OncosphereTreatment paradigms · for clinicians
Advanced Bladder / Urothelial cancer
First line for fit patients: enfortumab vedotin + pembrolizumab (EV-302) is the preferred standard (NCCN, ESMO). If EV-pembro is not possible: platinum chemo — gemcitabine-cisplatin + nivolumab (CheckMate-901) or platinum then avelumab maintenance (JAVELIN Bladder 100). Test FGFR3 for later lines.
Insights
Explore cancer history, treatments, and latest research.
Key first-line evidence
- EV-302 (n=886): EV + pembrolizumab vs gemcitabine + platinum. PFS 12.5 vs 6.3 mo (HR 0.45); OS 31.5 vs 16.1 mo (HR 0.47); ORR 67.7% vs 44.4%. [NEJM 2024] Updated analysis (median follow-up 29.1 mo): OS 33.8 vs 15.9 mo (HR 0.51); PFS 12.5 vs 6.3 mo (HR 0.48); confirmed CR 30.4% vs 14.5%. [Ann Oncol 2025] Benefit regardless of cisplatin eligibility and PD-L1.
- CheckMate-901 (cisplatin-eligible): nivolumab + gem-cis vs gem-cis. OS 21.7 vs 18.9 mo (HR 0.78); PFS 7.9 vs 7.6 mo (HR 0.72); CR 21.7% vs 11.8%. [NEJM 2023]
- JAVELIN Bladder 100: avelumab maintenance after response/stable disease on platinum. OS 21.4 vs 14.3 mo (HR 0.69). [NEJM 2020]
JAVELIN OS measured from randomisation after chemotherapy. Do not compare across trials.
Toxicity to anticipate with EV-pembro
Skin reactions (SJS/TEN rare but serious), peripheral neuropathy, hyperglycaemia, ocular surface toxicity, plus immune-related AEs. Check HbA1c and baseline neuropathy.
Later lines
- FGFR3 alteration: erdafitinib (THOR: OS 12.1 vs 7.8 mo vs chemo; HR 0.64). [NEJM 2023] Since Jan 2024 the US label covers susceptible FGFR3 alterations only (FGFR2 dropped), after ≥1 prior systemic line; not recommended if the patient is eligible for but has not yet received a PD-1/PD-L1 inhibitor. [FDA 2024]
- Sacituzumab govitecan: US accelerated indication was withdrawn in 2024 (announced 18 Oct; final 22 Nov 2024) after the confirmatory TROPiCS-04 trial did not improve OS. [FDA]
- HER2-expressing tumours: trastuzumab deruxtecan has a US tumour-agnostic accelerated approval (HER2 IHC 3+, after prior systemic therapy with no satisfactory alternative; DESTINY-PanTumor02 ORR 51.4% across tumour types). [FDA 2024]
Trial design notes
- EV-302: open-label phase 3; enfortumab vedotin 1.25 mg/kg on days 1 and 8 plus pembrolizumab 200 mg on day 1 of 3-week cycles, vs gemcitabine with cisplatin or carboplatin. Dual primary endpoints PFS and OS. [NEJM 2024] EV continues until progression; pembrolizumab is capped (up to 35 cycles).
- CheckMate-901: cisplatin-eligible patients only; nivolumab 360 mg with gem-cis for up to 6 cycles, then nivolumab 480 mg every 4 weeks for up to 2 years. [NEJM 2023] The OS gain is modest and the trial did not test carboplatin.
- JAVELIN Bladder 100: randomised only patients without progression after 4–6 cycles of platinum chemotherapy, so it selects a favourable group; avelumab was given every 2 weeks until progression. [NEJM 2020]
- THOR (cohort 1): FGFR3/2-altered tumours after anti-PD-(L)1 therapy; erdafitinib vs investigator’s choice chemotherapy (docetaxel or vinflunine). Besides OS, PFS was 5.6 vs 2.7 months (HR 0.58) and ORR 45.6% vs 11.5% (investigator-assessed). [NEJM 2023] FDA’s review lists confirmed ORR 35.3% vs 8.5%. [FDA 2024]
Cisplatin eligibility in practice
Commonly used criteria (Galsky consensus): patients are usually considered cisplatin-ineligible with ECOG PS ≥2, creatinine clearance <60 mL/min, grade ≥2 hearing loss or neuropathy, or NYHA class III heart failure. [JCO 2011] Split-dose cisplatin is used in borderline renal function but is not well validated. With EV-pembro, cisplatin eligibility matters less for first-line choice, but it still guides the fallback option.
Monitoring checklist
- EV: blood sugar every cycle (hyperglycaemia can be severe even without diabetes), skin review in cycle 1–2, neuropathy grading, eye lubrication.
- Pembrolizumab/nivolumab/avelumab: TSH, LFTs, creatinine, cortisol if symptoms; educate on colitis and pneumonitis.
- Erdafitinib: serum phosphate (hyperphosphataemia is expected and drives dose titration), ophthalmology for central serous retinopathy, nail and mouth care.
Moving upstream: what changed in earlier-stage bladder cancer (US approvals)
The drugs of the metastatic setting are now being used before relapse, so many patients reaching first-line metastatic therapy will already have seen a PD-1/PD-L1 inhibitor or EV. [FDA]
- Mar 2025 — durvalumab + gemcitabine-cisplatin neoadjuvant, then adjuvant durvalumab after cystectomy, for MIBC (NIAGARA).
- Nov 2025 — EV + pembrolizumab neoadjuvant then adjuvant for cisplatin-ineligible MIBC; Jul 2026 extended to all MIBC patients who are cystectomy candidates.
- May 2026 — atezolizumab adjuvant after cystectomy for MIBC with ctDNA molecular residual disease (FDA-authorised test).
- May 2026 — durvalumab + BCG for BCG-naïve high-risk NMIBC; Oct 2026 — nogapendekin alfa (Anktiva) + BCG widened to BCG-unresponsive papillary-only high-grade NMIBC.
Practical point: record the date and response to any perioperative immunotherapy or EV. Patients relapsing soon after perioperative EV-pembro are not the population studied in EV-302, so its results do not transfer directly; platinum chemotherapy or a clinical trial is the usual tumour-board discussion (editorial opinion, not a guideline statement).
Upper tract and variant histology
Upper-tract urothelial carcinoma was included in the main trials and is treated similarly in the metastatic setting. Pure non-urothelial histologies (squamous, adenocarcinoma, small cell) were largely excluded; small-cell bladder cancer follows small-cell lung cancer–type regimens.
The original oncosphere.in article was image-based and could not be recovered; this is a rewritten, referenced version under the same title.
Sources
- Powles T, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer (EV-302). N Engl J Med 2024;390:875-888
- van der Heijden MS, et al. Nivolumab plus gemcitabine–cisplatin (CheckMate 901). N Engl J Med 2023;389:1778-1789
- Powles T, et al. Avelumab maintenance (JAVELIN Bladder 100). N Engl J Med 2020;383:1218-1230
- Loriot Y, et al. Erdafitinib vs chemotherapy (THOR). N Engl J Med 2023;389:1961-1971
- Powles T, et al. EV-302 updated analysis (2.5-year median follow-up). Ann Oncol 2025
- FDA: erdafitinib regular approval for FGFR3-altered urothelial carcinoma (19 Jan 2024)
- FDA: withdrawn cancer accelerated approvals (sacituzumab govitecan, urothelial — 22 Nov 2024)
- FDA: trastuzumab deruxtecan accelerated approval for HER2-positive (IHC 3+) solid tumors (5 Apr 2024)
- Galsky MD, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 2011;29:2432-8
- FDA Oncology/Hematologic Malignancies Approval Notifications (bladder entries Mar 2025 – Oct 2026)
- NCCN Guidelines — Bladder Cancer
- ESMO Clinical Practice Guidelines — Bladder cancer
Educational summary, not medical advice. Opinions are labelled as such and are the author's own. Approvals and availability in India (CDSCO) may differ from the US/EU.