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Case 1: Patient Details (Thomas)

Thomas is a 75-year-old man who presents to your practice with gross hematuria, a 4-cm bladder mass, and liver metastases on CT scan. Histology confirms the diagnosis of metastatic urothelial carcinoma.

Thomas is otherwise generally healthy without known comorbidities and with an ECOG performance status score of 1. He was a past smoker but has been abstinent for more than 20 years.

Laboratory testing reveals:

· Creatinine clearance, 45 mL/min

· Other results within normal limits

**Question 1**

What systemic therapy would be most appropriate for this patient?

Correct Answer

Enfortumab vedotin (EV) + pembrolizumab

Incorrect Answers

Gemcitabine + cisplatin followed by nivolumab maintenance

Gemcitabine + carboplatin followed by avelumab maintenance

Rationale/Key Points – Correct Answer

Combination therapy with EV and pembrolizumab is the most appropriate option for Thomas’ initial therapy. EV-pembrolizumab is the preferred first-line treatment for metastatic bladder cancer based on the results of the phase 3 EV-302 clinical trial, which showed that EV and pembrolizumab was associated with significantly better outcomes than platinum-based chemotherapy.1,2

In the open-label, randomized EV-302 trial, patients with previously untreated locally advanced or metastatic urothelial carcinoma were randomized to receive 3-week cycles of EV + pembrolizumab (n = 442) or platinum-based chemotherapy (with or without maintenance therapy) (n = 444). After a median follow-up of 17.2 months, EV-pembrolizumab resulted in significantly longer median progression-free survival (PFS) (12.5 vs 6.3 months; hazard ratio [HR], 0.45; P < .001) and median overall survival (OS) (31.5 vs 16.1 months; HR, 0.47; P < .001).1 These results were supported by long-term 2.5-year follow-up analysis, which showed that median OS in the EV-pembrolizumab arm was 33.8 months compared with 15.9 months in the chemotherapy arm (HR, 0.51).3

If EV-pembrolizumab is not available, platinum-based chemotherapy followed by nivolumab or avelumab maintenance would be a reasonable option for this patient.2

Case 1 Continued: Patient Update

Thomas initiates treatment with EV-pembrolizumab for advanced urothelial carcinoma. After 6 cycles, Thomas has a partial response (PR), with a reduction of 75% in the size of the bladder mass and stable liver metastases.

However, Thomas has now developed mild sensory loss and moderate paresthesia in the fingers and toes (grade 2 peripheral neuropathy).

**Question 2**

How do you address his PN?

Correct Answer

Withhold EV and continue pembrolizumab

Incorrect Answers

Continue treatment at same dose with careful monitoring

Reduce EV dose and continue pembrolizumab

Rationale/Key Points – Correct Answer

For most treatment-related adverse events (AEs) with EV-pembrolizumab, prompt recognition of symptoms and early intervention with dose holding or modification yields the greatest chance of resolution and may extend the time patients can remain on treatment. This is especially true for peripheral neuropathy, which is one of the most common AEs reported with EV treatment and is a cumulative toxicity that can worsen with longer duration of treatment. In the case of grade 2 neuropathy, EV should be withheld until symptoms decrease to grade 1 or resolve completely.4

In the EV-302 trial, 50% of patients treated with EV-pembrolizumab experienced peripheral sensory neuropathy, and 6.8% had grade 3 or higher peripheral neuropathy. Peripheral neuropathy took a median of 6.6 months to improve and 7.2 months to completely resolve. Other common AEs reported with EV-pembrolizumab included pruritus (39.8%), alopecia (33.2%), maculopapular rash (32.7%), fatigue (29.3%), and diarrhea (27.5%).1

Case 1 Continued: Patient Update

You withhold EV and continue pembrolizumab treatment. Over the next 4 months, Thomas maintains his response, with no progression on imaging. During this time, peripheral neuropathy improves to grade 1.

**Question 3**

What is your recommended next step?[cl1]

Correct Answer

Reintroduce EV

Incorrect Answers

Continue montioring

Discontinue EV

Rationale/Key Points – Correct Answer

EV-related peripheral neuropathy often improves or resolves with dose withholding after a median of about 7 months, and EV may be reintroduced once symptoms have improved to grade 1 or resolved completely.4 In EV-103, which evaluated first-line EV-pembrolizumab in cisplatin-ineligible patients with advanced or metastatic urothelial carcinoma, 69.8% of patients who experienced peripheral neuropathy had symptom improvement or resolution at their last assessment.4-6

There is no evidence that dose interruption or reduction reduces the efficacy of EV-pembrolizumab. Indeed, in an exploratory subgroup analysis of complete responders from EV-302, rates of treatment-related AEs leading to dose interruption (71%) and dose reduction (65%) were similar to those reported in the general population.7

Case 1 Continued: Patient Update

After 6 cycles of EV and pembrolizumab, imaging showed the development of new liver lesions.

**Question 4**

What do you recommend?

Correct Answer

Order molecular profiling

Incorrect Answers

Continue EV + pembrolizumab

Switch to gemcitabine + carboplatin

Rationale/Key Points – Correct Answer

Since Thomas has new metastases and has progressed on EV-pembrolizumab, biopsy and molecular profiling of the new liver lesion is recommended, both to confirm tumor histology and to obtain updated biomarker information to help with treatment decision making. Current US guidelines recommend molecular profiling at diagnosis of advanced bladder cancer as well as after disease progression.2 If metastatic site biopsy is not feasible, archival tissue testing or circulating tumor DNA (ctDNA) testing may be considered as an alternative to determine biomarker status.8

When possible, repeat molecular profiling after progression of advanced disease is recommended because the genomic landscape of urothelial carcinoma can change substantially over the course of treatment. In a longitudinal sequencing study, only 28% of mutations were shared between pre-treatment and post-treatment tumor samples from the same patient, showing that tumor clones evolve dynamically under therapeutic pressure. Furthermore, some metastatic or post-treatment lesions acquired new driver alterations not present in the primary tumor, while others lost previously detected alterations, underscoring that reliance on archival tissue may misrepresent the biology of the progressing disease.9 As a result, updated molecular profiling helps ensure that biomarker-directed therapies—such as FGFR inhibitors—are selected based on the current dominant tumor clone and also helps identify newly emergent alterations that may confer eligibility for late-line treatments or clinical trials.

Case 1 Continued: Patient Update

Metastatic site biopsy reveals a pathogenic FGFR3 alteration.

**Question 5**

What is the recommended next line of therapy for this patient?

Correct Answer

Erdafitinib

Incorrect Answers

Gemcitabine + carboplatin

Gemcitabine + cisplatin

Rationale/Key Points – Correct Answer

Since Thomas has a susceptible FGFR3 alteration, an FGFR inhibitor is the preferred treatment approach. Current US guidelines recommend biomarker-directed treatment as second-line therapy for patients with advanced bladder cancer, regardless of previous treatment.2

The use of erdafitinib for patients with previously treated, FGFR2/3-altered advanced or metastatic urothelial carcinoma is supported by the results of the phase 3 THOR clinical trial, which randomized 266 patients to receive erdafitinib or investigator’s choice of chemotherapy (docetaxel or vinflunine). After a median follow-up of 15.9 months, erdafitinib was associated with significantly longer median PFS (5.6 vs 2.7 months; HR, 0.58; P < .001) and median OS (12.1 vs 7.8 months; HR, 0.64; P = .005) than chemotherapy.10

In the THOR clinical trial, the most common erdafitinib-related AEs included hyperphosphatemia (80%), diarrhea (62%), stomatitis (48%), dry mouth (39%), and palmar–plantar erythrodysesthesia (30%). Common grade 3 or 4 erdafitinib-related AEs included palmar–plantar erythrodysesthesia (9.6%), stomatitis (8.1%), onycholysis (5.9%), and hyperphosphatemia (5.2%). Although erdafitinib AEs can typically be managed with dose withholding and/or dose reduction, a subset of patients may need to discontinue treatment.10

Case 1 Continued: Patient Update

Thomas initiates treatment with erdafitinib. In the first 3 months, Thomas requires 3 erdafitinib dose reductions due to dermatologic AEs and central serous retinopathy. He has had substantial unintentional weight loss due to anorexia. On assessment, his ECOG performance status has declined from 1 to 2, and functional impairment has worsened despite supportive measures. He reports reduced engagement in his usual activities and difficulty completing instrumental activities of daily living.

His disease is currently stable, with no new or progressing lesions on imaging. You temporarily halt treatment and then resume at a lower dose.

**Question 6**

If a pathogenic FGFR3 alteration was not present, what would be the most appropriate treatment for this patient after progression on EV + pembrolizumab?[cl2]

Correct Answer

Gemcitabine + carboplatin

Incorrect Answers

Erdafitinib

Gemcitabine + cisplatin

Rationale/Key Points – Correct Answer

An estimated 17% to 21% of patients with advanced urothelial carcinoma have clinically relevant alterations in FGFR3, meaning that most patients will not be eligible for targeted therapy such as erdafitinib.10,11 In the absence of a pathogenic FGFR3 alteration, platinum-based chemotherapy is the most appropriate next-line treatment after EV-pembrolizumab. In a real-world, single-center cohort study of patients who progressed on EV-pembrolizumab, the ORR among patients who received platinum-based chemotherapy was 49%, and the median duration of response was 4.6 months. Ultimately, median OS was 11 months after initiation of chemotherapy.12

Since Thomas is ineligible for cisplatin due to his performance status, gemcitabine-carboplatin is the recommended next-line therapy in the absence of a pathogenic FGFR3 alteration.13

References

1. Powles T, Valderrama Begoña P, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(r)). Bladder cancer. Version 2.2025. 2025. Accessed November 13, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

3. Powles TB, Van der Heijden MS, Loriot Y, et al. Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial. Ann Oncol. 2025;36(10):1212-1219. doi:10.1016/j.annonc.2025.05.536

4. Brower B, McCoy A, Ahmad H, et al. Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer. Front Oncol. 2024;14:1326715. doi:10.3389/fonc.2024.1326715

5. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023;41(1):22-31. doi:10.1200/jco.22.01643

6. Gupta S, Rosenberg JE, McKay RR, et al. Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin + pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up. J Clin Oncol. 2023;41(16_suppl):4505-4505. doi:10.1200/JCO.2023.41.16_suppl.4505

7. Gupta S, Bedke J, Van Der Heijden MS, et al. Exploratory analysis of responders from the phase 3 EV-302 trial of enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025;43(16_suppl):4502-4502. doi:10.1200/JCO.2025.43.16_suppl.4502

8. Bellmunt J, Russell BM, Szabados B, Valderrama BP, Nadal R. Current and Future Role of Circulating DNA in the Diagnosis and Management of Urothelial Carcinoma. Am Soc Clin Oncol Educ Book. 2025;45(2):e471912. doi:10.1200/EDBK-25-471912

9. Faltas BM, Prandi D, Tagawa ST, et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet. 2016;48(12):1490-1499. doi:10.1038/ng.3692

10. Loriot Y, Matsubara N, Park Se H, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023;389(21):1961-1971. doi:10.1056/NEJMoa2308849

11. Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122(5):702-711. doi:10.1002/cncr.29826

12. Sternschuss M, Whiting K, Arbuiso A, et al. Treatment patterns and clinical outcomes with platinum-based chemotherapy after enfortumab vedotin and pembrolizumab in patients with metastatic urothelial carcinoma. J Clin Oncol. 2025;43(16_suppl):4573-4573. doi:10.1200/JCO.2025.43.16_suppl.4573

13. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-2438. doi:10.1200/jco.2011.34.8433

Case 2 Continued: Patient Details

Anita is a 70-year-old woman who presents with progressive weight loss and abdominal discomfort and pain. CT imaging reveals bulky retroperitoneal lymphadenopathy, with the largest node measuring 6 cm. Cystoscopy and transurethral biopsy confirms the diagnosis of urothelial carcinoma of the bladder with nodal metastases.

Anita has type 2 diabetes (T2D) with glycemic parameters above target levels (HbA1c, 9%). She also has grade 2 diabetic neuropathy of the feet. Her ECOG performance status score is 1, and laboratory test results indicate preserved renal and hepatic function.

**Question 1**

What is the most appropriate first-line treatment option?

Correct Answer

Gemcitabine + carboplatin

Incorrect Answers

Gemcitabine + cisplatin

Enfortumab vedotin (EV) + pembrolizumab

Rationale – Correct Answer

Anita is ineligible for both cisplatin and EV, making gemcitabine-carboplatin the most appropriate treatment option for this patient.

In patients with advanced urothelial carcinoma, cisplatin eligibility is determined by the Galsky criteria. According to these criteria, patients with advanced urothelial carcinoma should be considered unfit for cisplatin if they have any of the following1:

· ECOG performance status of ≥2

· Creatinine clearance of ≤60 mL/min

· Grade ≥2 hearing loss

· Grade ≥2 neuropathy

· NYHA Class III heart failure

Treatment with EV is not recommended in patients with certain comorbidities, including those with ongoing grade 2 or higher neuropathy or uncontrolled diabetes due to the risk of worsening neuropathy or hyperglycemia, respectively.2,3

Case 2 Continued: Patient Update?

After completing 4 cycles of gemcitabine plus carboplatin, Anita has a partial response, with an 80% reduction in the size of her retroperitoneal lymph nodes. She is tolerating treatment well overall. Her diabetes remains under routine management, and her baseline peripheral neuropathy is stable without significant worsening.

**Question 2**

What is the most appropriate next step?

Correct Answer

Continue treatment for 2 cycles followed by avelumab maintenance

Incorrect Answers

Continue treatment for 2 cycles followed by observation

Switch to EV + pembrolizumab

Rationale/Key Points – Correct Answer

After Anita completes 6 cycles of chemotherapy, avelumab maintenance therapy is the guideline-recommended treatment strategy based on the results of the JAVELIN Bladder 100 phase 3 clinical trial.4,5

In JAVELIN Bladder 100, 700 patients with advanced or metastatic urothelial carcinoma without progression after 4 to 6 cycles of platinum-based chemotherapy were randomly assigned to receive avelumab maintenance therapy or observation in conjunction with best supportive care. After more than 19 months of follow-up, median overall survival (OS) was significantly longer with avelumab than with observation (21.4 vs 14.3 months; HR, 0.69; P = .001).5 After more than 2 years of follow-up, avelumab maintenance continued to extend OS relative to maintenance (HR, 0.76; P = .0036).6 Adverse events (AEs) reported with avelumab were consistent with its mechanism of action as an immune checkpoint inhibitor, with 29% of patients experiencing immune-related AEs, including 7.0% of patients with a grade 3 immune-related AE.5

Case 2 Continued: Patient Update

After completing chemotherapy, Anita remained on avelumab for nearly 2 years with stable disease. Her most recent follow-up imaging reveals disease progression in multiple lymph nodes.

Updated molecular profiling does not identify FGFR2/3 alterations. HER2 immunohistochemistry (IHC) of the recurrent tumor shows HER2 overexpression with an IHC score of 3+.

Anita still has grade 2 peripheral neuropathy.

**Question 3**

What is your recommended next-line treatment?

Correct Answer

Trastuzumab deruxtecan (T-DXd)

Incorrect Answers

EV monotherapy

EV + pembrolizumab

Rationale/Key Points – Correct Answer

Current US guidelines recommend T-DXd for patients with advanced bladder cancer and HER2 overexpression defined as an IHC score of 3+ based on the results of the open-label phase 2 DESTINY-PanTumor02 trial.4 It is estimated that about 14% of patients with bladder cancer have HER2 overexpression (IHC 3+).7 Given Anita’s HER2 status, T-DXd is the most appropriate next-line treatment.

In DESTINY-PanTumor02, researchers enrolled 267 patients with previously treated advanced or metastatic solid tumors, including 41 patients with bladder cancer, who had HER2 IHC 2+ or 3+ expression. In the bladder cancer cohort, the objective response rate (ORR) with T-DXd was 39.0%, and among the 16 patients with bladder cancer and HER2 IHC 3+ expression, the ORR was 56.3%. Furthermore, in the full bladder cancer cohort, median PFS was 7.0 months, and median OS was 12.8 months.8 Based on the results of this and other studies, T-DXd received pan-tumor approval from the Food & Drug Administration for previously treated HER2 IHC 3+ advanced cancers without other treatment options.9

Case 2 Continued: Patient Update

Anita begins treatment with trastuzumab deruxtecan. After 3 cycles, imaging shows a 70% reduction in the size of her metastatic lymph nodes. However, a CT scan of the chest reveals patchy ground-glass opacities.

**Question 4**

What is your recommended next step?

Correct Answer

Withhold T-DXd and initiate steroids

Incorrect Answers

Continue trastuzumab deruxtecan and initiate steroids

Decrease trastuzumab deruxtecan dose and monitor closely

Rationale/Key Points – Correct Answer

Extensive evidence from breast cancer clinical trials and DESTINY-PanTumor02 has helped to define the toxicity profile of T-DXd. Interstitial lung disease (ILD)/pneumonitis has been reported in 10% to 15% of patients treated with trastuzumab deruxtecan in clinical trials.8,10 Although most cases of ILD are grade 1 or 2, fatal instances of T-DXd–related ILD have been reported in clinical trials.8 As such, routine monitoring with chest CT and early detection of asymptomatic ILD is critically important to allow for appropriate intervention. In Anita’s case of asymptomatic (grade 1) ILD, T-DXd should be withheld until ILD is completely resolved, and steroid therapy may be considered (1 mg/kg/day prednisone). For patients with grade 2 or higher ILD, permanent T-DXd discontinuation is recommended, along with pulmonology referral for more extensive evaluation and treatment.10

Case 2 Continued: Patient Update

T-DXd is withheld, and Anita is started on corticosteroids for suspected treatment-related ILD. Anita is closely monitored. Six weeks after T-DXd withholding, follow-up chest CT shows complete resolution of ground-glass opacities.

**Question 5**

Do you resume treatment with trastuzumab deruxtecan?

Correct Answer

Yes, at a reduced dose

Incorrect Answers

Yes, at the same dose

No, switch to chemotherapy

Rationale/Key Points – Correct Answer

In patients with grade 1 ILD, treatment with T-DXd should not be restarted until complete resolution of signs and symptoms of lung disease. Once ILD has resolved to grade 0, treatment with T-DXd should be restarted, with the restarted dose dependant on the time from dose withholding to ILD resolution. If ILD resolves within 28 days, T-DXd may be reinitiated at the same dose; however, if ILD takes more than 28 days to resolve, T-DXd should be reinitiated at a reduced dose level. Since Anita’s ILD did not resolve within 28 days, T-DXd should be started at a lower dose.

References

1. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-2438. doi:10.1200/jco.2011.34.8433

2. Brower B, McCoy A, Ahmad H, et al. Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer. Front Oncol. 2024;14:1326715. doi:10.3389/fonc.2024.1326715

3. Powles T, Valderrama Begoña P, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(r)). Bladder cancer. Version 2.2025. 2025. Accessed November 13, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

5. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788

6. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023;41(19):3486-3492. doi:10.1200/jco.22.01792

7. Bryant D, Feldman R, Abdulla F, et al. A Real-World Experience in Pan-Tumor Testing for HER2 IHC in More Than 65 000 Solid Tumors. JAMA Oncol. 2025;11(8):919-921. doi:10.1001/jamaoncol.2025.1791

8. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/jco.23.02005

9. US Food & Drug Administration (FDA). FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. 2025. Accessed November 14. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

10. Ciruelos E, García-Sáenz JÁ, Gavilá J, Martín M, Rodríguez CA, Rodríguez-Lescure Á. Safety profile of trastuzumab deruxtecan in advanced breast cancer: Expert opinion on adverse event management. Clinical and Translational Oncology. 2024;26(7):1539-1548. doi:10.1007/s12094-024-03383-x

Case 3: Patient Details[cl3]

James is a 72-year-old man who presents with new-onset gross hematuria. CT imaging reveals a large bladder mass, and cystoscopic evaluation confirms a muscle-invasive urothelial carcinoma. He is a former smoker and reports a history of grade 2 hearing loss[cl4] . His creatinine clearance is 40 [cl5] mL/min, and his ECOG performance status is 1. Despite these comorbidities, the multidisciplinary team determines that he is an appropriate surgical candidate.

**Question 1**

Do you recommend neoadjuvant treatment?

Correct Answer

Yes, EV + pembrolizumab

Incorrect Answers

Yes, gemcitabine + cisplatin

Rationale – Correct Answer

Neoadjuvant EV-pembrolizumab is the recommended neoadjuvant therapy for this patient. The phase 3 KEYNOTE-905/EV-303 trial compared EV-pembrolizumab with observation alone in 344 cisplatin-ineligible patients with MIBC undergoing radical cystectomy and pelvic lymph node dissection. Based on results presented at ESMO 2025, perioperative EV-pembrolizumab significantly extended median event-free survival (EFS) relative to observation (not reached [NR] vs 15.7 months; HR, 0.,40; P < .0001).1 Similarly, EV-pembrolizumab also extended median OS (NR vs 41.7 months; HR, 0.50; P = .0002). The toxicity profile of EV-pembrolizumab was consistent with past studies of the combination regimen and did not appear to increase the rates of surgical complications, highlighting perioperative EV-pembrolizumab as a new standard of care for neoadjuvant therapy in cisplatin-ineligible patients with MIBC undergoing surgery.

Case 3 Continued: Patient Update[JM6]

James receives 3 cycles of EV-pembrolizumab before undergoing radical cystectomy. Pathology reveals pT3N0 disease.

**Question 2**

What treatment do you recommend?

Correct Answer

Adjuvant EV-pembrolizumab

Incorrect Answers

Adjuvant pembrolizumab alone

Adjuvant EV alone

Rationale/Key Points – Correct Answer

After receiving neoadjuvant EV-pembrolizumab and radical cystectomy, James should go on to receive adjuvant EV-pembrolizumab in accordance with the protocol of the phase 3 KEYNOTE-905/EV-303 trial. After patients in the EV-pembrolizumab arm underwent radical cystectomy, they received 6 cycles of EV-pembrolizumab followed by 8 cycles of pembrolizumab monotherapy.2

Case 3 Continued: Patient Update[cl7]

James starts treatment with EV-pembrolizumab. After 6 weeks of adjuvant treatment, he develops a widespread grade 3 erythematous rash involving approximately 40% of his body surface area. You suspect an EV-associated reaction based on the presentation.

**Question 3**

In addition to a dermatology referral, what do you recommend?

Correct Answer

Withhold EV and initiate steroid treatment

Incorrect Answers

Close monitoring

Reduce EV dose and closely monitor

Rationale/Key Points – Correct Answer

Both EV and pembrolizumab are associated with risks of dermatologic toxicity, but EV-related skin reactions usually appear earlier in therapy and often affect flexural, intertriginous, acral, or truncal regions, where the skin may become delicate, thin, or easily damaged due to expression of Nectin-4 in the epidermis and EV-induced direct cytotoxicity.3,4 In contrast, pembrolizumab-related rashes are typically maculopapular or itchy, arise later in the course of treatment, and don’t usually compromise skin integrity.3 Because James developed a widespread erythematous rash around 6 weeks involving areas commonly affected by EV and showing features of skin fragility, the presentation is more consistent with an EV-associated reaction than an immune-mediated reaction.

In a pooled safety population of 680 patients receiving EV monotherapy, 55% of patients experienced cutaneous AEs, with the most common presentations including maculopapular rash and pruritus. Grade 3 cutaneous AEs were reported in 13% of patients and included erythematous rash such as the one experienced by James.4 Because of the extent of the rash in this patient, EV treatment withholding is recommended, with treatment resumption upon improvement of skin rash to grade 1. Supportive care in patients with cutaneous adverse events includes topical steroids, oral antihistamines, and/or oral steroids.4 Because of the extent of James’ skin reaction, both topical steroids and systemic steroids are recommended.

Case 3 Continued: Patient Update

James starts treatment with EV-pembrolizumab. After 12 weeks of adjuvant treatment, James undergoes routine surveillance imaging, which shows new lymph node enlargement consistent with recurrent urothelial carcinoma. Molecular profiling and IHC show no clinically actionable genomic alterations.

He remains in good functional health, with an ECOG performance status of 1.

**Question 4**

What is the most appropriate treatment for this patient?

Correct Answer

Gemcitabine + carboplatin[JM8]

Incorrect Answers

EV monotherapy

EV + pembrolizumab

Rationale/Key Points – Correct Answer

Patients with advanced bladder cancer who have progressed on EV and immunotherapy are eligible for treatment with platinum-based chemotherapy.5 Since this patient is ineligible for cisplatin due to his grade 2 hearing loss, gemcitabine-carboplatin is the recommended next-line therapy.6

Currently, there is no data to support rechallenge with immune checkpoint inhibitors when patients progress.

References

1. Vulsteke C. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at ESMO Congress; Berlin, Germany: October 18, 2025. Accessed November 15, 2025. https://oncologypro.esmo.org/congress-resources/esmo-congress-2025?presentation=perioperative__periop__enfortumab_vedotin__ev__plu.

2. Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303). ClinicalTrials.gov ID: NCT03924895. Updated August 228, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT03924895

3. Brower B, McCoy A, Ahmad H, et al. Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer. Front Oncol. 2024;14:1326715. doi:10.3389/fonc.2024.1326715

4. Lacouture ME, Patel AB, Rosenberg JE, O'Donnell PH. Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin. Oncologist. 2022;27(3):e223-e232. doi:10.1093/oncolo/oyac001

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(r)). Bladder cancer. Version 2.2025. 2025. Accessed November 13, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

6. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-2438. doi:10.1200/jco.2011.34.8433

Case 4: Patient Details

Eleanor is an 85-year-old woman with a history of muscle-invasive urothelial carcinoma treated with radical cystectomy 3 years ago for pT2N0 disease. She is a lifelong nonsmoker and has remained disease-free on surveillance imaging until recently. Over the past several weeks, she has developed new abdominal pain. CT and bone imaging now reveal new liver and bone lesions.

Her ECOG performance status is 0, and her creatinine clearance is 55 mL/min.

**Question 1**

Given this patient’s older age, what is your recommendation for first-line treatment?

Correct Answer

Enfortumab vedotin (EV) + pembrolizumab

Incorrect Answers

Gemcitabine + carboplatin

Pembrolizumab monotherapy

Rationale – Correct Answer

Older age is not a contraindication to EV-pembrolizumab in patients who are otherwise relatively fit without comorbidities such as peripheral neuropathy or uncontrolled diabetes. In a recent exploratory subgroup analysis of EV-302—the phase 3 trial that compared first-line EV-pembrolizumab with chemotherapy in patients with advanced or metastatic urothelial carcinoma—researchers evaluated the clinical outcomes in individuals aged 75 years or older. Among the 210 older patients enrolled in EV-302, EV-pembrolizumab maintained its benefit over chemotherapy, with median overall survival (OS) extended by 49% (24.4 vs 11.6 months). The researchers also showed that the toxicity profile of EV-pembrolizumab in older adults was consistent with that in the general population, supporting the efficacy and safety of EV-pembrolizumab for this patient.1 Pembrolizumab monotherapy is generally recommended only for patients who are ineligible for carboplatin.2

Case 4 Continued: Patient Update

During the second cycle of EV plus pembrolizumab, Eleanor develops acute hyperglycemia. Routine laboratory testing reveals a blood glucose level of 400 mg/dL and additional testing confirms diabetic ketoacidosis (DKA).

The patient is admitted to the hospital, with an urgent endocrinology referral.

**Question 2**

what is the most appropriate next step for this patient?

Correct Answer

Withhold EV and pembrolizumab

Incorrect Answers

Withhold EV and continue pembrolizumab

Withhold pembrolizumab and continue EV

Rationale/Key Points – Correct Answer

Hyperglycemia and diabetic ketoacidoses (DKA) are potentially serious adverse events (AEs) associated with treatment with both EV and immune checkpoint inhibitors such as pembrolizumab. With pembrolizumab, insulin-dependent diabetes is a rare immune-related AE that can occur in about 1.8% of patients treated with immune checkpoint inhibitors and is typically irreversible due to autoimmune-induced islet cell destruction. In contrast, hyperglycemia caused by EV is more common (17%) but typically resolves with appropriate management.3

In cases of EV-pembrolizumab–associated DKA as experienced by this patient, both EV and pembrolizumab should be withheld, and urgent referral to endocrinology and hospital admission are warranted.3

Case 4 Continued: Patient Update

Once Eleanor’s DKA has resolved, scans show partial response. The patient is now on insulin, and her blood glucose is very controlled.

**Question 3**

How do you recommend resuming treatment?

Correct Answer

Resume EV and pembrolizumab

Incorrect Answers

Discontinue pembrolizumab

Discontinue EV

Rationale/Key Points – Correct Answer

It is reasonable to reinitiate EV therapy once patients meet the following criteria3:

· Non-fasting blood glucose levels improved to ≤250 mg/dL

· Clinically stable

· Metabolically stable

With close monitoring, including blood glucose testing prior to each EV dose, EV may be resumed at the same dose level. It is also reasonable to restart EV at a reduced dose level if there are concerns about other toxicities.3

Case 4 Continued: Patient Update

EV-pembrolizumab is resumed at the same dose level once Eleanor’s metabolic status has stabilized. She continues to do well on treatment until cycle 9, when she develops bothersome dry eye symptoms.

**Question 4**[cl9]

What risk factor increases this patient’s risk for ocular disorders with EV treatment?

Correct Answer

Older age

Incorrect Answers

Female sex

History of cystectomy

Rationale/Key Points – Correct Answer

Ocular disorders are common AEs reported with EV therapy, and older age is a risk factor for developing ocular AEs.3 Other risk factors for ocular disorder include contact lens use and a history of keratitis or corneal ulcerations.

The patient should receive symptomatic management for dry eye, which was reported in 24% of patients treated with EV-pembrolizumab in EV-302.4 Supportive care for dry eye associated with EV therapy includes cool compresses over closed eyes and topical treatments as clinically indicated (eg, lubricating ointment, artificial tears, steroid eye drops). Ophthalmology referral is also indicated for evaluation and management of eye AEs.3

1. Mar N, Gupta S, Powles TB, et al. 3073P Enfortumab vedotin (EV) + pembrolizumab (P) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC): An exploratory analysis in older patients (pts) and those with comorbidities from EV-302. Ann Oncol. 2025;36:S1591-S1592. doi:10.1016/j.annonc.2025.08.3687

4. Powles T, Valderrama Begoña P, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

[cl1]Dr. G: We are unable to identify a reference to support dose reduction so we modified the answer options and reworded the rationale to underscore the importance of reintroduction.

"Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤1, then resume treatment reduced by one dose level." (page 3 of the PI at https://astellas.us/docs/PADCEV_label.pdf)

This is also the protocol that was used in the EV-302 trial and is quoted in several review articles.

[cl2]Dr. G: New question and rationale to address non-FGFR population

[cl3]Dr. G: Case 3 still follows your recommended path, but has been updated to reflect the new FDA approval.

[cl4]Dr G: This was added for NIAGARA eligibility – do you still want to include

[cl5]Dr. G: Do you still want this changed from 35 to 40?

[JM6]Colleen: replaced q about NIAGARA postop protocol with q about KN-905 postop protocol

[cl7]Dr. G: Patient details and rationale were adjusted to account for the combination including pembro

[JM8]Colleen: Answer had to be changed since he is no longer eligible for EV monotherapy

[cl9]Dr. G: Question updated to reflect the approved rationale