examined SG-treated pts in the UNITE study and hypothesized that outcomes would be similar between pts with pure urothelial histology (pUC) and any VH component. Methods: UNITE is a multi-site retrospective study of pts with aUC treated (Tx) with targeted agents, such as enfortumab vedotin (EV) and SG. Pts who received SG monotherapy were included in this analysis. Observed response rate (ORR) was assessed by investigators at each site for evaluable pts with scans after ≥ 1 SG cycle using χ2 and logistic regression. Progression-free and overall survival (PFS, OS) from SG start were assessed using KM method and Cox proportional hazards model. Results: Among 633 total pts in UNITE, 116 received SG monotherapy at 11 US sites. Median age was 70; 79 (68%) male; 97 (84%) Caucasian; 86 (74%) ECOG PS 0/1; 84 (72%) lower tract tumor; 90 (78%) visceral or bone mets; 48 (41%) Bellmunt score ≥2; 72 pts (62%) had pUC and 44 (38%) VH, including 33 (28%) with UC predominant (<50% VH) and 11 (9%) with variant predominant (≥50% VH). For prior therapy, 109 pts (94%) received >2 prior lines; 75 (65%) PBT; 102 (88%) CPI; 109 (94%) EV. Median time from metastatic diagnosis to SG start was 18.6 months (mo) (0.9-84.5). Median follow up from SG start was 10.6 mo (8.5-15.4). Median time on SG was 1.6 mo (0.2-14.7). ORR to SG was 24% (20/84); median PFS and OS from SG start were 3.7 mo (95% CI 3.0-4.6) and 6.7 mo (95% CI 5.3-10.8). VH (n ≥1) included: squamous (SQH) (19, 16%), micropapillary (9, 8%), plasmacytoid (8, 7%), adenocarcinoma (3, 3%), neuroendocrine (NE) (2, 2%). In evaluable pts with VH, ORRs: squamous (3/14), micropapillary (1/4), plasmacytoid (0/6), adenocarcinoma (2/3), NE (1/2). No significant differences were observed in outcomes between pUC and any VH or pUC and SQH (Table). Conclusions: Pts with aUC treated with SG appear to have similar clinical outcomes between pUC and any VH. Responses to SG are observed across different VH. Limitations include low power, tumor heterogeneity, lack of central pathology/scan review, selection and confounding biases. These hypothesis-generating findings suggest activity of SG post-PBT, CPI, and EV in pts with VH, but should be validated in larger cohorts with adequate sample size of specific VH and longer follow up. [Table: see text]

523 Background: In the TROPHY study, 8.8% of the 113 patients (pts) were enrolled post EV treatment, with ORR to SG of 30% in that small subset. Response to SG post EV in real world populations has not been previously reported. SG has accelerated FDA approval for treatment refractory UC, with ORR of 27% in the TROPHY-U-01 trial. SG was developed contemporaneously to EV, which like SG, is also an antibody-drug conjugate (ADC), composed of an alternate antibody linker and chemotherapy payload. The EV ORR is 40-52% in single agent studies, and outcomes following SG to EV have not been reported. Optimal therapy sequence for advanced UC, concerns for cross resistance between ADCs and other targeted therapies, and biomarker selection for agents is underexplored. We describe clinical outcomes in pts with advanced UC treated with SG following EV. Methods: In this retrospective study of pts with UC treated with SG after progression on EV at the Johns Hopkins Greenberg Bladder Cancer Institute between November 2020 and October 2022, 17 pts were identified. Fourteen received SG in the next line following EV, 3 had other interval therapies between EV and SG. Response was determined by physician assessed RECIST criteria. All pts were response evaluable for prior EV. Three pts died shortly after C1 SG without imaging and were not response evaluable. Results: In our cohort 8 (47%) pts were female, 3 (17.6%) were African-American and 14 (82.4%) were Caucasian. Mean age was 68.3 years. Primary location was bladder for 9 (52.9%) pts and UTUC for 7 (41.2%). One (5.9%) patient had disease in both primary sites. Two (11.8%) pts had lymph node only disease, 8 (47.1%) had metastatic disease in the lungs, 6 (35.3%) in the liver and 1(5.9%) in bone. Mean number of EV cycles was 5.9 (1-12) and PFS was 5.9 months. Best EV response was CR in 1 (5.9%), PR in 10 (58.8%), SD in 2 (11.8%) and PD in 4 (23.5%) pts. SG was dose reduced in C1 with prophylactic growth factor support in 13/17 pts in this heavily pretreated population. Mean number of SG cycles was 3.8 (1.5-6). Best SG response for the 14 response evaluable pts was PR for 3 (21.4%) pts and SD for 3 (21.4%), for a clinical benefit (CR+PR+SD) rate of 42.8%. Eight pts had best response of PD (57.1%). SG discontinuation was for PD in 8 pts (57.1%) and 4 (28.6%) due to functional decline or toxicity. One patient had PD to SG in C2 but received 3 additional cycles due to therapeutic benefit. Three (21.4%) pts continue SG, after 6 cycles with PR and after 5 and 4 cycles with SD. For 14 response evaluable pts, the PFS on SG was 2.4 months. Conclusions: In this retrospective analysis, pts with advanced UC and PD following EV had meaningful clinical benefit rate to SG of 42.8% despite dose reduction in this small late line cohort. Defining optimal sequence of ADCs and other therapies in UC remains an unmet need. Updated data will be presented.

Background: SG and Dato-DXd are antibody drug conjugates (ADCs) used in aBC. Both target humanized anti-trophoblast cell-surface antigen 2 (TROP2) and both have a similar (irinotecan-based) payload. There are few comparative data on these drugs. Methods: We searched MEDLINE, as well as proceedings from ASCO, ESMO and SABCS. Eligible studies were trials (dose expansion phase 1, phase 2 or 3) that evaluated Dato-DXd or SG in aBC patients. Safety (adverse effects [AE]) data were pooled as the mean, weighted by individual study sample size and indirect comparisons were performed using the test of two proportions (z score). For randomized trials of ADCs compared to chemotherapy, we performed a network metanalysis (using WINBUGS within Microsoft Excel) and report the hazard ratio (HR) for efficacy (overall survival [OS], progression free survival [PFS]) and odds ratio (OR) for AEs comparing Dato-DXd to SG. Statistical significance was defined as p<0.05. Results: Nine studies were included in the analysis, 3 for Dato-DXd and 6 for SG. A total of 450 patients were treated with Dato-DXd and 831 with SG. Median prior lines of treatment were 1 (range 1-6) for Dato-DXd and 4 (range 0-7) for SG. There were no significant differences in discontinuation due to toxicity (OR 0.97; 95% confidence interval [CI] 0.38-2.48)) or in toxic deaths (OR 1.11; 95% CI 0.15-8.34). Similarly, there were no significant differences in PFS (HR 0.95; 95% CI 0.71-1.28) or in OS (HR 1.06; 95% CI 0.74-1.53). Comparison of individual AEs between Dato-DXd and SG demonstrated the following: all grade AE (94.8% vs 100%, p < 0.01), grade≥ 3 AE (20.7% vs 75%, p< 0.01) and dose reduction (19.5% vs 26%, p=0.01). Ocular AE(all grade, 25.2%; grade ≥3, 1%), infusion reaction (all grade, 11.8%) and interstitial lung disease (ILD, all grade, 2.6%; grade ≥3 1%) were reported only with Dato-DXd, whereas febrile neutropenia (5.6%) and neuropathy (all grade, 11.8%; grade ≥3, 0.7%) were reported only with SG. SG showed more frequent hematological toxicities: anemia (grade ≥3, 1.7% vs 19%, p<0.01), neutropenia (grade ≥3, 1% vs 49%, p<0.01) and thrombocytopenia (grade ≥3, 0% vs 1.6%). SG was associated with more diarrhea (16.5% vs 58%, p<0.01, grade ≥3[SG only], 9.2%) while stomatitis was seen more with Dato-DXd (60.1% vs 11.9%, p<0.01; grade ≥3, 6.9% vs 1.4%, p<0.01). Alopecia (36% vs 45.6%, p<0.01) and fatigue (27% vs 46.7%, p<0.01; grade ≥3, 2.5% vs 5%, p=0.03) were more common with SG. Risk of grade 3 nausea and vomiting, as well as skin related AEs and dyspnea were similar. Conclusions: Both Dato-DXd and SG have similar risk of discontinuation without progression and toxic death. The side effect profile of SG is driven by hematological toxicities. AEs such as ILD, ocular and infusion reactions appear unique to Dato-DXd. Febrile neutropenia, neuropathy and fatigue were observed predominantly with SG. Among GI AEs, stomatitis is prominent for Dato-DXd and diarrhea with SG. There does not appear to be any meaningful difference in efficacy. These results may inform choice of therapy in clinical practice. Citation Format: Neha Pathak, Sudhir Kumar, Yael Berner-Wygoda, Abhenil Mittal, Diego Malon, Massimo Di Iorio, Jacqueline Savill, Consolacion Molto Valiente, Meredith Li, Michelle Nadler, Eitan Amir. Indirect comparison of sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) in advanced breast cancer (aBC): safety and efficacy analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-02-02.

Patients with recurrent or metastatic endometrial cancer who have progressed on or after platinum-based chemotherapy and PD-(L)1 inhibitor therapy have limited treatment options and a poor prognosis. Sacituzumab govitecan is a trophoblast cell-surface antigen 2-directed antibody-drug conjugate approved for certain types of breast cancer. In the phase II TROPiCS-03 trial, sacituzumab govitecan demonstrated encouraging efficacy and manageable safety in heavily pretreated patients with advanced or metastatic endometrial cancer. The ASCENT-GYN-01 trial aims to assess the efficacy and safety of sacituzumab govitecan versus treatment of the physician's choice in patients with endometrial cancer who have received platinum-based chemotherapy and PD-(L)1 inhibitor therapy. The primary objective is to compare the effect of sacituzumab govitecan versus treatment of the physician's choice on progression-free survival, assessed by blinded independent central review, and on overall survival. Patients with pretreated recurrent or persistent endometrial cancer will have improved progression-free survival and overall survival with sacituzumab govitecan compared with treatment of the physician's choice. ASCENT-GYN-01 (ClinicalTrials.gov identifier NCT06486441) is a randomized, open-label, global phase III study. Patients will be randomized in a 1:1 ratio to receive sacituzumab govitecan or treatment of the physician's choice (doxorubicin or paclitaxel). Patients aged 18 years and older with documented evidence of recurrent or persistent endometrial cancer (endometrial carcinoma or carcinosarcoma) will be enrolled. Up to 3 prior lines of systemic therapy for endometrial cancer are allowed, including platinum-based chemotherapy and PD-(L)1 inhibitor therapy, either in combination or separately. Key exclusion criteria include uterine leiomyosarcoma or endometrial stromal sarcomas and prior treatment with a trophoblast cell-surface antigen 2-directed antibody-drug conjugate or topoisomerase I inhibitor. Dual primary endpoints are progression-free survival assessed by blinded independent central review and overall survival. Approximately 640 patients. June 2029. NCT06486441; GOG-3104; ENGOT-en26; APGOT-EN2.

4581 Background: SG is a TROP-2 directed antibody-drug conjugate (ADC) approved as advanced-line treatment for mUC after platinum-based chemotherapy and a checkpoint inhibitor, based on phase II study (TROPHY-U-01) that demonstrated objective response rate (ORR) of 28%, median progression free survival (PFS) of 5.4 months (mo) and median overall survival (OS) of 10.9 mo. Current guidelines for mUC endorse using SG in post EV setting, more so with the recent FDA approval of EV and pembrolizumab as the new standard of care for 1st line. Data is scarce regarding the efficacy of SG in patients previously treated with EV, as only 10 patients (8.8%) included in TROPHY-U-01 cohort 1 had prior EV exposure. Here, we report real-world clinical outcomes for SG post EV. Methods: This is a single center retrospective cohort of patients with mUC treated with SG after prior exposure to EV. Demographics and clinical data were collected retrospectively by chart review. Clinical response to SG and EV was defined by physician assessment. Cases with objective response to SG per clinical review [complete response (CR) + partial response (PR)] were then confirmed by formal radiological evaluation using RECIST 1.1. PFS and OS defined from start of SG were calculated using the Kaplan-Meier method. Results: 82 patients were identified, median age was 71 years (range 47-83), 70% male and 37% upper tract primary. Lung, bone, liver and brain metastases were present in 67%, 62%, 50% and 13% of patients, respectively. Median prior treatment lines were 3 (range 1-8), 68% of patients received SG directly post EV. Most patients were treated with single agent EV, though 8 patients (10%) received combination of EV + pembrolizumab. PR was confirmed in 8 patients, and none had CR, resulting in an ORR of 10% (95% CI 4.3%, 18.3%). Stable disease (SD) was achieved in 16 patients (20%, 95% CI 11.9%, 30.4%) amounting to disease control rate (DCR = CR+PR+SD) of 30% (95% CI 20.3%, 41.3%). Median PFS was 2.1 mo (95% CI 1.9, 2.5) and median OS was 6.0 mo (95% CI 4.5, 7.0). There was no association between response to EV and ORR, PFS or OS after SG (p>0.8). Sequencing SG directly after EV was associated with improved ORR (p = 0.028) and PFS (HR=0.43, 95% CI 0.21, 0.87, p=0.02, adjusted for tumor location, treatment line and liver metastasis) but not OS. Dose reductions were required upfront in 18%, on treatment in 44% or both in 7%. Prophylactic granulocyte stimulating factor (GCSF) was used in 57 patients (70%), rates of G3-4 neutropenia, anemia and thrombocytopenia were 36%, 36% and 4% respectively. Conclusions: In our large cohort of real-world advanced mUC patients with prior exposure to EV, SG resulted in limited clinical efficacy compared to previous reports. There was an association between SG administration directly after EV and improved clinical outcomes. Further investigations are warranted to explore optimal treatment sequencing.

4579 Background: Patients (pts) with mUC have an estimated 5-year overall survival (OS) rate of 14%. Trop-2 is a transmembrane glycoprotein with elevated expression in many cancers, including UC. SG is a Trop-2–directed antibody-drug conjugate with accelerated FDA approval for pts with LA unresectable or mUC who previously received platinum (PT) and a checkpoint inhibitor (CPI). SG has demonstrated activity in 3 phase 2 TROPHY-U-01 mUC cohorts: Cohort 1 (C1), 28% objective response rate (ORR); Cohort 2 (C2), 32% ORR; and Cohort 3 (C3), 41% ORR. Here, we assess efficacy outcomes in C1-3 by Trop-2 archival tumor expression. Methods: Pts (≥18 years) with previously treated (PT [C3], CPI [C2], or both [C1]) LA or mUC received SG (10 mg/kg IV) on D1 and D8 of 21-D cycles; C3 pts also received pembrolizumab (200 mg) on D1 of 21-D cycles. The primary endpoint was ORR by independent review. Archival tumor samples collected at enrollment were assessed for Trop-2 protein expression using SP295 anti–Trop-2 antibody by IHC with assessment by histological scores (H-scores; scale, 0-300) and % of membrane-positive tumor cells (Roche Tissue Services). Trop-2 association with clinical endpoints was evaluated using unstratified Cox proportional hazards models for survival data and logistic regression for ORR. Results: At data cutoff, 192 pts were enrolled in C1-3; 144 pts (75%) had samples evaluable for Trop-2 prevalence and 139 pts (72%) were evaluable for efficacy analysis by Trop-2 expression (5 pts not assigned to any cohort were excluded). Baseline characteristics for pts with evaluable samples were consistent with the overall population. Median (IQR) Trop-2 H-score and % of membrane-positive tumor cells for evaluable pt samples were 215 (180-247) and 92% (75-98), respectively; these readouts were highly correlated (ρ=0.82, P<0.001). ORRs for C1 samples with below (n=42) and above (n=45) median Trop-2 H-scores were 24% and 29% ( P=0.59), respectively; median progression-free survival (PFS) was 3.4 and 6.7 months (HR=0.765, P=0.262), respectively; and median OS was 9.9 and 10.9 months (HR=0.978, P=0.927), respectively. Median PFS for C1 samples with below and above median Trop-2 membrane positivity were 3.9 and 6.2 months (HR=0.835, P=0.443), respectively. Analyses of efficacy endpoints for C2 and C3 pt samples by Trop-2 expression were consistent with C1 results. Conclusions: In this analysis of archival tumor samples from pts with pretreated LA or mUC, Trop-2 protein was highly expressed across cohorts, supporting prior Trop-2 expression analyses in UC. Similar outcomes were observed between C1 pts with samples that were below and above median Trop-2 H-score with most pronounced numerical differences observed for PFS. These results suggest that SG activity may be independent of Trop-2 expression in UC, but additional studies are needed to confirm these results. Clinical trial information: NCT03547973 .

4514 Background: SG, a Trop-2–directed antibody-drug conjugate, was granted FDA accelerated approval for pts with mUC previously treated with PT-based chemotherapy and a CPI. Approval was based on the pivotal TROPHY-U-01 Cohort 1 study of 113 pts, where SG demonstrated an objective response rate (ORR) of 27%, a median overall survival (OS) of 10.9 mo, and a manageable safety profile (median follow up 9.1 mo [range, 0-19.9], Tagawa et al. JCO 2021). A phase 3 confirmatory study TROPiCS-04 (NCT04527991) is ongoing. Here, we report updated safety outcomes by UGT1A1 status. Methods: Cohort 1 pts were ≥18 y, had progression of UC following PT and a CPI, and ECOG PS 0-1. Pts received SG 10 mg/kg on D1 and D8 of 21-D cycles (growth factor was allowed per investigator discretion). The primary endpoint was ORR per central review by RECIST 1.1. Post hoc safety analyses were exploratory with descriptive statistics reported. Results: As of July 26, 2022, the median follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts were heavily pretreated with a median of 3 prior therapies (78% male; median age 66 y; 66% with visceral metastases). Known baseline comorbidities included chronic kidney disease (12%), coronary artery disease (10%), myocardial infarction (8%), and diabetes mellitus II (8%). Grade (Gr) ≥3 treatment-related adverse events (TRAEs) occurrence and treatment-related discontinuation were consistent with prior reports. In total, 94% of treated pts (n=106) had evaluable UGT1A1 status (wild-type [*1|*1], n=45 [42%]; heterozygous [*1|*28], n=47 [44%]; and homozygous [*28|*28], n=14 [13%]). Gr ≥3 TRAEs occurred in 62% of wild-type, 60% of heterozygous, and 79% of homozygous pts. The incidence of treatment-related any Gr diarrhea was 53%, 72%, and 71%, respectively; any Gr neutropenia was 38%, 55%, and 50%, respectively; and any Gr anemia was 38%, 32%, and 29%, respectively. The incidence of treatment-emergent Gr ≥3 diarrhea was 4%, 15%, and 7%, respectively; Gr ≥3 neutropenia was 31%, 36%, and 50%, respectively; and Gr ≥3 anemia was 13%, 19%, and 29%, respectively. TRAEs led to SG discontinuation in 7%, 6%, and 14% of pts with wild-type, heterozygous, and homozygous status, respectively; incidence of SG interruption was 42%, 43%, and 71%, respectively and incidence of SG dose reduction was 38%, 34%, and 43%, respectively. Conclusions: With longer follow-up, SG safety profile was consistent with prior reports. The incidence of adverse events varied across UGT1A1 subgroups, with dose interruptions being more frequently observed in homozygous pts. This was an exploratory analysis with relativity low numbers in each subgroup. Additional studies are needed to confirm the impact of UGT1A1 status on safety outcomes with SG in UC. Clinical trial information: NCT03547973 .

4501 Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC without progression following 1L platinum-based chemotherapy (PBC). The JAVELIN Bladder Medley phase 2 trial is investigating the combination of avelumab with other antitumor agents in this pt population to assess efficacy and safety vs avelumab maintenance monotherapy. SG is a Trop-2–directed antibody and topoisomerase inhibitor drug conjugate being investigated in solid tumors. Here we report an interim analysis of avelumab + SG vs avelumab monotherapy. Methods: Eligible pts had unresectable locally advanced or metastatic UC, ECOG performance status (PS) 0-1, and no disease progression after 4-6 cycles of 1L PBC. Pts were randomized 2:1 to avelumab + SG or avelumab monotherapy, stratified by presence of visceral metastases at start of 1L PBC. Primary endpoints were investigator-assessed PFS and safety; OS was a secondary endpoint. For PFS and OS analyses, data in the avelumab monotherapy arm were extended per protocol using propensity score-weighted JAVELIN Bladder 100 data. Results: At data cutoff (Sep 16, 2024), 38 of 74 pts (51.4%) in the avelumab + SG arm and 10 of 37 pts (27.0%) in the avelumab monotherapy arm were still receiving study treatment. In the avelumab + SG and avelumab monotherapy arms, respectively, median age was 70 and 67 years, 50.0% and 51.4% had visceral metastases at start of 1L PBC, and a lower proportion of pts in the avelumab + SG arm had ECOG PS of 1 (31.1% vs 54.1%). Median PFS was 11.17 months (95% CI, 7.43-not estimable [NE]) with avelumab + SG vs 3.75 months (95% CI, 3.32-6.77) with avelumab monotherapy (hazard ratio [HR], 0.49 [95% CI, 0.31-0.76]). OS data were immature at cutoff; median OS was not reached (95% CI, 15.51-NE) in the avelumab + SG arm vs 23.75 months (95% CI, 18.79-30.82) in the avelumab monotherapy arm (HR, 0.79 [95% CI, 0.42-1.50]). In the avelumab + SG and avelumab monotherapy arms, respectively, treatment-related adverse events (TRAEs) of any grade occurred in 71 (97.3%) vs 23 pts (63.9%), and were grade ≥3 in 51 (69.9%) vs 0 pts. TRAEs led to discontinuation of both avelumab + SG in 4.1% (SG only in 12.3%) vs avelumab monotherapy in 2.8%. One pt in the avelumab + SG arm had a SG-related AE that led to death (acute subarachnoid hemorrhage in the setting of sepsis and pancytopenia). Conclusions: In pts with aUC without progression after 1L PBC, avelumab + SG as maintenance treatment improved PFS vs avelumab monotherapy. TRAEs were more frequent in the combination arm and were consistent with the known safety profile of SG and avelumab. Further investigation of avelumab in combination with anti–Trop-2 antibody-drug conjugates in aUC is warranted. Clinical trial information: NCT05327530 .

520 Background: Pts with PT-ineligible mUC have limited treatment options following CPI therapies; thus, new treatment options are needed. SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 for pts with mUC who progressed after PT and CPI therapies based on the positive results of the pivotal TROPHY-U-01 Cohort 1 study. In Cohort 1, SG demonstrated an objective response rate (ORR) of 27%, a median overall survival (OS) of 10.9 mo, and a manageable safety profile in 113 pts with locally advanced or mUC (Tagawa, et al. J Clin Oncol. 2021). SG demonstrated an ORR of 28% in PT-ineligible pts with mUC who progressed after CPI therapy in preliminary results of the phase 2 TROPHY-U-01 Cohort 2 study (Petrylak et al. J Clin Oncol. 2020). Here, we report the primary analysis of TROPHY-U-01 Cohort 2. Methods: Cohort 2 pts (≥18 y) were PT-ineligible at screening, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG on D1 and D8 of 21-day continuous cycles. The primary endpoint was ORR per central review by RECIST 1.1. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS), per central review, and OS. Target enrollment was approximately 40 pts. Assuming the second-line ORR of 40%, 40 pts would give a 95% CI with a lower limit of 25% (CI is 0.25 to 0.57) for ORR. Results: As of July 26, 2022, the median follow-up was 9.3 mo (range, 0.5-30.6) for treated pts (N=38); median age, 72.5 y (range, 41-87), 61% male, 50% ECOG PS 1, and 66% visceral metastases (29% liver). Median number of prior therapies was 2 (range, 1-5); 50% received prior (neo)adjuvant PT, 18% received prior enfortumab vedotin, and 3% received prior erdafitinib. Median time since last prior anticancer therapy was 1.6 mo (range, 1-8) and median duration of last prior anticancer therapy was 4.2 mo (range, 1-12). Per central review, ORR was 32% (95% CI, 17.5-48.7; 32% partial response); median DOR was 5.6 mo (95% CI, 2.8-13.3; n=12); and median PFS was 5.6 mo (95% CI, 4.1-8.3). Median time to response was 1.4 mo (range, 1.3-1.5) and median OS was 13.5 mo (95% CI, 7.6-15.6). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 68% of pts; the most common Grade ≥3 TRAEs were neutropenia (34%), anemia (21%), leukopenia (18%), fatigue (18%), and diarrhea (16%). TRAEs resulted in an 18% discontinuation rate. No treatment-related deaths were reported. Conclusions: SG monotherapy demonstrated a high response rate with an overall manageable safety profile in PT-ineligible pts with mUC who progressed after CPI therapy. No new safety signals were observed. These data support further evaluation of SG in pts with mUC post CPI therapy. Clinical trial information: NCT03547973 .

518 Background: Pembro is standard of care for pts with mUC who progress after 1L PT therapy but only ~21% of pts respond, highlighting an unmet need (Bellmunt, et al. NEJM. 2017). SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In Cohort 1 of the TROPHY-U-01 study, SG demonstrated a 27% objective response rate (ORR) with manageable safety in 113 pts with locally advanced or mUC who previously received PT and a checkpoint inhibitor (CPI; Tagawa, et al. J Clin Oncol. 2021), leading to accelerated FDA approval in this pt population. Preliminary results of the phase 2 TROPHY-U-01 Cohort 3 study showed that SG plus Pembro demonstrated a high ORR (34%) as a 2L therapy in 41 CPI-naive pts with mUC who progressed after PT (Grivas et al. J Clin Oncol. 2021). Here we present the primary analysis of Cohort 3. Methods: Cohort 3 pts (≥18 y) had progression of mUC following PT in the metastatic setting or following ≤12 mo of PT in the (neo)adjuvant setting and ECOG PS 0-1. Pts received 10 mg/kg of SG on D1 and D8 and 200 mg of Pembro on D1 of a 21-D cycle for ≤2 y. The primary endpoint was ORR [complete response (CR) + partial response (PR)] per central review by RECIST 1.1. Secondary endpoints include clinical benefit rate [CBR; CR + PR + stable disease for at least 6 mo], duration of response (DOR) and progression-free survival (PFS) per central review; and safety. Target enrollment was approximately 41 pts based on a Simon two-stage design for 90% power at one-sided α of 0.05 to demonstrate 21% improvement in ORR, with a null hypothesis of historical ORR ≤20% and an alternate hypothesis of ORR ≥41%. Results: As of July 26, 2022, median follow-up was 12.5 mo (range, 0.9-24.6) for treated pts (N=41); median age, 67 y (range, 46-86), 83% male, 61% ECOG PS 1, 76% ≥1 Bellmunt risk factors, and 78% visceral metastases (29% liver). Median duration of last prior anti-cancer therapy was 2.7 mo (range, 0-13). Per central review, ORR was 41% (95% CI, 26.3-57.9; 20% CR); CBR was 46% (95% CI, 30.7-62.6); median DOR was 11.1 mo (95% CI, 4.8-NE [not estimable]; n=17); and median PFS was 5.3 mo (95% CI, 3.4-10.2). Median time to response was 1.4 mo (95% CI, 1.3-2.7) and median OS was 12.7 mo (95% CI, 10.7-NE). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 61% of pts; most common Grade ≥3 TRAEs were neutropenia (37%; 10% febrile neutropenia), leukopenia (20%), and diarrhea (20%). TRAEs led to a 15% discontinuation rate. Systemic steroid and G-CSF use were both 34%. No treatment-related death occurred. Conclusions: SG plus Pembro demonstrated a high ORR and CBR with a manageable safety profile in 2L mUC in CPI-naive pts who progressed after PT-based therapy. No new safety signals were observed with the combination. These data support further evaluation of SG plus CPI in mUC. Clinical trial information: NCT03547973 .

8599 Background: EVOKE-01 (NCT05089734) assessed the efficacy and safety of SG vs docetaxel in pts with mNSCLC that progressed after platinum-based chemotherapy and anti–PD-(L)1 (IO) treatment. The study did not meet statistical significance for overall survival (OS) at final analysis. Here, we report updated survival and safety outcomes after longer follow-up, providing insight into the tolerability of SG over a prolonged period of administration. Methods: Pts were randomized 1:1 to receive SG (n = 299; 10 mg/kg IV, days 1 and 8) or docetaxel (n = 304; 75 mg/m 2 IV, day 1) in 21-day cycles until progression or unacceptable toxicity. OS was the primary endpoint, while safety was a key secondary endpoint. Results: As of Oct 21, 2024, median follow-up was 23.5 months. Median exposure with SG vs docetaxel was 3.5 vs 2.3 months; 33.4% vs 17.7% of pts, respectively, were exposed to study drug for ≥6 months. The longer follow-up preserved the numerical improvement in OS favoring SG in the intent-to-treat population (HR 0.89, 95% CI: 0.74–1.07; P = .1028) and in subgroups of interest, including nonresponders to prior IO, and across squamous and nonsquamous histologies ( Table ). Most common any-grade treatment-emergent adverse events (TEAEs) with SG vs docetaxel were fatigue (57.8% vs 56.6%), diarrhea (52.7% vs 33.7%), and alopecia (43.6% vs 30.2%). In line with the primary analysis, 68.6% vs 76.0% of pts receiving SG vs docetaxel experienced grade ≥3 TEAEs, mainly neutropenia (25.3% vs 36.8%), fatigue (12.5% vs 9.7%), and diarrhea (10.5% vs 3.8%). Discontinuations due to TRAEs were seen in 7.4% vs 14.2% of pts receiving SG vs docetaxel. There were no additional AEs leading to death reported with longer follow-up (Table). Conclusions: Consistent with the final analysis, SG showed a numerical improvement in OS vs docetaxel. Long-term safety showed SG is well tolerated, consistent with minimal increase in AE rates since prior report and an improved safety profile over docetaxel, despite longer treatment exposure. Clinical trial information: NCT05089734 . Median OS, mo (95% CI) HR (95% CI) SG Doc Nonresponsive (SD/PD) to last IO n = 19211.8 (9.6–12.8)0.83 (0.66–1.04) n = 1918.3 (6.9–10.2) Responsive (CR/PR) to last IO n = 1069.7 (8.4–14.3)1.05 (0.78–1.43) n = 11310.8 (9.2–12.8) Squamous n = 8410.3 (8.1–13.2)0.89 (0.63–1.25) n = 809.2 (6.9–11.0) Nonsquamous n = 21511.6 (9.4–12.9)0.89 (0.72–1.11) n = 2249.9 (7.9–11.2) With prior therapy for AGA n = 1912.9 (7.2–23.9)0.63 (0.31–1.29) n = 257.0 (5.2–11.6) TEAE, % (safety population)Any gradeGrade ≥3Serious TEAEsLeading to dose reductionLeading to discontinuationTRAEs leading to discontinuationLeading to deathTRAEs leading to death n = 296 99.768.647.629.710.17.43.41.4 n = 288 98.376.044.439.216.714.24.21.0

LBA1001 Background: HR+/HER2– disease is the most common subtype of metastatic breast cancer (MBC). Treatment includes sequential endocrine therapy combined with targeted agents followed by single-agent chemotherapy, with increasingly shorter durations of benefit. SG is an anti–Trop-2 antibody-drug conjugate approved for metastatic triple-negative breast cancer with ≥2 prior therapies (≥1 for MBC). The HR+/HER2– MBC cohort of the phase 1/2 IMMU-132-01 study (n = 54) had an objective response rate (ORR) of 31.5%, median progression-free survival (PFS) of 5.5 mo, median overall survival (OS) of 12 mo, and a manageable safety profile with SG. TROPiCS-02 is a phase 3 randomized study (NCT03901339) to confirm SG outcomes in HR+/HER2– advanced breast cancer. Methods: Adults with locally determined, HR+/HER2– unresectable locally advanced or MBC, ECOG performance status of 0 or 1, and 2-4 prior chemotherapy regimens for MBC were eligible; 1 prior therapy for MBC was allowed if disease progressed ≤12 mo after (neo)adjuvant therapy. Pts must have received ≥1 prior taxane, CDK4/6 inhibitor, and endocrine therapy in any setting. Pts were randomized 1:1 to receive SG (10 mg/kg IV on d1 and 8, every 21d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST v1.1 by blinded independent central review (final analysis) with key secondary endpoint of OS (1st planned interim analysis). Results: At data cutoff on Jan 3, 2022, 272 vs 271 pts were randomized to receive SG vs TPC, respectively. Pt characteristics in the SG vs TPC arms were similar (3 median prior chemotherapy regimens for MBC [range, 0-8]; 95% had visceral metastases, 86% had prior endocrine therapy for MBC for ≥6 mo, 60% and 38% received prior CDK4/6 inhibitors for ≤12 and > 12 mo, respectively). SG (vs TPC) improved median PFS (5.5 vs 4.0 mo; HR, 0.66; 95% CI, 0.53-0.83; P= 0.0003); PFS rates at 6 and 12 mo were 46% vs 30% and 21% vs 7%, respectively. SG vs TPC showed a numeric but nonsignificant difference in OS (13.9 vs 12.3 mo; HR, 0.84; P= 0.143); ORR (21% vs 14%) and clinical benefit rate (34% vs 22%) were higher with SG vs TPC and median duration of response was 7.4 vs 5.6 mo, respectively. Overall, 74% vs 60% of patients (SG vs TPC) had grade ≥3 treatment-emergent adverse events (AEs); neutropenia (51% vs 39%) and diarrhea (10% vs 1%) were most common. AEs leading to discontinuation of SG vs TPC were low (6% vs 4%). There was 1 treatment-related death in the SG arm; none in the TPC arm. Conclusions: SG had a statistically significant, clinically meaningful PFS benefit over single-agent chemotherapy and a manageable safety profile in pts with heavily pre-treated HR+/HER2– endocrine-resistant, unresectable locally advanced or MBC, who have limited treatment options. Clinical trial information: NCT03901339.