ESMO 2024: Real-World Characteristics and Outcomes in Patients with Muscle-Invasive Urothelial Carcinoma Treated with Adjuvant Nivolumab with or Without Neoadjuvant Chemotherapy

(UroToday.com) The 2024 European Society for Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13^th and 16^th, 2024 was host to a genitourinary cancers poster session. Dr. Hedyeh Ebrahimi presented the results of a real-world study evaluating the characteristics and outcomes of patients with muscle-invasive urothelial carcinoma (MIUC) receiving nivolumab +/- neoadjuvant chemotherapy.

Nivolumab was approved in 2021 in the adjuvant setting for patients with urothelial carcinoma at high risk of recurrence following radical resection.¹ The CheckMate-274 trial demonstrated improved disease-free survival with adjuvant nivolumab, compared with placebo, in patients with muscle-invasive urothelial carcinoma (MIUC).² With an extended follow-up of CheckMate-274, the interim analysis demonstrated an overall survival benefit of adjuvant nivolumab over placebo.³ 

There is limited real-world evidence on the use of adjuvant nivolumab for MIUC after radical resection, particularly surrounding the use of neoadjuvant chemotherapy (NAC). Evidence from a real-world setting can complement data from the CheckMate 274 trial to inform clinical decision-making. In this study, Dr. Ebrahimi and colleagues described patient characteristics, treatment patterns, and outcomes of real-world patients with MIUC who received adjuvant nivolumab in CheckMate-274, stratified by receipt of prior NAC. The results of this study may inform treatment sequencing for patients with MIUC. 

This was a retrospective, multisite study that relied on extensive medical chart reviews. Physicians in the Cardinal Health Oncology Provider Extended Network (OPEN) were invited to participate. Participating physicians abstracted de-identified patient data from electronic medical records and entered it into a web-based electronic case report form. This study maintained a double-blind design, ensuring anonymity between the physicians and the sponsor. Data were collected between May 11^th, 2023, and June 21^st, 2023. The study was reviewed and overseen by a central institutional review board, which granted a waiver of patient informed consent.
The study inclusion criteria were as follows:

• Adults ≥ 18 years old at confirmed diagnosis of MIUC (stage II-Illa [T2a-T4al) originating in the bladder or upper urinary tract (renal pelvis or ureter)
• Underwent radical resection of MIUC of the bladder or upper urinary tract (renal pelvis or ureter)
• Received adjuvant nivolumab (index date) during index period (e.g., September 1, 2021, and December 11, 2022) and within 120 days of radical resection of MIUC
• ≥6 months of follow-up data available from index treatment date unless deceased before 6 months)

The exclusion criteria were as follows:

• Received therapy for MIUC as part of a clinical trial during the study period
• The patient had MIUC recurrence before treatment with nivolumab or platinum-based chemotherapy

Demographics/clinical characteristics. Treatment patterns. and survival point estimates were summarized by treatment cohort (i.e., NAC versus no NAC) using descriptive statistics. The Kaplan-Meier method was used to estimate time-to-event outcomes, including point estimates at 18 months after nivolumab initiation. For this study, all comparisons conducted were exploratory. Chi-square or t-tests, or their nonparametric equivalents (e.g., Wilcoxon rank-sum test, Fisher’s exact test), were used to test for differences between the cohorts. Log-rank tests and pairwise z-tests were used to test for cohort differences in the Kaplan-Meier curves and fixed time point comparisons, respectively. All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC. USA).

Data were abstracted on 253 patients, of whom 141 (56%) received prior NAC treatment. Patients who received NAC were, on average, younger at MIUC diagnosis (mean: 64 years) than those who did not receive NAC (mean: 71 years). Medicare insurance was less commonly present in patients who received NAC (48%) compared to patients who did not receive NAC (82%). Sex, race, and ethnicity were similar across patients who did or did not receive NAC.

At the initiation of adjuvant nivolumab, a higher proportion of patients who received NAC had stage IIIB disease (31% vs 18%), better functional status (ECOG PS 0 or 1: 97% vs 63%), and fewer comorbidities (mean NCI comorbidity index: 0.3 vs 0.7), compared with patients who did not receive NAC. Most patients who did not receive NAC were cisplatin-ineligible (79%). The criterion most frequently used for determining cisplatin eligibility was creatinine clearance (used for 89% of all patients). The median follow-up from start of adjuvant nivolumab was similar in patients who received NAC compared with those who did not (13.3 vs 12.3 months).
Among patients who received NAC, gemcitabine/cisplatin was the most common neoadjuvant treatment (84%), followed by dose-dense methotrexate + vinblastine + doxorubicin+ cisplatin (ddMVAC: 10%). The median duration of NAC was 2.8 months. All patients had discontinued adjuvant nivolumab at the time of data collection, with a median duration of adjuvant nivolumab of 11.2 months for both patients who received NAC as well as those that did not receive NAC.

Patients who received NAC had better 18-month overall survival compared with patients that did not receive NAC (90% versus 56%).
Patients who received NAC also had better 18-month disease-free survival (82% versus 55%).\
Patients who received NAC also had better 18-month distant metastasis-free survival (87% versus 55%).
Dr. Ebrahimi noted that as these were unadjusted analyses, potential confounding factors were not accounted for. Additionally. the cohorts had relatively short follow-up periods, potentially affecting the robustness of long-term outcomes. 

She concluded as follows:

• Patients who received NAC before adjuvant nivolumab treatment were generally younger, had fewer comorbidities, had better functional status, and presented with higher-stage disease.
• Gemcitabine/cisplatin was the most common NAC received, and patients had similar duration of adjuvant nivolumab treatment regardless of whether they received NAC.
• Compared with patients who received adjuvant nivolumab alone, these findings suggest potentially improved real-world outcomes in patients who received NAC before adjuvant nivolumab, despite having higher-stage disease. This aligns with data from clinical trials showing improved overall survival among patients who received NAC before adjuvant nivolumab.
• Extended follow-up periods and adjustment for potential confounders are necessary to clarify the observed differences and support the application of NAC as standard of care for eligible patients with high-risk MIUC before resection and adjuvant nivolumab.

Presented by: Hedyeh Ebrahimi, MD, MPH, Postdoctoral Fellow, City of Hope, Los Angeles, CA

Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024. 

1. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma.  Accessed on Sep 15, 2024.
2. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021; 384(22):2102-2114.
3. Galsky MD, et al. Oral presentation at the 39^th Annual European Association of Urology (EAU) Congress (EAU24);
April 5-8, 2024; Paris, France.