(UroToday.com) The 2024 IBCN annual meeting included a session on advancements in circulating biomarkers, featuring a presentation by Dr. Brigida Maiorano discussing the biomarker analysis from the Nure-COMBO trial assessing neoadjuvant nivolumab + nab-paclitaxel in muscle invasive bladder cancer. Approximately 20% of patients with urothelial carcinoma are staged with muscle invasive bladder cancer at the time of diagnosis. After radical cystectomy, >40% will relapse within 2 years, with neoadjuvant chemotherapy improving the 5 year overall survival rate by 6% in cisplatin eligible patients. Importantly, approximately 50% of muscle invasive bladder cancer patients are unfit for cisplatin-based chemotherapy. Previous work with immune checkpoint inhibitors suggests they are highly active in the peri-operative setting, with initial data suggesting that Nab-paclitaxel is active when combined with immune checkpoint inhibitors in urothelial carcinoma. However, not all muscle invasive bladder cancer patients benefit from immune checkpoint inhibitor-based treatment, thus prognostic and predictive biomarkers are needed. Nure-Combo was the first study that demonstrated the efficacy of neoadjuvant nivolumab + nab-paclitaxel followed by radical cystectomy in patients affected by muscle invasive bladder cancer. The trial design of the Nure-COMBO trial is as follows:
The identification of predictive biomarkers of pathological complete response (ypT0N0) to neoadjuvant therapies is a primary goal of ongoing clinical research in muscle invasive bladder cancer. For this trial, peripheral fresh blood samples from all patients were collected at 5 time points:
- Baseline (T0)
- Before 2nd cycle of neoadjuvant therapy (T1)
- Before radical cystectomy (T2)
- After radical cystectomy (T3)
- End of treatment (T4)
Circulating myeloid cells (CD33+/CD11b+) levels were identified by flow cytometry in the laboratory and two populations were identified: polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), defined as CD33+/CD11b+/HLADR-/CD15+/CD66b+, and monocytic myeloid cells, defined as CD33+/CD11b+/HLADRint/CD14+/CD66b-. In the present analyses, Dr. Maiorano reported results from T0, T1, and T2.
There were 31 patients enrolled from December 2021 to June 2023, with the following demographics and clinical characteristics:
Total CD11b+CD33+ myeloid cells were elevated in partial responders (ypTis/a/1) and non-responders (ypT≥2 and/or ypN+; 70.4%) compared with pathological complete response (52.7%) blood samples (p = 0.024):
When they characterized the phenotype of these cells, they found that PMN-MDSCs were more represented in partial responders/non-responders (median: 58.85% vs 49.4% in pathological complete response, p = 0.029). They also found a higher percentage of CD45+CD14+CD16+ intermediate monocytes in partial responders/non-responders patients at baseline (median: 1.26% vs 0.73%, p = 0.0441). Longitudinal analyses showed that at T1, the fraction of CD11b+CD33+CD14+HLA-DRlow/intermediate monocytic myeloid cells increased in both pathological complete response and partial responders/non-responders, tending to normalize to baseline values at T2. Intermediate monocytes also increased during neoadjuvant therapy in pathological complete response, possibly resulting from treatment-related inflammation.
Dr. Maiorano concluded her presentation by discussing the biomarker analysis from the Nure-COMBO trial assessing neoadjuvant nivolumab + nab-paclitaxel in muscle invasive bladder cancer with the following take-home points:
- NureCOMBO provides clinical evidence that we can expand the use of chemotherapy agents, in combination with immune checkpoint inhibitors, and also beyond platinum
- CD11b+CD33+HLADR-/lowCD15+ PMN-MDSC- like cells and intermediate monocytes are potentially predictive biomarkers of pathologic complete response to pre-operative nab-paclitaxel + nivolumab combination in muscle invasive bladder cancer (at baseline)
- Confirmation in larger studies and with different drugs is warranted
- Future steps include: efficacy results at 2 years of follow-up, correlation between immunological signature and event free survival, and analysis of PBMCs
Presented by: Brigida Maiorano, MD, IRCCS San Raffaele Hospital, Milan, Italy
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, Bern, Switzerland, Thurs, Sept 19 – Sat, Sept 21, 2024.