What is the best treatment approach for a patient with metastatic urothelial cancer to the retroperitoneum who has failed Gemcitabine (gemcitabine), radiation therapy, Keytruda (pembrolizumab), and enfortumab?

Treatment for Metastatic Urothelial Cancer After Multiple Failed Lines

For a patient with metastatic urothelial cancer who has failed gemcitabine, radiation, pembrolizumab (Keytruda), and enfortumab vedotin, the best treatment option is rechallenge with platinum-based chemotherapy if the patient had a prior response and remains platinum-eligible, or alternatively, erdafitinib if FGFR2/3 genetic alterations are present. 1

Critical Assessment of Prior Therapy

This patient has exhausted the most effective modern therapies for metastatic urothelial cancer:

• First-line therapy: Gemcitabine (likely with platinum, though not specified) 1
• Immunotherapy: Pembrolizumab (PD-1 inhibitor) 1
• Antibody-drug conjugate: Enfortumab vedotin 1
• Local therapy: Radiation 1

The treatment landscape after these agents is limited, and clinical trial enrollment is strongly recommended at this stage. 1

Primary Treatment Recommendation: Platinum Rechallenge

If the patient had a platinum-free interval of ≥6-12 months after initial gemcitabine-based therapy and remains platinum-eligible (GFR >50 mL/min for cisplatin or >30 mL/min for carboplatin), rechallenge with platinum-based chemotherapy is the preferred approach. 1

Evidence for Platinum Rechallenge:

• A retrospective analysis (RISC cohort, n=296) demonstrated that subsequent platinum-based chemotherapy achieved a higher disease control rate (57.4% vs 44.8%, p=0.041) and longer overall survival (7.9 vs 5.5 months, p=0.035) compared to non-platinum-based chemotherapy in platinum-sensitive patients 1
• Platinum sensitivity is defined as progression occurring at least 6-12 months after completion of first-line platinum-based chemotherapy 1

Specific Regimen Options:

• Gemcitabine plus cisplatin (if cisplatin-eligible with GFR >50 mL/min) 1
• Gemcitabine plus carboplatin (if cisplatin-ineligible but GFR >30 mL/min) 1
• Dose-dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) with growth factor support (if excellent performance status and cisplatin-eligible) 1

Alternative Treatment: Erdafitinib for FGFR-Altered Tumors

If the patient has FGFR2/3 mutations or FGFR3 fusions confirmed by FDA-approved testing, erdafitinib is a strong alternative option. 1

Key Points About Erdafitinib:

• Erdafitinib is specifically indicated for patients previously treated with platinum-containing chemotherapy who had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor and who harbor FGFR DNA genomic alterations 1
• FGFR3 alterations are common in urothelial carcinoma, making testing highly relevant 2
• This represents a targeted therapy approach with a different mechanism of action than prior treatments 1

Testing for FGFR2/3 genetic alterations should be performed immediately if not already done, as this may open a therapeutic window. 1, 2

Other Chemotherapy Options

If platinum rechallenge is not feasible (platinum-refractory disease, inadequate renal function, or intolerance), consider the following single-agent chemotherapies:

Taxane-Based Options:

• Paclitaxel monotherapy 1
• Docetaxel monotherapy 1
• Nab-paclitaxel 1

Gemcitabine/Paclitaxel Combination:

• The paclitaxel/gemcitabine combination showed promising response rates in small studies, though it lacks phase 3 RCT validation 1
• This may be considered if the patient has not recently received gemcitabine 1

Vinflunine:

• Vinflunine showed a modest objective response rate (8.6%) and survival benefit only in the per-protocol population of a phase 3 trial 1
• Vinflunine should only be offered as a third- or subsequent-line treatment if immunotherapy or combination chemotherapy is not feasible 1

Other Single Agents:

• Ifosfamide 1
• Pemetrexed (particularly in patients refractory to platinum-containing agents) 1

Alternative Immunotherapy Agents

Although the patient has failed pembrolizumab, other checkpoint inhibitors may be considered, though cross-resistance is likely:

• Atezolizumab (PD-L1 inhibitor) 1
• Nivolumab (PD-1 inhibitor) 1
• Durvalumab (PD-L1 inhibitor) 1
• Avelumab (PD-L1 inhibitor) 1

However, given prior progression on pembrolizumab, the likelihood of response to another checkpoint inhibitor is low, and these should not be prioritized over platinum rechallenge or erdafitinib. 1

Role of Palliative Radiation

Palliative radiation therapy should be strongly considered for symptomatic metastatic sites, particularly bone metastases or sites causing pain or obstruction. 1

• Radiation can be combined with low-dose chemotherapy as a radiosensitizer, though concurrent chemotherapy is inappropriate if high-dose radiation (>3 Gy fractions) is used 1
• Possible radiosensitizing chemotherapy regimens include cisplatin (category 2A), docetaxel or paclitaxel (category 2B), 5-FU with or without mitomycin C (category 2B), capecitabine (category 3), and low-dose gemcitabine (category 2B) 1

Clinical Trial Enrollment

Clinical trial enrollment is strongly recommended for all patients at this stage of disease, as data for subsequent-line therapy beyond third-line are highly variable and limited. 1

• Emerging therapies such as sacituzumab govitecan are being investigated in clinical trials and may be an option for patients who have exhausted standard therapies 1
• Novel combinations and targeted therapies are continuously being evaluated 1

Treatment Algorithm Summary

1. First priority: Assess platinum sensitivity (progression ≥6-12 months after initial platinum therapy) and renal function

   • If platinum-sensitive and adequate renal function → Rechallenge with gemcitabine/cisplatin or gemcitabine/carboplatin 1

2. Second priority: Test for FGFR2/3 alterations if not already done

   • If FGFR2/3 mutations or FGFR3 fusions present → Erdafitinib 1

3. Third priority: If platinum-refractory or FGFR-negative → Consider single-agent chemotherapy

   • Paclitaxel or docetaxel (preferred) 1
   • Gemcitabine/paclitaxel combination 1
   • Vinflunine (if other options exhausted) 1

4. Concurrent consideration: Palliative radiation for symptomatic sites 1

5. Strongly recommended: Clinical trial enrollment 1

Critical Pitfalls to Avoid

• Do not delay FGFR testing – This may be the only targeted therapy option available and should be pursued immediately 1, 2
• Do not attempt platinum rechallenge in platinum-refractory patients (those who progressed during or within 6 months of platinum therapy) – These patients have poor response rates to platinum re-treatment 1
• Do not use carboplatin in place of cisplatin if the patient is cisplatin-eligible – Cisplatin provides superior outcomes when tolerated 1
• Do not overlook performance status – Patients with ECOG performance status >2 may not tolerate aggressive chemotherapy and should be considered for best supportive care or clinical trials 1
• Do not forget palliative care integration – Early palliative care consultation improves quality of life in metastatic disease 1

Expected Outcomes

At this stage of heavily pretreated metastatic urothelial cancer, expected outcomes are modest:

• Median overall survival with subsequent-line chemotherapy is typically 5-7 months 1
• Response rates to single-agent chemotherapy range from 8-30% depending on the agent 1
• Platinum rechallenge in platinum-sensitive patients may achieve disease control rates of approximately 57% 1

The primary goals at this stage are prolonging survival, maintaining quality of life, and controlling symptoms. 1