Perioperative Enfortumab Vedotin and Pembrolizumab Moves Beyond Survival to Value in Bladder Cancer
An economic model published in JAMA Network Open examined whether perioperative enfortumab vedotin plus pembrolizumab offers a cost-effective strategy for patients with localized muscle-invasive bladder cancer who cannot receive cisplatin-based neoadjuvant chemotherapy. The analysis focused on a population that remains clinically important and therapeutically difficult: patients with localized disease who would ordinarily proceed straight to radical cystectomy because cisplatin is not an option. In that setting, treatment decisions are not only about efficacy, but about whether the extra benefit justifies the added cost to the health system.
The model compared two strategies over a 10-year horizon from a Medicare payer perspective. One arm used neoadjuvant EV plus pembrolizumab before radical cystectomy, followed by adjuvant EV plus pembrolizumab. The comparator was radical cystectomy alone. Trial data from KEYNOTE-905/EV-303 informed the effectiveness and safety inputs, with a median follow-up of 25.6 months. Analysts then projected lifetime-like outcomes using a decision-analytic Markov framework, translating short-term trial signals into long-term survival, quality of life, and direct medical costs.
Survival Gains Came With Higher Upfront Spending
The modeled cohort included 10,000 patients with a baseline age of 73 years; 77.9% were men. Over 10 years, adding perioperative EV plus pembrolizumab increased projected survival from 4.12 to 5.63 life-years per patient. Quality-adjusted survival rose from 3.20 to 4.51 QALYs per patient. Those gains did not come free. Total costs increased from $317,513 with surgery alone to $412,160 with the perioperative regimen.
The economic tradeoff was driven by the familiar structure of cancer care spending: more intense treatment early, less spending later if disease control improves. Patients assigned to perioperative EV plus pembrolizumab incurred higher upfront treatment costs, but those costs were partly offset by a steep drop in postprogression spending. Postprogression costs were estimated at $12,578 per patient in the intervention arm versus $238,729 per patient in the control arm. In practical terms, the model assumes that better disease control prevents expensive downstream treatment cascades after recurrence or progression.
The resulting incremental cost-effectiveness ratio was $72,460 per QALY gained, which falls below the prespecified willingness-to-pay threshold of $100,000 per QALY. On that basis, the perioperative strategy met the study definition of cost-effective in the US setting modeled here.
Why the Model Favors Earlier Disease Control
The economic logic is straightforward. For muscle-invasive bladder cancer, delaying systemic therapy until after recurrence can allow micrometastatic disease to establish itself, leading to more expensive and less effective salvage treatment. A perioperative regimen may alter that trajectory by attacking residual disease before surgery and again after cystectomy, when microscopic spread may still be present. In the model, that translated into longer survival and fewer costly downstream events.
The result also reflects a broader pattern in oncology economics: therapies with high drug acquisition costs can still be value-based when they substantially extend life or prevent expensive progression. Here, the projected reduction in postprogression costs was large enough to preserve favorable cost-effectiveness despite the expense of dual immunotherapy and antibody-drug conjugate treatment around surgery.
Sensitivity Analyses Expose the Fragility of Value Claims
The conclusion did not rest on a single set of assumptions. One-way and scenario analyses showed that cost-effectiveness shifted with several inputs, including time horizon length, adjuvant therapy use rates, patient age, postprogression treatment mix, drug costs, and preprogression health utility. In plain terms, the economic case weakens or strengthens depending on how long patients are followed, how often adjuvant treatment is actually delivered, and what price is assigned to the drugs themselves.
A single-sentence takeaway matters here: the value proposition is favorable, but not fixed.
The probabilistic sensitivity analysis reinforced that uncertainty. At the $100,000 per QALY threshold, perioperative EV plus pembrolizumab had a 53% probability of being cost-effective compared with radical cystectomy alone. That figure leaves room for confidence, but not complacency. A probability barely above coin-flip territory means that small changes in assumptions could move the therapy across the cost-effectiveness boundary.
Clinical Meaning for Cisplatin-Ineligible Patients
This study addresses a common therapeutic gap in localized bladder cancer. Cisplatin-based neoadjuvant chemotherapy remains the standard for eligible patients, but nearly half of patients are not eligible and historically have moved directly to surgery without a neoadjuvant systemic option. For those patients, the appearance of a perioperative EV plus pembrolizumab strategy changes the discussion from “surgery alone” to “surgery plus an active systemic program with measurable modeled value.”
The model does not replace clinical outcomes data, and it should not be read as proof that every patient will benefit equally. It does, however, provide a payer-facing estimate that the regimen may be worth the investment when measured against survival and quality-adjusted survival gains. The analysis is especially relevant in the US, where coverage decisions often hinge on whether a regimen can justify its price against a formal threshold.
What Still Depends on Future Follow-Up
The analysis relied on trial-informed inputs from a study with a median follow-up of 25.6 months, then projected those findings over 10 years. That design is standard in health economics, but it carries an unavoidable dependence on assumptions about durability of benefit, future treatment patterns, and long-term toxicity or utility effects. The result is strongest as a model-based estimate, not as a final accounting of lifetime value.
Longer follow-up from KEYNOTE-905/EV-303 will matter for confirming whether the survival advantage persists and whether the downstream savings modeled here appear in routine practice. Drug pricing will also remain central, since the ICER shifted with drug cost assumptions. For now, the economic evaluation suggests that perioperative enfortumab vedotin plus pembrolizumab is a plausible and likely cost-effective option for cisplatin-ineligible patients with localized muscle-invasive bladder cancer, but its final place in practice will depend on how durable the clinical benefit proves to be and how the therapy is priced in the real world.