Pathologic complete response to combination therapy with enfortumab vedotin and pembrolizumab in a patient with metastatic ureteral cancer

TPS595 Background: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle invasive urothelial cancer (MIUC) before radical cystectomy (RC) and lymph node dissection in cisplatin-eligible patients (pts). However, many pts are cisplatin-ineligible and while PD-1/PD-L1 inhibitors have had encouraging results in this population, they are not approved for MIUC; new therapies are needed. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In a phase 2 study, EV monotherapy had a confirmed ORR of 44% in 125 heavily pre-treated metastatic urothelial cancer (mUC) pts (Rosenberg JCO 2019). In the present study, an initial analysis of EV combined with the PD-1 inhibitor, pembrolizumab (P) had a confirmed ORR of 71% in 45 cisplatin-ineligible mUC pts in the first-line setting (Hoimes ESMO 2019). These results suggest that EV and EV+P may be suitable for research in MIUC. Methods: Study EV-103 (NCT03288545) mUC cohorts were described previously (Hoimes ASCO 2019). Sequential cohorts were added to test EV alone (Cohort H, n = 20) and EV+P (Cohort J, n = 20) as neoadjuvant therapy in cisplatin-ineligible pts (stage cT2-T4a, N0, M0) with treatment naive MIUC. Eligible pts are ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and scheduled for RC. Cohort H pts receive 3 cycles of EV (1.25 mg/kg) on Days 1 and 8 of each 3-week cycle. Cohort J pts receive 3 cycles of EV as described for Cohort H plus P on Day 1 of each cycle. Following EV or EV+P, pts undergo their scheduled RC. Pathological complete response (pCR) rate per local pathology review is the primary endpoint of the MIUC cohorts. Secondary endpoints include assessment of pCR and pathological response (PaR) rate per central pathology review, PaR per local pathology review, PFS and investigator assessed disease-free survival per RECIST v1.1, OS, and assessment of safety and tolerability, including planned surgeries delayed due to treatment-related adverse events. The ongoing study opened Oct 2017 and was amended to include MIUC cohorts Aug 2019. Clinical trial information: NCT03288545.

Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study.

4582 Background: Up to 25% of all patients (pts) diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with muscle invasive bladder cancer (MIBC). Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit previously treated locally advanced or metastatic urothelial cancer pts in phase 2 and 3 trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (ypT0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating EV in MIBC. Clinical trial information: NCT03288545.

435 Background: Up to 25% of all pts diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe, and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with MIBC. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit locally advanced or metastatic urothelial cancer pts in Phase II and III trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (yp T0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts, with 1 case pending central pathology review. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing Phase II and III programs evaluating EV in MIBC. Clinical trial information: NCT03288545.

Background: PD-(L)1-targeted immune checkpoint inhibitors (CPIs), such as pembrolizumab, are approved for patients with locally advanced or metastatic urothelial cancer (la/mUC) who progress after platinum, are ineligible for first-line (1L) cisplatin (PD-L1 positive), or are ineligible for 1L platinum. However, la/mUC remains a lethal disease, with an ORR of ~25% for all CPI-treated patients, and a combination approach may provide additional benefit. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which are found in 97% of mUC patient samples (Petrylak, ASCO 2017). In a phase 1 study (NCT02091999), EV (1.25 mg/kg) was generally well tolerated with a confirmed ORR of 43% in 112 mUC patients (Rosenberg, ASCO-GU 2019). These encouraging results, along with the potential for an enhanced immune response, suggest that EV+pembrolizumab may improve response rates and extend response durability. Trial Design: EV-103, a phase 1b trial for nonresectable la/mUC patients with no prior CPI, added an additional 4 cohorts (Parts 2 and 3) in an Oct. 2018 amendment. Anticipated enrollment is now approximately 159 patients. Dose-escalation patients (EV+pembrolizumab, 1L or 2L) must be ineligible for 1L cisplatin-based chemotherapy or have disease progression during/following treatment with ≥1 platinum-containing regimen. Dose expansion (Part 1) will evaluate EV+pembrolizumab in 1L (Cohort A) and 2L settings (Optional Cohort B). Part 2 will evaluate 1L EV+cisplatin (Cohort D), 1L EV+carboplatin (Cohort E), and 1L or 2L EV+gemcitabine (Optional Cohort F). Part 3 (Cohort G) will evaluate 1L EV+pembrolizumab+cisplatin or carboplatin, depending on patients' cisplatin-eligibility. In all cohorts, patients receive EV on Days 1 and 8 of each 3-week cycle. In combination therapies, patients receive pembrolizumab, cisplatin, and carboplatin on Day 1 or gemcitabine on Days 1 and 8 of each cycle. The primary objective is to assess the safety and tolerability of EV+pembrolizumab and/or chemotherapy. Secondary objectives are establishing the recommended EV dose for combination cohorts, assessing ORR per RECIST for all cohorts and per iRECIST for therapies with pembrolizumab, as well as assessing disease control rate, duration of response, progression-free survival, overall survival, pharmacokinetics, and biomarkers. The study opened in Oct. 2017. Citation Format: Christopher J. Hoimes, Jonathan E. Rosenberg, Daniel P. Petrylak, Anne-Sophie Carret, Amal Melhem-Bertrandt, Thomas W. Flaig. The EV-103 Trial: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for patients with locally advanced or metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A23.

4564 Background: For patients (pts) with MIBC who are cisplatin-ineligible and undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), no neoadjuvant treatment options have been shown to improve survival. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. EV, alone and in combination w/ pembrolizumab, has been shown to improve OS vs chemotherapy in pts with previously treated and untreated locally advanced or metastatic urothelial cancer, respectively (Powles NEJM 2021; Powles ESMO 2023). In Cohort H of the EV-103 phase 1b/2 study, promising results for 1-year EFS and antitumor activity, including pathological complete response (pCR) and pathological downstaging (pDS) rates, were achieved in cisplatin-ineligible pts with MIBC after neoadjuvant monotherapy EV treatment (Petrylak ASCO GU 2022; Flaig ASCO 2023). Here we report updated results, including 2-year EFS. Methods: Cohort H of the EV-103 study enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), safety, and EFS per investigator assessment (radiographic progression prior to RC, failure to undergo RC, gross residual disease at time of RC, recurrence, or death). Results: 22 pts (median age 74.5 years) were enrolled and treated; 15 pts (68.2%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had urothelial carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2-59.3) and the pDS rate was 50.0% (95% CI, 28.2-71.8). The EFS rate at 24 months was 62.0% (95% CI, 38.2-78.9). Median EFS has not been reached. All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs: the most common were procedural pain (18.2%), anemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and 2-year EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905/EV-303, KN-B15/EV-304). Clinical trial information: NCT03288545 .

TPS4587 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS < 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124.

Enfortumab vedotin (EV) is a novel treatment for patients with advanced urothelial carcinoma who have failed platinum-based chemotherapy and immunotherapy.1 EV is an antibody-drug conjugate (ADC) composed of a humanized anti-nectin-4 monoclonal antibody attached to a microtubule inhibitor.2 We report 3 individuals with unique cutaneous reactions after EV treatment.

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.

BackgroundPatients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population.MethodsIn this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody–drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety.ResultsA total of 344 participants underwent randomization (170 in the enfortumab vedotin–pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin–pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin–pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin–pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%).ConclusionsPerioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.)

EV is a Nectin-4 targeting antibody-drug conjugate (ADC) with an MMAE payload, recently approved for bladder cancer treatment. We established and characterized 18 bladder XPDX models representing primary and metastatic disease from naïve or clinically treated patients, some with actionable mutations. To better understand the potential additive benefit of EV in bladder cancer, we evaluated the ADC alone and in combination with agents targeting ERBB2, PIK3CA or FGFR3. In addition, we tested EV alone in ST5420B, a model established from a patient who progressed on EV after five cycles, as well as ST975B, a model which harbors a novel NECTIN4 fusion. 18 bladder XPDX models were established in immune-deficient mice, including 5 from newly diagnosed patients (2 from primary site), and 13 from recurrent disease (2 from primary site). Nectin-4, Trop2 protein and ERBB2 receptor expression was tested, and models profiled using WES and RNAseq. For in vivo studies, all models were evaluated against cisplatin, T-DXd, SG, and EV. Models with actionable mutations were tested with alpelisib, erdafitinib, and neratinib alone and in combination with EV. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C&amp;lt;0%) versus Day 0 tumor volume was also reported. Most models stained positive for Nectin-4 and Trop-2. FGFR3 variants were found in five models and ERBB2 mutations in two while several models reported PIK3CA variants; deletions in RB1 and CDKN2A were common. In vivo studies reported differential responses to cisplatin with the most sensitive models established from treatment-naïve patients. EV and SG tested alone reported activity in several models; EV added benefit in some combination treatments. We have characterized a panel of bladder XPDX models and benchmarked them against T-DXd, EV and SG alone and EV in combination with targeted therapies. This data is a valuable tool in further developing EV and identifying novel therapies for bladder cancer. Citation Format: Johnnie Flores, Heaven Sessions, Alyssa Simonson, Natalia Banos, Tahmineh Rouzbahani, Armando Diaz III, Jim Lund, Emiliano Calvo, Victor Moreno, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Scott Ulmer, Luis Rodriguez, Michael Wick. Enfortumab vedotin (EV): Efficacy comparison with trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) and its potential for combination benefit in bladder cancer XPDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6899.

e16574 Background: Enfortumab vedotin (EV) monotherapy and its combination with pembrolizumab (EV/P) are established treatment options in metastatic urothelial carcinoma (mUC). However, significant toxicities associated with EV and EV/P often lead to treatment discontinuation. Despite this, some patients maintain disease control beyond discontinuation, suggesting the potential for treatment re-challenge. This study aimed to evaluate pts who discontinued EV for &gt;8 weeks to examine the time to disease progression after discontinuation and the efficacy of EV re-challenge. Methods: This retrospective study analyzed clinical data from 86 pts who received either EV or EV/P for mUC in either the first or subsequent lines of therapy between January 2018 and June 2024.Descriptive statistics were employed for data analysis, and the Kaplan-Meier estimator was used to calculate survival probabilities. The interquartile range (IQR) was calculated to assess the median duration. Results: Among 86 pts, 43 received EV alone and 43 received EV/P, with a median age of 74. Most pts were male (69, 80%), with 59 reporting a history of smoking. Baseline neuropathy was present in 19 pts (22%). Prior cystectomy or nephroureterectomy was reported in 34 pts (39.5%). Overall, 59 pts (68%) discontinued EV for at least 8 weeks, 36 pts (84%) in EV alone, 23 pts (53%) in EV/P group. Most EV discontinuations were due to toxicity (52 pts, 60%). 12 pts (21%) discontinued due to complete response. The median duration of tx before EV discontinuation was 3.7 months (IQR 4.2), with 3.2 months (IQR 3.9) in the EV-alone group and 5.0 months (IQR 4.7) in the EV/P group. Following discontinuation, progression occurred in 34 of 56 (57%) pts, 23 in EV alone, and 11 in EV/P group. 39% pts remained disease-free despite discontinuing EV at the time of last follow-up. The median time to progression after treatment discontinuation was 5.92 months (IQR 5.06–10.85) overall, with 7.82 months (IQR 3.62–NA) in the EV/P group and 5.88 months (IQR 4.41–NA) in the EV-alone group. EV rechallenge was attempted in 23 of 56 (41%) pts discontinuing EV, and the median duration of EV rechallenge was 3.0 months (IQR 1.9).Upon EV re-challenge (N = 23), 5 pts had partial responses, 5 pts had stable disease, and 12 pts had progressive disease. No significant correlation was observed between the duration of EV tx before the tx discontinuation and response to EV upon re-challenge in either group (two-sided Mann-Whitney test p-value = 0.59. Conclusions: This study highlights that tx discontinuation due to toxicities is common in mUC pts receiving EV and EV/P. About 60% pts experienced disease progression after EV discontinuation with a median time to progression of 6 months. EV re-challenge was associated with responses in some pts and should be considered by those who may tolerate it.

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&gt;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.

According to the World Health Organization data, in 2022 bladder cancer (BC) was the 9th (614,298) most common cancer. In Russia, most patients (58.8 %) were diagnosed with non-muscle invasive BC (stage I) but the percentage of muscle invasive cancer (stages II–III) and metastatic BC (mBC) remains high: 32.1 and 8.3 % cases, respectively. Mortality in patients with BC in the first year since diagnosis remains high: 12.28 %. Decrease in BC mortality in the last 10 years in Russia by 22.84 % is probably due to development of new more effective drugs for mBC treatment which are the subject of this literature review.Currently, the 2nd line standards of treatment of patients with mBC changed due to appearance in the guidelines of the majority of the world oncological societies of new drugs classified as conjugated and targeted drugs. In patients with progression during platinum-based chemotherapy and/or immune checkpoint inhibitors, therapy with conjugate enfortumab vedotin (EV) is possible.Enfortumab vedotin is the first of its class drug, a conjugate of a monoclonal antibody against the nectin-4 protein which is highly expressed by urothelial carcinoma and a cytotoxic chemotherapy drug monomethyl auristatin E (ММАЕ) affecting microtubules. EV was approved by the US Food and Drug Administration (FDA) in December of 2019 based on phase II trial EV-201 as part of the expedited review program due to high rate of objective responses in patients with inoperable locally advanced and mBC who previously received platinum-based chemotherapy and immune checkpoint inhibitors. In Russia, the drug was approved in 2023.Median overall survival in all phase I–III EV trials were around 1 year and varied between 11.7 and 12.91 months, progression-free survival was a little below 6 months and varied between 5.5 and 5.8 months. In the UNITE trial based on routine practice data, median progression-free survival and overall survival since the start of EV therapy were a little higher than in the randomized trails: 6.8 and 14.4 months, respectively. Objective response rate in all clinical trials was above 40 %; in particular, in phase I trial EV-101 it was 43 %, in phase II trial EV-201 – 44 %, in phase III trial EV-301 – 41 %, and in UNITE – 52 %, while complete response rates were 5; 12; 6.9 and 7 %, respectively. In phase III clinical trial EV-301, EV therapy decreased the risk of death by 30 % compared to standard treatment (ST) and significantly increased overall survival from 8.94 months in the ST group to 12.91 months in the EV group. The risk of progression and death decreased by 37 % in the EV group, and median progression-free survival increased from 3.71 months in the ST group to 5.5 months in the EV group (p 0.00001). Additionally, objective response rate was more than 2-fold higher for EV compared to ST: 41.32 % versus 18.58 %. Approximately 30 % of patients in the EV group are alive at year 2 of the study compared to 20 % in the ST group. Safety profile also demonstrates similar results to the intermediate and primary analyses. The rates of treatment-associated adverse events of grade III or higher in the EV group in both intermediate and primary analyses of the EV-301 trial (51.4 and 52.4 %, respectively) were similar to the rates in the ST group (49.8 % and 50.5 %, respectively). The most common adverse events in the EV therapy group were rash, hyperglycemia, and peripheral neuropathy. At the same time, quality of life in the EV therapy group was higher compared to the standard therapy which confirms safety and effectiveness of EV in patients with urothelial carcinoma.

TPS587 Background: The current standard of care for patients (pts) with newly diagnosed MIBC is neoadjuvant cisplatin (cis)-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). For the 20-50% pts who are cis-ineligible, the current standard of care is RC+PLND alone (Galsky Future Oncol 2021). Adjuvant therapy is currently recommended for cis-ineligible patients with high-risk features at cystectomy. Due to the high rates of recurrence in cis-ineligible pts with RC+PLND alone, there is a need to develop new therapies in this setting. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In EV-301, a phase 3 study, EV showed an overall survival (OS) benefit vs chemotherapy in pts with locally advanced (la) or metastatic urothelial carcinoma (mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). EV has also demonstrated activity and a tolerable safety profile in cis-ineligible pts with la/mUC (Yu Lancet Oncol 2021). Given the efficacy of EV in la/mUC, it is being evaluated as perioperative therapy in cis-ineligible MIBC in EV-103 cohort L. Methods: Study EV-103 (NCT03288545) la/mUC and MIBC cohorts were described previously (Hoimes ASCO 2019; Hoimes ASCO-GU 2020). Cohort L was added to evaluate EV monotherapy (n = 50) as perioperative therapy in cis-ineligible pts with MIBC (cT2-T4aN0M0 or cT1-T4aN1M0). Eligible pts are previously untreated for MIBC, ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and agree to undergo curative intent RC+PLND. Pts with pT1 disease are eligible only if they have N1 disease. Pts receive 3 cycles of neoadjuvant EV (1.25 mg/kg IV) on Days 1 and 8 of each 3-week cycle, followed by RC+PLND and then 6 cycles of adjuvant EV starting 8 weeks post-RC on the same schedule. Pathological complete response rate per central pathology review is the primary endpoint. Secondary endpoints include event-free survival and disease-free survival by blinded independent central review and investigator, pathological downstaging rate per central pathology review, OS, safety and tolerability. Cohort L is currently enrolling pts in the US and Canada. Clinical trial information: NCT03288545.