HRQoL is preserved with perioperative EV plus pembrolizumab in MIBC

An exploratory patient-reported outcome (PRO) analysis from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) found that perioperative enfortumab vedotin-ejfv (EV, Padcev) plus pembrolizumab (Keytruda) combined with radical cystectomy and pelvic lymph node dissection (RC + PLND) was not associated with a clinically meaningful detriment in general health-related quality of life (HRQOL), cystectomy-specific HRQOL, or overall health status compared with RC + PLND alone in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or declined cisplatin-based chemotherapy.

Peter H. O'Donnell, MD, the Fred C. Buffett Professor of Medicine at the University of Chicago, presented the data at the 2026 American Society of Clinical Oncology Annual Meeting.¹

Background

In KEYNOTE-905, perioperative EV plus pembrolizumab combined with RC + PLND previously demonstrated significant and meaningful improvements in event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) vs RC + PLND alone in patients with MIBC who were ineligible for or declined cisplatin therapy.² EFS (primary end point): HR, 0.40 (95% CI, 0.28-0.57); 1-sided P < .0001. OS (key secondary end point): HR, 0.50 (95% CI, 0.33-0.74); 1-sided P = .0002. pCR (key secondary end point): 57.1% vs 8.6%; 1-sided P < .000001. Based on these results, EV plus pembrolizumab was approved by the FDA as perioperative treatment for adult patients with MIBC who are ineligible for cisplatin-containing chemotherapy. The current presentation reports prespecified exploratory PROs from this study.

Study design and PRO methods

KEYNOTE-905/EV-303 enrolled adults with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC and at least 50% urothelial histology who were cisplatin ineligible or declining, with ECOG performance status 0 to 2. Patients were randomly assigned 1:1 to RC + PLND alone (control arm; n=174) or neoadjuvant EV (1.25 mg/kg on days 1 and 8 every 3 weeks for 3 cycles) plus pembrolizumab (200 mg intravenously every 3 weeks for 3 cycles), followed by RC + PLND, then adjuvant EV (1.25 mg/kg on days 1 and 8 every 3 weeks for 6 cycles) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 14 cycles) (EV + pembrolizumab arm; n=170).

Four validated PRO instruments were used: the Functional Assessment of Cancer Therapy–General (FACT-G; 27-item questionnaire assessing general HRQOOL; meaningful change threshold, 7 points or greater); the Functional Assessment of Cancer Therapy–Bladder Cystectomy (FACT-BI-Cys; cystectomy-specific symptoms; total score meaningful change threshold, 6-12 points; Trial Outcome Index [TOI] threshold, 5-9 points); the Bladder Cancer Index (BCI; 36-item instrument covering urinary, bowel, and sexual function and bother; meaningful change thresholds: urinary, 6-9 points; bowel, 5-8 points; sexual, 7-11 points); and the Euro-QoL 5-dimension 5-level (EQ-5D-5L) visual analog scale (VAS; self-rated overall health, 0-100; meaningful change threshold, 7 points or greater). Higher scores on all instruments indicate better HRQOL or function.

PRO assessments were collected at baseline and at presurgery weeks 4, 7, and 10, then at postsurgery weeks 9, 12, and 18 and every 12 weeks thereafter in the EV plus pembrolizumab arm, and at baseline, postsurgery week 9, postsurgery week 18, and every 12 weeks thereafter in the control arm. The PRO analysis population comprised all randomly assigned participants who completed a baseline and at least 1 postbaseline PRO assessment. The prespecified primary time point of interest was postsurgery week 18, selected in a blinded fashion as the point at which completion and compliance rates in the overall population approximated 60% and 80%, respectively. PRO changes over time were evaluated in each arm separately; no between-group comparisons were made.

Completion and compliance rates

At postsurgery week 18, completion and compliance rates were considered robust for a perioperative setting involving radical cystectomy. For the FACT-BI-Cys, completion rates were approximately 65% in the EV plus pembrolizumab arm (n=157) and approximately 72% in the control arm (n=104), with compliance rates of approximately 85% and approximately 93%, respectively. Similar patterns were observed for the BCI and EQ-5D-5L. O'Donnell noted that patients who did not complete a week 18 assessment represented less than 10% of patients who had withdrawn from the trial due to an adverse event, and that the disposition of PRO completers mirrored the overall trial population with respect to adjuvant therapy receipt, supporting the representativeness of the data.

General HRQOL and cystectomy-specific outcomes at postsurgery week 18

At postsurgery week 18, mean changes from baseline in the FACT-G total score were -2.73 (95% CI, -6.22 to 0.75) in the EV plus pembrolizumab arm (n=102) and -2.84 (95% CI, -6.11 to 0.43) in the control arm (n=75)—neither of which crossed the 7-point threshold for clinically meaningful deterioration. Mean changes in the FACT-BI-Cys subscale/symptom index total score were 1.31 (95% CI, -0.70 to 3.32) and 1.85 (95% CI, -0.59 to 4.29), respectively, indicating stable or slightly improved cystectomy-specific HRQOL in both arms. FACT-BI-Cys TOI changes were -1.89 (95% CI, -5.61 to 1.84) with EV plus pembrolizumab and -0.58 (95% CI, -4.35 to 3.20) with control. EQ-5D-5L VAS changes were -2.52 (95% CI, -7.23 to 2.19) and -0.39 (95% CI, -5.14 to 4.36), respectively. None of these changes exceeded established thresholds for clinically meaningful deterioration in either arm.

Longitudinal assessment of FACT-G total scores over time showed that the nadir in both arms occurred at postsurgery week 9, consistent with the anticipated functional impact of radical cystectomy, followed by recovery toward baseline values in subsequent assessments. The mean score changes remained within the threshold for clinically meaningful deterioration throughout the observation period in both arms.

"Mean changes in general HRQOL, cystectomy-specific HRQOL, and overall health status did not exceed the established thresholds for a clinically meaningful deterioration," O'Donnell said.

BCI domain scores over time

In the BCI urinary domain, mean change from baseline to postsurgery week 18 was -2.03 (95% CI, -6.12 to 2.07) in the EV plus pembrolizumab arm and -0.05 (95% CI, -5.90 to 5.80) in the control arm—neither exceeding the 6- to 9-point threshold for meaningful deterioration. O'Donnell noted a slight improvement in urinary scores in the EV plus pembrolizumab arm during the presurgical phase, which he attributed to tumor-related symptom relief from effective neoadjuvant therapy. Both arms showed a postsurgical nadir at week 9, with modest recovery over time.

In the BCI bowel domain, mean changes at postsurgery week 18 were -4.75 (95% CI, -8.73 to -0.77) in the EV plus pembrolizumab arm and -4.27 (95% CI, -7.93 to -0.61) in the control arm. These changes approached or slightly crossed the 5- to 8-point meaningful change threshold, with nadir scores occurring at week 9 postsurgery in both arms and subsequent partial recovery. O'Donnell characterized these findings as consistent with the known functional impact of radical cystectomy.^3,4

The most pronounced domain-level decline was observed in BCI sexual scores, where mean changes at postsurgery week 18 were -15.46 (95% CI, -20.53 to -10.39) in the EV plus pembrolizumab arm and -17.88 (95% CI, -24.36 to -11.40) in the control arm, both substantially exceeding the 7- to 11-point threshold for meaningful deterioration. These declines were evident in both arms from postsurgery week 9 onward and persisted over the entire follow-up period. O'Donnell attributed these findings to the surgical procedure itself, noting that they were observed at comparable magnitudes in both arms and are a well-established consequence of radical cystectomy.^3,4

Conclusions

O'Donnell concluded that perioperative EV plus pembrolizumab was not associated with a clinically meaningful detriment in general HRQOL, cystectomy-specific HRQOL, or overall health status relative to cystectomy alone. Declines in BCI bowel and sexual domain scores were observed in both arms and were consistent with the established functional consequences of radical cystectomy rather than representing treatment-specific toxicity.

"Together with the efficacy and safety results, these PRO findings support the overall benefit-risk profile of perioperative EV plus [pembrolizumab] as the new standard of care in this patient population," O'Donnell said.

DISCLOSURES: O’Donnell reported disclosures related to AbbVie, Advarra, American Society for Clinical Pharmacology & Therapeutics, AmerisourceBergen, Astellas Pharma, Axiom Healthcare Strategies, CLD, Inc, Curio Science, EMD Serono, Health Advances, ImmunityBio, IntrinsiQ, Loxo/Lilly, Med-IQ, MedLearning Group, Medscape, Merck, Parexel International Corp, Pfizer, Research to Practice, Thermo Fisher Scientific, Vaniam Group, Acerta Pharma, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Janssen, Seagen, Hart Wagner LLP, NAMCP, Dragonfly Therapeutics, Duke University, G1 Therapeutics, and Nektar.

REFERENCES

1. O'Donnell PH, Adra N, Alimohamed N, et al. Health-related quality of life (HRQoL) with neoadjuvant and adjuvant (neoadj-adj) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin ineligible: phase 3 KEYNOTE-905 study. J Clin Oncol. 2026;44(suppl 16):4510. doi:10.1200/JCO.2026.44.16_suppl.4510

2. Vulsteke C, Adra N, Danchaivijitr P, et al; KEYNOTE-905/EV-303 Investigators. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674

3. Gore JL, Wolff EM, Nash MG, et al; CISTO Collaborative group. Twelve-month results from the CISTO study comparing radical cystectomy versus bladder-sparing therapy for recurrent high-grade non-muscle-invasive bladder cancer. J Clin Oncol. 2026;44(4):274-285. doi:10.1200/JCO-25-01324

4. Griebsch I, Juul K, Bottomley A, et al. Life after radical cystectomy: a mixed-methods targeted review of patient-reported quality of life following bladder removal. BJUI Compass. 2025;6(9):e70049. doi:10.1002/bco2.70049