Navigating first-line treatment UC (2).pptx

locally advanced and metastatic first line treatment

1. 1 Navigating first-line treatment approaches in la/ mUC By Ass.Prof . Shokry El- Azab 19.8.2025

2. 2 Navigating first-line treatment approaches in la/mUC WHERE WE COME FROM…

3. 3 Title of Presentation | DD.MM.YYYY 1L COMBINATION THERAPIES (PLATINUM BASED)

4. 4 The current treatment landscape in la/mUC1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only Gem/cis + nivolumab ‡ EV+pembro *† ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Gem/carbo Gem/cis Pembro* Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible EV+pembro * † (US only) 2L Maintenance a velumab ¶ Maintenance nivolumab Pembro or atezo * 1L Maintenance

5. 5 The current 1L treatment landscape in la/mUC 1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Pembro * Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible 2L Maintenance avelumab ¶ Maintenance nivolumab 1L Maintenance Gem/cis + nivolumab ‡ EV+pembro *† Gem/carbo Gem/cis EV+pembro * † (US only) Pembro or atezo *

6. 6 The current 1L treatment landscape in la/mUC 1–3 Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only ??? Gem/cis Gem/carbo Erdafitinib * Sacituzumab govitecan Taxanes Vinflunine No PD Pembro * Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible 2L Maintenance avelumab ¶ Maintenance nivolumab 1L * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Maintenance Gem/cis + nivolumab ‡ EV+pembro *† Gem/carbo Gem/cis EV+pembro * † (US only) Pembro or atezo *

7. 7 High response rates are observed in patients who are platinum-eligible and treated with 1L PBC 1 Avelumab 1L maintenance is an important therapeutic option to address the challenge of CT resistance 5,6 82.9% DCR with nivolumab + gem/cis 2 1L, first-line; cis, cisplatin; CT, chemotherapy; DCR, disease control rate; gem, gemcitabine; PBC, platinum-based chemotherapy. 1. Yu E, et al. Ther Adv Urol 2023; doi : 10.1177/17562872221147760; 2. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789; 3. Grivas P, et al. Target Oncol 2019;14:505–525; 4. Liu S, et al. J Adv Res 2022;39:187–202; 5. Powles T, et al. N Engl J Med 2020;383:1218–1230; 6. Dr Birtle. Personal opinion/experience. Up to 80% of patients achieve disease control with 1L PBC 1 However, efficacy with PBC is not durable, necessitating the need for avelumab 1L maintenance 3,4

8. 8 JAVELIN Bladder 100: avelumab 1L maintenance + BSC vs BSC alone in la/mUC 1,2 Treatment-free interval (4 – 10 weeks) (Radiological assessment of response) Unresectable la/mUC (N=700) CR, PR, or SD with standard 1L CT (4 – 6 cycles) Cisplatin + gemcitabine or Carboplatin + gemcitabine Avelumab 10 mg/kg IV Q2W + BSC* n=350 BSC alone* n=350 Until PD, unacceptable toxicity, or withdrawal R 1:1 All endpoints measured post-randomization (after CT) Primary endpoint OS Primary analysis populations All randomized patients PD-L1+ population † Secondary endpoints PFS OR Time to response Response duration Disease control ‡ Safety and tolerability PROs Stratification Best response to 1L CT (CR or PR vs SD) Metastatic site (visceral vs non-visceral) *Supportive care was administered per local practice, based on patient needs and clinical judgment, and included antibiotics, nutritional support, hydration, and pain management; other systemic antitumor therapy was not permitted, but palliative local radiotherapy for isolated lesions was acceptable; † PD-L1+ status was defined as PD-L1 expression in ≥25% of tumor cells or in ≥25% or 100% of tumor-associated immune cells if the percentage of immune cells was >1% or ≤1%, respectively, using the Ventana SP263 assay; 358 patients (51%) had a PD-L1-positive tumor ; ‡ Defined as response or SD for ≥6 weeks. 1L, first-line; BSC, best supportive care; CR, complete response; CT, chemotherapy; IV, intravenous; la/mUC, locally advanced/metastatic urothelial carcinoma; OR, overall response; OS, overall survival; PD, progressive disease; PD-L1, programmed cell death protein-ligand 1; PFS, progression-free survival; PR, partial response; PRO, patient-reported outcome; Q2W, every 2 weeks; R, randomization; SD, stable disease. 1. Powles T, et al. N Engl J Med 2020;383:1218–1230; 2. Powles T, et al. J Clin Oncol 2023;41:3486–3492.

9. 9 JAVELIN Bladder 100: long-term follow-up outcomes from start of avelumab 1L maintenance 1,2 OS BSC alone 49.8% 36.0% 38.4% 29.8% 350 318 274 237 216 183 140 99 74 53 31 13 4 164 1 350 304 243 190 158 131 103 82 62 46 27 10 7 121 20 30 40 50 60 70 100 90 80 10 OS (%) Months No. at risk Avelumab + BSC 4 8 12 16 20 28 32 36 40 44 52 60 24 56 48 PFS 20 30 40 50 60 70 100 90 4 8 12 16 20 28 32 36 40 44 52 60 Months 24 PFS (%) Avelumab + BSC BSC alone No. at risk 56 48 23.4% 15.9% 7.1% 5.3% 350 182 126 105 88 73 43 32 25 12 6 67 350 101 51 33 24 19 14 13 9 6 4 1 1 19 80 10 Long-term follow-up of the JAVELIN Bladder 100 trial continues to show prolonged OS and PFS with avelumab 1L maintenance Data cut-off: June 4, 2021. Median follow-up was 38.0 months with avelumab + BSC and 39.6 months with BSC alone (≥2 years in all patients). 1L, first-line; BSC, best supportive care; CI, confidence interval; HR, hazard ratio; mo , months; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival. 1. Powles T, et al. N Engl J Med 2020;383:1218–1230; 2. Powles T, et al. J Clin Oncol 2023;41:3486–3492. Avelumab + BSC BSC alone Avelumab + BSC BSC alone 23.8 mo (19.9–28.8) HR 0.76 (95% CI 0.63–0.91) mOS (95% CI) 15.0 mo (13.5–18.5) 5.5 mo (4.2–7.2) HR 0.54 (95% CI 0.46–0.64) mPFS (95% CI) 2.1 mo (1.9–3.0)

10. 10 JAVELIN Bladder 100: 29.7-month mOS data from start of 1L PBC 1 Exploratory post hoc analysis of OS from the start of 1L PBC in select patients treated with avelumab 1L maintenance following no PD on 1L PBC* 1 Probability of OS, % M onths Ave + BSC 350 350 334 288 247 220 191 171 145 114 86 58 36 17 7 BSC alone 350 349 317 255 207 168 141 1 25 111 89 68 54 33 12 8 No. at risk mOS : 29.7 months mOS : 20.5 months Long-term outcomes with avelumab + BSC (vs BSC alone) are similarly reflected in RW practice 2–4 *Median follow-up of ≥38 months. OS data calculated from the start of 1L CT is inclusive of 4–6 cycles of platinum-containing CT, 4–10 weeks of treatment-free interval, randomized study treatment with avelumab + BSC or BSC alone, and subsequent therapy. This is an exploratory, post hoc analysis of OS data calculated from the start of CT, and there are limitations to the interpretation of these data. 1L, first-line; ave , avelumab; BSC, best supportive care; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; mo , months; (m)OS, (median) overall survival; PBC, platinum-based chemotherapy; PD, progressive disease; RW, real-world. 1. Grivas P, et al. ESMO Open 2023;8:102050; 2. Barthelemy P, et al. ASCO GU 2024 (Abstract No. 561 – poster); 3. Bracarda S, et al. ASCO GU 2024 (Abstract No. 558 – poster); 4. Grivas P, et al. ASCO GU 2024 (Abstract No. 697 – poster); 5. Dr Birtle. Personal opinion/experience. Sound familiar? 5 29.7 mo (25.2–34.0) HR 0.77 (95% CI 0.64–0.92) mOS (95% CI) 20.5 mo (19.0–23.5)

11. 11 Title of Presentation | DD.MM.YYYY JAVELIN BLADDER 100

12. 12 JAVELIN Bladder 100: safety outcomes Most common TRAEs observed with avelumab + BSC in initial analysis and ≥2-year follow-up in JAVELIN Bladder 100 1 1L, first-line; BSC, best supportive care; RW, real-world; TRAE, treatment-related adverse event. 1. Powles T, et al. J Clin Oncol 2023;41:3486–3492 (suppl); 2. Prescribing information for BAVENCIO. March 2024. Available at https://www.emdserono.com/us-en/pi/bavencio-pi.pdf (last accessed September 2024); 3. Summary of Product Characteristics for BAVENCIO. March 2023. Available at https://www.ema.europa.eu/en/documents/product-information/bavencio-epar-product-information_en.pdf (last accessed September 2024); 4. Kearney M, et al. ISPOR 2024 (Abstract No. CO68). 13.7 10.5 9.6 9.9 10.2 9.9 7.3 6.7 7.0 7.0 6.7 6.1 5.2 4.4 0.3 0.3 0.3 0.9 2.0 1.1 1.2 0.3 0.5 0.3 3.8 0.3 2.9 2 4 6 8 10 12 14 16 Pruritus Hypothyroidism Fatigue Asthenia Diarrhea Infusion-related reaction Rash Arthralgia Nausea Chills Pyrexia Hyperthyroidism Dry skin Amylase increased Lipase increased Patients (n=344), % TRAEs of any grade TRAEs of grade ≥3 Initial analysis Since initial analysis Initial analysis Since initial analysis 0.6 0.3 0.3 0.3 0.3 0.5 0.6 0.6 0.6 The long-term safety profile of avelumab 1L maintenance: Supports continued treatment until disease progression 2,3 Demonstrates a consistent safety profile across clinical and RW studies 1,4

13. 13 AE, adverse event; BSC, best supportive care; CI, confidence interval; OS, overall survival; TRAE, treatment-emergent adverse event. 1. Grivas P, et al. ESMO 2024 (Abstract No. 1975P – poster). OS (%) OS (%) No. at risk No. at risk Patients with ≥1 year of avelumab treatment (n=118) Probability of additional OS beyond 1 year, % (95% CI) 6 months 1 year 1.5 years 2 years 97.5 (94.7–100) 93.2 (88.8–97.9) 86.8 (80.8–93.3) 79.6 (72.0–88.0) Patients with ≥2 years of avelumab treatment (n=68) Probability of additional OS beyond 2 years, % (95% CI) 6 months 1 year 1.5 years 100 (100–100) 95.8 (90.2–100) 90.3 (81.6–99.9) Patients with ≥1 year of avelumab treatment n/N=118/350 (33.7%) Patients with ≥2 years of avelumab treatment n/N=68/350 (19.4%) Months (beyond 1 year) Months (beyond 2 years) No new safety concerns identified with long treatment duration Patients experiencing any TRAE for ≥1 year was 50% and for ≥2 years was 35.5% JAVELIN Bladder 100: long-term conditional survival and AE probability 1

14. 14 JAVELIN Bladder 100: long-term PROs show preserved HRQoL and control of cancer-related symptoms with manageable treatment-related toxicity 1 Data cut-off: June 4, 2021. Median follow-up in the avelumab + BSC arm (n=350) was 38.0 months (≥2 years in all patients), and median duration of treatment was 5.8 months. BSC, best supportive care; HRQoL , health-related quality of life; NFBISI-18, NCCN/FACT Bladder Symptom Index-18; PRO, patient-reported outcome; QoL, quality of life. 1. Grivas P, et al. ASCO GU 2024 (Abstract No. 581 – oral presentation). Change in symptoms, general health, and QoL (NFBISI-18 and EQ-5D-5L scores) PRO scores remained stable throughout treatment No clinically important changes from baseline were reported Being bothered by treatment side effects (NFBISI-18) ~75% reported no change or a decrease in how much they were bothered by treatment side effects throughout 24 months of treatment

15. 15 The current treatment landscape in la/mUC 1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only Gem/cis + nivolumab ‡ EV+pembro *† ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Gem/carbo Gem/cis Pembro* Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible EV+pembro * † (US only) 2L Maintenance a velumab ¶ Maintenance nivolumab Pembro or atezo * 1L Maintenance

16. 16 The current 1L treatment landscape in la/mUC 1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Pembro * Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible 2L Maintenance avelumab ¶ Maintenance nivolumab 1L Maintenance Gem/cis + nivolumab ‡ EV+pembro *† Gem/carbo Gem/cis EV+pembro * † (US only) Pembro or atezo *

17. 17 CheckMate 901 substudy: nivo + gem/cis vs gem/cis in la/mUC 1,2 Phase III, international, open-label, randomized trial to evaluate the efficacy and safety of nivo plus gem/cis vs gem/cis for previously untreated unresectable UC or mUC Previously untreated cis-eligible la/ mUC (N=608) Gem/cis + nivo Gem/cis* R 1:1 Combination phase Monotherapy phase Nivo Until PD, unacceptable toxicity, withdrawal, or ≤24 months Primary endpoints: OS, PFS per BICR Key secondary endpoints: OS and PFS by PD-L1 ≥1%, HRQoL Exploratory endpoints: ORR per BICR, safety 3 weeks 11% (32/304) of patients received 1L avelumab maintenance following a response to platinum-based CT *Patients who discontinued cisplatin could be switched to gem + carboplatin for the remainder of the platinum doublet cycles (≤6 total). 1L, first-line; BICR, blinded independent central review; cis, cisplatin; CT, chemotherapy; gem, gemcitabine; HRQoL , health-related quality of life; la/mUC, locally advanced/metastatic urothelial carcinoma; nivo , nivolumab; ORR, overall response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed cell death protein-ligand 1; PFS, progression-free survival; R, randomization; UC, urothelial carcinoma. 1. Van der Heijden MS, et al. ESMO 2023 (Abstract No. LBA7 – presentation); 2. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789.

18. 18 CheckMate 901 substudy: OS, PFS, and TRAE outcomes – overall population 1 *One grade 5 event occurred in each group (sepsis in the nivolumab plus gemcitabine–cisplatin group and acute kidney injury in the gemcitabine–cisplatin group). AE, adverse event; BICR, blinded independent central review; CI, confidence interval; cis, cisplatin; gem, gemcitabine; HR, hazard ratio; mo , months; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; TRAE, treatment-related adverse event. 1. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789; 2. Dr Birtle. Personal opinion/experience. OS PFS by BICR 6 12 18 24 30 36 42 48 54 60 66 Time (months ) Patients (%) No. at risk Nivolumab + gem/cis Gem/cis 100 90 80 70 60 50 40 30 20 10 304 264 196 142 97 69 48 25 15 7 2 304 242 166 122 82 49 33 17 13 4 1 70.2 (95 % CI 64.6–75.1) 46.9 (95 % CI 40.7–52.8) 62.7 (95 % CI 56.8–68.1) 40.7 (95 % CI 34.6–46.7) Nivolumab + gem/cis Gem/cis HR 0.78 (95% CI 0.63–0.96); p=0.02 mOS (95% CI) 18.9 mo (14.7–22.4) 7.9 mo (7.6–9.5) HR 0.72 (95% CI 0.59–0.88); p=0.001 mPFS (95% CI) 7.6 mo (6.1–7.8) 21.7 mo (18.6–26.4) OS benefit was seen after 6 months 2 Nivolumab + gem/cis was associated with improved OS (+2.8 months) and PFS (+0.3 months) vs gem/cis AE Nivolumab + gem/cis (n=304) Gem/cis alone (n=288) Any grade n (%) Grade ≥3 * n (%) Any grade n (%) Grade ≥3 * n (%) Anemia 174 (57.2) 67 (22.0) 137 (47.6) 51 (17.7) Nausea 142 (46.7) 1 (0.3) 138 (47.9) 3 (1.0) Neutropenia 93 (30.6) 57 (18.8) 86 (29.9) 44 (15.3) Most common (≥30%) TRAEs

19. 19 The current treatment landscape in la/mUC 1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only Gem/cis + nivolumab ‡ EV+pembro *† ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Gem/carbo Gem/cis Pembro* Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible EV+pembro * † (US only) 2L Maintenance a velumab ¶ Maintenance nivolumab Pembro or atezo * 1L Maintenance

20. 20 The current 1L treatment landscape in la/mUC 1–3 * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin ; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/mUC, locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024). Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only ??? Gem/cis Gem/carbo Erdafitinib ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Pembro * Atezo * 3L Erdafitinib ‡ § EV ‡ Sacituzumab govitecan ‡ Taxanes ** Vinflunine ** Pembro Platinum-ineligible 2L Maintenance avelumab ¶ Maintenance nivolumab 1L Maintenance Gem/cis + nivolumab ‡ EV+pembro *† Gem/carbo Gem/cis EV+pembro * † (US only) Pembro or atezo *

21. 21 EV-302: EV+pembro vs PBC in la/mUC 1,2 *Maintenance therapy could be used following completion or discontinuation of platinum-containing therapy – this amendment to the protocol was made late in the enrollment period. 1L, first-line; 2L, second-line; BICR, blinded independent central review; carbo, carboplatin; cis, cisplatin; CT, chemotherapy ; EV, enfortumab vedotin ; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; ORR, overall response rate; OS, overall survival; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab; PFS, progression-free survival; R, randomization; RECIST, Response Evaluation Criteria in Solid Tumors . 1. Powles T, et al. ESMO 2023 (Abstract No. LBA6 – presentation); 2. Powles T, et al. N Engl J Med 2024;390:875–888; 3. Dr Birtle, p ersonal opinion/experience. EV+pembro Gem/cis (≤6 cycles)* or Gem/carbo (≤6 cycles)* Dual primary endpoints PFS by BICR; OS Key secondary endpoints ORR per RECIST v1.1 by BICR and investigator assessment Safety Until PD, unacceptable toxicity, or completion of maximum cycles A Phase III open-label study of EV+pembro in untreated la/mUC 1,2 Previously untreated la/ mUC (N=886) R 1:1 32.2% (143/444) received 1L avelumab maintenance following a response to platinum-based CT Patients did not receive EV in 2L 3

22. 22 EV-302: OS and PFS outcomes 1 *Median follow-up: 17.2 months; †Data cut-off: August 8, 2023. BICR, blinded independent central review; CI, confidence interval; CT, chemotherapy; EV, enfortumab vedotin ; HR, hazard ratio; mo , months; NE, not estimable; (m)OS, (median) overall survival; pembro , pembrolizumab; (m)PFS, (median) progression-free survival. 1. Powles T, et al. N Engl J Med 2024;390:875–888. PFS by BICR †1 OS* †1 EV+pembro CT No. at risk EV+pembro CT No. at risk 442 426 409 394 376 331 270 222 182 141 108 67 36 22 12 8 1 1 442 409 361 303 253 204 167 132 102 73 45 33 17 6 3 1 444 423 393 356 317 263 209 164 125 90 60 37 25 18 12 7 2 1 444 380 297 213 124 78 56 41 30 19 8 6 5 3 2 1 1 100 80 60 40 20 Percentage of patients, % 2 6 8 10 12 14 18 20 22 26 28 30 36 38 Months 90 70 50 30 10 4 16 24 34 100 80 60 40 20 Percentage of patients, % 2 6 8 10 12 14 18 20 22 26 28 30 32 34 Months 90 70 50 30 10 4 16 24 1 6 32 78.2 69.5 61.4 44.7 50.7 43.9 21.6 11.7 EV+pembro EV+pembro CT CT 31.5 mo (25.4–NE) HR 0.47 (95% CI 0.38–0.58); p<0.001 mOS (95% CI) 16.1 mo (13.9–18.3) 12.5 mo (10.4–16.6) HR 0.45 (95% CI 0.38–0.54); p<0.001 mPFS (95% CI) 6.3 mo (6.2–6.5) EV+pembro vs CT demonstrated increased OS and PFS outcomes

23. 23 EV-302: response rates 1 *Overall response and DoR , as assessed by blinded independent central review according to the RECIST v1.1, were evaluated in all the patients in the ITT population who had measurable disease at baseline according to RECIST v1.1; †Patients had a post-baseline assessment of response, but the best overall response could not be evaluated according to RECIST v1.1; ‡Patients had no post-baseline assessment of response. CI, confidence interval; CR, complete response; CT, chemotherapy; DCR, disease control rate; EV, enfortumab vedotin ; ITT, intention-to-treat; (m) DoR , (median) duration of response; NE, not evaluable; NR, not reported; PD, progressive disease; Pembro, pembrolizumab ; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. 1. Powles T, et al. N Engl J Med 2024;390:875–888. DCR 86.6% DCR 78.3% CR CR PR PR EV+pembro (n= 437) CT (n= 441) Confirmed overall response,* % (95% CI) 67.7 (63.1–72.1) 44.4 (39.7–49.2) p value <0.001 Confirmed best overall response , n (%) CR PR SD PD Could not be evaluated † No assessment ‡ 127 (29.1) 169 (38.7) 82 (18.8) 38 (8.7) 21 (4.8) 55 (12.5) 141 (32.0) 149 (33.8) 60 (13.6) 4 (0.9) 32 (7.3) mDoR,* months ( 95% CI) NR (20.2–NE) 7.0 (6.2–10.2) Median time to response , months ( range) 2.1 (1.3–12.3) 2.1 (1.6–8.3) SD SD DCR rate: EV+pembro vs CT, 86.6% vs 78.3%

24. 24 EV-302: PROs show no observed detriment in overall QoL in either arm 1,2 Change in worst pain (BPI-SF) Predefined clinically meaningful thresholds were not met in either arm Numerically greater improvements in EV+pembro vs CT arm Change in worst pain and HRQoL in patients with moderate-to-severe pain (BPI-SF and EORTC QLQ-C30) Clinically meaningful improvements in both arms Numerically greater improvements in EV+pembro vs CT arm Time to pain progression No statistically significant difference between EV+pembro vs CT HR 0.92 (95% CI 0.72–1.20) More research is needed to assess PRO endpoints further to include impact of EV+pembro treatment-related toxicities BPI-SF, brief pain inventory short-form; CI, confidence interval; CT, chemotherapy; EORTC QLQ, European Organisation for Research and Treatment of Cancer , quality of life questionnaire; EV, enfortumab vedotin ; HR, hazard ratio; HRQoL , health-related quality of life; pembro , pembrolizumab; PRO, patient-reported outcome; QoL, quality of life. 1. Gupta S, et al. ASCO 2024 (Abstract No. 4502 – presentation); 2. Takavorian S. ASCO 2024 (Abstract No. 4502 – discussant).

25. 25 EV-302: safety outcomes – TRAEs 1,2 Data cut-off: August 8, 2023. TRAEs are any grade by preferred term in ≥20% of patients for any grade in either arm. *Per investigator, and cause of EV+pembro deaths included asthenia, diarrhea, immune-mediated lung disease, multiple organ dysfunction syndrome. †Cause of CT deaths included febrile neutropenia, myocardial infarction, neutropenic sepsis, sepsis. AE, adverse event; CT, chemotherapy; EV, enfortumab vedotin ; pembro , pembrolizumab; TRAE, treatment-related adverse event. 1. Powles T, et al. ESMO 2023 (Abstract No. LBA6 – presidential symposium); 2. Powles T, et al. N Engl J Med 2024;390:875–888. Grade 1/2 events occurred more frequently with EV+pembro vs CT EV+pembro was associated with a high incidence of AEs, treatment interruption, dose reduction, and discontinuation TRAEs leading to death EV+pembro :* 4 CT: † 4 Pruritus Fatigue Decreased appetite Neutropenia 100 70 60 50 40 30 10 10 30 40 50 80 100 Incidence (%) Peripheral sensory neuropathy Alopecia Diarrhea Anemia Thrombocytopenia 80 20 20 70 60 90 90 Maculopapular rash Nausea EV+pembro (N=440) CT (N=433) 97.0 50.0 9.9 39.8 33.2 32.7 29.3 27.5 26.8 20.2 13.9 9.1 3.4 4.8 7.9 36.0 11.1 22.6 38.8 56.6 41.6 34.2 0.2 3.2 4.2 0.7 1.4 2.8 31.4 30.0 19.4 EV+pembro CT Grades 1/2 Grade ≥3 3.6 1.1 0.5 7.7 3.0 3.6 1.1 1.1 3.4 4.8 0.5 TRAEs leading to discontinuation EV+pembro : 154 (35%) CT: 80 (18.5%) TRAEs leading to interruption EV+pembro : 299 (68%) CT: 229 (52.9%) TRAEs leading to dose reduction EV+pembro : 179 (40.7%) CT: 164 (37.9%) Patients with any grade AE EV+pembro : 427 (97%) CT: 414 (95.6%)

26. 26 EV-302: safety outcomes – TRAEs of special interest* 1,2 TRAEs of special interest for EV, n (%) EV+pembro (n=440) CT (n=433) Any grade Grade ≥3 Any grade Grade ≥3 Skin reactions 294 (66.8) 68 (15.5) 60 (13.9) 1 (0.2) Peripheral neuropathy 278 (63.2) 30 (6.8) 53 (12.2) Ocular disorders 94 (21.4) 12 (2.8) Hyperglycemia 57 (13.0) 27 (6.1) 3 (0.7) Infusion-related reactions 9 (2.0) 9 (2.1) TRAEs of special interest for pembro Severe skin reactions Any grade, 17.0% Grade ≥3, 11.8% *There are differences in the rates of skin reactions reported for EV treatment-related AESIs and pembro TEAEs of special interest because these adverse events were reported via different methodologies developed for EV and pembro monotherapies, respectively. AESI, adverse events of special interest; CT, chemotherapy; EV, enfortumab vedotin ; pembro , pembrolizumab; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event. 1. Powles T, et al. ESMO 2023 (Abstract No. LBA6 – presidential symposium); 2. Powles T, et al. N Engl J Med 2024;390:875–888. Serious TRAEs EV+pembro : 122 (27.7%) CT: 85 (19.6%) Skin reactions and peripheral neuropathy were the most common TRAE of special interest with EV A higher rate of serious TRAEs was observed with EV+pembro vs CT

27. 27 EV-302 and EV-103 pooled safety analysis: safety profile aligned with those previously reported for EV+pembro 1 *The majority of the skin reactions that occurred with EV+pembro included maculo-papular rash, macular rash, and papular rash. Grade 3–4 skin reactions occurred in 17% of patients, including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). AE, adverse event; EV, enfortumab vedotin ; mUC, metastatic urothelial carcinoma; pembro , pembrolizumab; PI, prescribing information. 1. Prescribing information for PADCEV. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s024s025lbl.pdf (last accessed September 2024); 2. Wu S, Adamson A. Dermatol Online J 2019;25:13030/qt4j44w7w6. Of patients with evaluable data who experienced a skin reaction (N=328) 58% 190/328 had complete resolution 42% 138/328 had residual skin reaction 39% 53/137 had residual grade ≥2 skin reactions Of patients with evaluable data who experienced neuropathy (N=296) 11% 33/296 had complete resolution 89% 263/296 had residual neuropathy 50% 132/262 had residual grade ≥2 neuropathy US PI data Clinical image of rash due to EV treatment for mUC . Erythematous, scaly, pruritic papules on the chest and upper abdomen. Similar lesions were present on the back and extremities 2

28. 28 EV-302: treatment discontinuations, interruptions, and TRAEs leading to dose reductions 1,2 Data cut-off: August 8, 2023. TRAEs are any grade by preferred term in ≥20% of patients for any grade in either arm. CT, chemotherapy; EV, enfortumab vedotin ; pembro , pembrolizumab; TRAE, treatment-related adverse event. 1. Powles T, et al. ESMO 2023 (Abstract No. LBA6 – presidential symposium); 2. Powles T, et al. N Engl J Med 2024;390:875–888. EV+pembro : 154 (35%) CT: 80 (18.5%) EV+pembro : 299 (68%) CT: 229 (52.9%) EV+pembro : 179 (40.7%) CT: 164 (37.9%) TRAEs leading to discontinuation EV+pembro : 154 (35%) CT: 80 (18.5%) TRAEs leading to interruption EV+pembro : 299 (68%) CT: 229 (52.9%) TRAEs leading to dose reduction EV+pembro : 179 (40.7%) CT: 164 (37.9%)

29. 29 The current 1L treatment landscape in la/mUC 1–3 Platinum-eligible 2L/3L Subsequent lines Clinical trials PD Cisplatin-eligible only Gem/cis + nivolumab ‡ EV+pembro * † ??? Gem/cis Gem/carbo Erdafitinib * ‡ Sacituzumab govitecan Taxanes Vinflunine No PD Gem/carbo Gem/cis Pembro Atezo 3L Erdafitinib * † ‡ EV † Sacituzumab govitecan * † Taxanes ¶ Vinflunine ¶ Pembro Platinum-ineligible EV+pembro * † (US only) 2L Maintenance avelumab ¶ Maintenance nivolumab Pembro or atezo * 1L Maintenance Now that you know the 1L treatment options... How do you choose which is the best for your patient? * EV+pembro and nivo+gem /cis are not commercialized in Spain. Atezolizumab and pembrolizumab in 1L platinum-ineligible and pembrolizumab in platinum-eligible 2L/3L do not receive reimbursement in Spain. † FDA- and EMA-approved; ‡ESMO-MCBS v1.1 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms); §If FGFR3 mutation is present; ¶This should be assessed within 10 weeks of completion of PBC; **Rechallenge with PBC may be considered if progression occurred 12 months after the end of previous PBC or 12 months after the end of previous PBC and avelumab 1L maintenance. Platinum doublets to be considered if the treatment-free interval from the last PBC is >1 year. To be considered when other therapies are not available. 2 1L, first-line; 2L, second-line; 3L, third-line; atezo , atezolizumab; carbo, carboplatin; cis, cisplatin; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; EV, enfortumab vedotin; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; PBC, platinum-based chemotherapy; PD, progressive disease; pembro , pembrolizumab. 1. Witjes J, et al. 2024. Available at https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer (last accessed September 2024); 2. Powles T, et al. Ann Oncol 2024; doi : 10.1016/j.annonc.2024.03.001; 3. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024).

30. 30 In a rapidly evolving landscape, it is important to consider all treatment options to individualize therapy for each patient 1 *OS data calculated for patients who did not progress on 1L CT; †This was an exploratory post hoc analysis and therefore there are limitations to the interpretation of these data. 1L, first-line; cis, cisplatin; CT, chemotherapy; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; (m)OS, (median) overall survival; PD, progressive disease. 1. Dr Birtle. Personal opinion/experience; 2. Powles T, et al. N Engl J Med 2024;390:875–888; 3. Grivas P, et al. ESMO Open 2023;8:102050; 4. Powles T, et al. N Engl J Med 2020;383:1218–1230; 5. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789. Disease characteristics and comorbidities Access and cost Managing toxicities Shared decision-making Treatment duration Efficacy

31. 31 In a rapidly evolving landscape, it is important to consider all treatment options to individualize therapy for each patient 1 1L, first-line; cis, cisplatin; CT, chemotherapy; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; (m)OS, (median) overall survival; PD, progressive disease. 1. Dr Birtle. Personal opinion/experience; 2. Powles T, et al. N Engl J Med 2024;390:875–888; 3. Grivas P, et al. ESMO Open 2023;8:102050; 4. Powles T, et al. N Engl J Med 2020;383:1218–1230; 5. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789. Efficacy data in 1L la/ mUC treatment landscape 2–5 mOS : 31.5 months 2 EV+pembro 2 Disease characteristics and comorbidities Access and cost Managing toxicities Shared decision-making Treatment duration Efficacy

32. 32 In a rapidly evolving landscape, it is important to consider all treatment options to individualize therapy for each patient 1 *JAVELIN Bladder 100 mOS from randomization: 23.8 months. Data cut-off: June 4, 2021: median follow-up was 38.0 months with avelumab + BSC and 39.6 months with BSC alone (≥2 years in all patients); 2 † In select patients treated with avelumab 1L maintenance following no PD on 1L PBC. Median follow-up of ≥38 months. OS data calculated from the start of 1L CT is inclusive of 4–6 cycles of platinum-containing CT, 4–10 weeks of treatment-free interval, randomized study treatment with avelumab + BSC or BSC alone, and subsequent therapy. This is an exploratory, post hoc analysis of OS data calculated from the start of CT, and there are limitations to the interpretation of these data. 1L, first-line; cis, cisplatin; CT, chemotherapy; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; (m)OS, (median) overall survival; PD, progressive disease. 1. Dr Birtle. Personal opinion/experience; 2. Powles T, et al. N Engl J Med 2024;390:875–888; 3. Grivas P, et al. ESMO Open 2023;8:102050; 4. Powles T, et al. J Clin Oncol 2023;41:3486–3492 ; 5. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789. Efficacy data in 1L la/ mUC treatment landscape 2–5 mOS: 29.7 months from start of 1L platinum-based CT †3 Avelumab maintenance (no PD on 1L PBC)* 2,3 Disease characteristics and comorbidities Access and cost Managing toxicities Shared decision-making Treatment duration Efficacy

33. 33 In a rapidly evolving landscape, it is important to consider all treatment options to individualize therapy for each patient 1 1L, first-line; cis, cisplatin; CT, chemotherapy; gem, gemcitabine; la/ mUC , locally advanced/metastatic urothelial carcinoma; (m)OS, (median) overall survival; PD, progressive disease. 1. Dr Birtle. P ersonal opinion/experience; 2. Powles T, et al. N Engl J Med 2024;390:875–888; 3. Grivas P, et al. ESMO Open 2023;8:102050; 4. Powles T, et al. N Engl J Med 2020;383:1218–1230; 5. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789. Efficacy data in 1L la/ mUC treatment landscape 2–5 mOS : 21.7 months 5 Nivolumab + gem/cis 5 (cis-eligible only) Disease characteristics and comorbidities Access and cost Managing toxicities Shared decision-making Treatment duration Efficacy

34. 34 With the addition of emerging treatment options, defining eligibility and ineligibility criteria for identifying appropriate patients is crucial In a rapidly evolving landscape, it is important to consider all treatment options to individualize therapy for each patient 1 1. Dr Birtle, personal opinion/experience. Disease characteristics and comorbidities Access and cost Managing toxicities Shared decision-making Treatment duration Efficacy

35. 35 First-line treatment with PBC in patients with la/mUC continues to be guided by platinum eligibility criteria 1,2 Patients meeting one of the following five criteria may be deemed: Grade ≥2 neuropathy Galsky criteria for cisplatin-ineligibility 1 ECOG PS ≥2 CrCl <60 mL/min NYHA heart failure c lass III Grade ≥2 hearing loss Cisplatin-ineligible Gupta criteria for platinum-ineligibility 2 ECOG PS ≥3 CrCl <30 mL/min NYHA heart failure c lass >III ECOG PS 2 and CrCl <30 mL/min Platinum-ineligible* *Based on a survey of 60 genitourinary medical oncologists in the US. CrCl , creatinine clearance; ECOG PS, European Cooperative Oncology Group performance status; la/mUC, locally advanced/metastatic urothelial carcinoma; NYHA, New York Heart Association; PBC, platinum-based chemotherapy . 1. Galsky MD, et al. J Clin Oncol 2011;29:2432–2438; 2. Gupta S, et al. ASCO 2022 (Abstract No. 4577 – poster).

36. 36 EVITA: proposed EV ineligibility criteria 1 ECOG PS ≥2 CrCl or GFR ≤45 mL/min Grade ≥2 sensory or motor neuropathy Patients meeting at least two of the criteria may be deemed unsuitable for EV+pembro treatment: Any corneal or retinal abnormality Hemoglobin A1c ≥8% CrCl , creatinine clearance; ECOG PS, European Cooperative Oncology Group performance status; EUO, Eur Urol Oncol; EV, enfortumab vedotin; GFR, glomerular filtration rate; pembro , pembrolizumab. 1. Grande E, et al. Eur Urol 2024;390:875–888 (editorial). Recently published in EUO Autoimmune disease that has required systemic treatment in the past 2 years

37. 37 Platinum eligibility criteria remain relevant for EV+pembro in Europe 1,2 EV indication: Adult patients with unresectable or metastatic UC who are platinum-eligible 2 EMA approval of EV+pembro for 1L treatment of aUC in platinum-eligible patients 1 1L, first-line; aUC , advanced urothelial carcinoma; EMA, European Medicines Agency; EV, enfortumab vedotin ; pembro , pembrolizumab; UC, urothelial carcinoma. 1. Astellas. 2024. Available at https://www.astellas.com/en/news/29371 (last accessed September 2024); 2. EMA. Available at https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-padcev-ii-13_en.pdf (last accessed September 2024). “ Padcev , in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy ” 2

38. 38 mOS: 29.7 months 1,2 Conclusion: 1L treatment regimens for patients with la/mUC 1–4 1L, first-line; aUC , advanced urothelial carcinoma; cis, cisplatin; EV, enfortumab vedotin ; gem, gemcitabine; IO, immunotherapy; la/ mUC , locally advanced or urothelial carcinoma; mOS , median overall survival; PBC, platinum-based chemotherapy; PD, progressive disease. 1. Powles T, et al. N Engl J Med 2020;383:1218–1230; 2. Grivas P, et al. ESMO Open 2023;8:102050; 3. Powles T, et al. N Engl J Med 2024;390:875–888; 4. Van der Heijden MS, et al. N Engl J Med 2023;389:1778–1789. JAVELIN Bladder 100 ( post hoc analysis from start of 1L PBC) Positive Phase III studies with IO in 1L aUC * EV + pembrolizumab For patients who are platinum-eligible Cis /gem + nivolumab For patients who are cisplatin-eligible mOS: 31.5 months 3 mOS: 21.7 months 4

39. 39 Title of Presentation | DD.MM.YYYY Enfortumab Vedotin + Pembrolizumab (EV+P) Nivolumab + Gemcitabine/ Cisplatin ( Nivo+GC ) * GC + Maintenance Avelumab Criteria Category Not an absolute barrier: • Can be used in patients with renal impairment, including those on dialysis. • Dosing adjustments for EV are based on GFR. • A key advantage over cisplatin -based therapy. Absolute Exclusion for Cisplatin : • Requires GFR ≥ 60 mL/min to receive the cisplatin component. This is a major barrier for many patients. Critical for Chemo Phase: •  Cisplatin -containing: Requires GFR ≥ 50-60 mL/min. • Carboplatin-allowed: For cisplatin -ineligible pts ( GFR often ≥30 ). For Avelumab : No strict cutoff, but severe impairment may exclude. Renal Function More Lenient: • Approved for patients with ECOG PS 0-2. This includes a broader, frailer patient population. Strict: • Typically requires good PS (ECOG 0-1 ) to tolerate the intensive triple-drug combo. Strict for Chemo: • ECOG PS 0-1 required to start chemo. For Maintenance: • Avelumab is only started if PS is 0-2 and disease is stable/responding. Performance Status (PS) Key Exclusion: • Current or recent use of immunosuppressive therapy for autoimmune disease . History of severe (CNS) autoimmune disease. Key Exclusion: • Active autoimmune disease requiring systemic treatment in past 2 years. Key Exclusion: • Active autoimmune disease requiring immunosuppression in last 2 years. History of severe autoimmune disease. Autoimmune Disease Absolute Exclusion : • Pre-existing Grade ≥2 neuropathy is a major exclusion due to the high risk of worsening from Enfortumab Vedotin (a vedotin ADC). Relative Concern: • Grade ≥2 may exclude from cisplatin . Gemcitabine can also cause neuropathy. Relative Concern : • Grade ≥2 may exclude from cisplatin , leading to use of carboplatin instead. Peripheral Neuropathy Heightened Importance : • Pre-existing severe skin conditions are a significant concern due to the high incidence of skin reactions (rash, pruritus) with EV. Standard Exclusion: • Active uncontrolled skin disease. Standard Exclusion: • Active uncontrolled skin disease (e.g., severe psoriasis, pemphigus). Skin Disorders Critical Exclusion : • Uncontrolled diabetes (HbA1c ≥8% or fasting glucose ≥160 mg/ dL ). • EV can cause hyperglycemia, a serious and potentially fatal side effect. Standard monitoring. Standard monitoring. Diabetes & Hyperglycemia •  Ocular Disease : Active keratitis or corneal ulcers. • Requires adequate bone marrow, liver, and cardiac function to tolerate GC chemo. • No progression on initial chemo. • No unresolved toxicities (>Grade 1) from chemo before starting avelumab . Key Unique Exclusions

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