Exploring Neoadjuvant and Adjuvant Therapies for Patients With MIBC

This article is part 1 of a 2-part series from a Case-Based Roundtable event.

Case Summary

• A 74-year-old man presented to his primary care physician with intermittent episodes of painless macrohematuria.

History

• Stage IIIa chronic kidney disease, diabetes mellitus II
• New York Heart Association heart failure grade 2; medications: empagliflozin once daily; enalapril once daily
• Mild chronic obstructive pulmonary disease (COPD)
• Tobacco history: current smoker, 20 pack-years
• Retired textile chemist

Diagnostic workup: Focused physical examination and testing

• ECOG performance status: 1
• Pulmonary:diminished lung sounds, inspiratory rhonchi, expiratory wheezing on auscultation
• Chest x-ray: thick linear opacity consistent with mild COPD; no evidence of pleural effusion
• Laboratory profile:
  • Urinalysis: > 25 red blood cells per high power field (urine culture and sensitivity: negative for infectious etiology)
  • Estimated glomerular filtration rate: 45 mL/min

Action Plan: Refer to urologic oncologist for further evaluation

Evaluation by urologic oncologist

• History of renal insufficiency: cisplatin ineligible
• MRI and Magnetic Resonance Urography
  • Nodular, 6-cm lesion within the left, posterior bladder wall invasive into inner half of muscularis propria
  • No renal parenchymal masses
  • Enlarged single, regional, obturator node, measuring 8 mm
    • No evidence of lymph node involvement or hepatic metastasis
• White Light Cystoscopy + Barbotage
  • Detected single, penetrating lesion of cauliflower morphology along right lateral bladder wall
  • Bladder wash samples and multiple tissue specimens obtained
• Cytohistopathology
  • Nuclear-cytoplasm ratio > 0.7; nuclear pleomorphism; giant nuclei; loss of polarity; coarse chromatin; moderate to severe hyperchromasia
  • High-grade bladder cancer

Surgical Intervention

• Patient underwent radical cystectomy with orthotopic urinary diversion and extended template pelvic lymph node dissection
• Postoperative electrolyte panel: within normal limits
• pT2aN1M0: stage IIIa

Immunohistochemistry

• PD-L1 combined positive score: 70
• Tumor proportion score: 60%
• Staining + for CK7; CK20; p63; uroplakins II and III

Targeted Oncology: What are the recommended regimens for neoadjuvant in muscle-invasive blader cancer (MIBC)?

Matthew Galsky, MD: In the NCCN guidelines for urothelial cancer post cystectomy in patients who are at high risk for recurrence, neoadjuvant therapy is recommended.¹ Cystectomy alone is recommended for patients who are cisplatin ineligible. So right now, we still do not have neoadjuvant therapy for cisplatin-ineligible patients with MIBC. That might change in the not-too-distant future, but right now, we don't.

Which adjuvant therapies are options for patients such as this with MIBC?

Patients with high-risk features are patients with T3 or higher disease and/or pathological evidence of node-positive disease. For NCCN, the preferred adjuvant regimen in patients who are cisplatin eligible is dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]. I could talk for a full hour about whether or not that's supported by data, but that's [in] the NCCN guidelines. There's still a lot of debate about whether or not dose-dense MVAC vs gemcitabine/cisplatin are any different. I think the bulk of the data suggest minimal difference between the regimens. In my practice, I use them interchangeably.

Other recommended regimens are nivolumab [Opdivo], and then for patients who've already received previous neoadjuvant therapy and have T2 or higher disease in their specimen then there's a recommendation for adjuvant nivolumab. Why would the T stage be different in patients who didn't have neoadjuvant therapy and patients who did? If you have residual disease after neoadjuvant therapy, that's probably biologically aggressive disease, and so we know that patients with residual T2 disease after neoadjuvant therapy have outcomes that are pretty similar to patients with T3 disease who haven't had neoadjuvant therapy.

What were the set-up of the trials looking at potential adjuvant therapies this setting?

There were 3 studies designed around the same time asking exactly the same question: should we use adjuvant immune checkpoint blockade in patients with high-risk features after radical resection for urothelial cancer? This was the first generation of studies that included patients with both upper tract disease and patients with bladder cancer. These trials did include patients with ureteral and renal pelvis cancers as well.

The eligibility criteria for all 3 of the studies was virtually identical. If you had neoadjuvant therapy, you had to have T2 or higher disease in your surgical specimen. If you didn't have neoadjuvant therapy, you had to have T3 or high disease in your surgical specimen, and you had to be cisplatin ineligible, because otherwise adjuvant cisplatin-based therapy would be recommended, or patients could refuse cisplatin-based chemotherapy.

Patients were randomly assigned 1:1. CheckMate 274 [NCT02632409] was a placebo-controlled study. The other 2 studies in the space—the one with pembrolizumab [Keytruda] and the one with atezolizumab [Tecentriq]_—did not have placebo controls. They were open-label trials.

DISCLOSURES: Galsky previously reported receiving consulting fees from Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGenInc., Janssen, NumabTherapeutics, Dragonfly Therapeutics, GlaxoSmithKline, Basilea, UroGenPharms, and Rappta Therapeutics.

_Reference:

_{NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer; version 1.2025. Accessed April 11, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf}