In HCRN GU 16–257, a phase II, investigator-initiated, multicentre study, neoadjuvant treatment with gemcitabine, cisplatin, plus nivolumab after transurethral resection of bladder tumour (TURBT) was associated with a clinical complete response (cCR) rate of 43% among patients with muscle-invasive bladder cancer (MIBC). Clinical response assessment identified patients with particularly favourable outcomes and facilitated bladder sparing.
Genomic, imaging, and immunological biomarkers have the potential to refine this treatment paradigm, but they require further investigation. The study findings are published by Dr. Matthew D. Galsky of the Division of Hematology and Medical Oncology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, US, and colleagues on 2 October 2023 in the Nature Medicine.
The authors wrote in the background that radical cystectomy is a standard treatment for MIBC. However, radical cystectomy is a life-changing operation due to the need for urinary diversion and is associated with a 90-days mortality risk of up to 6-8%. Neoadjuvant cisplatin-based chemotherapy before radical cystectomy confers improved survival in patients with MIBC. Although the intent of neoadjuvant chemotherapy is eradication of micrometastatic disease, neoadjuvant cisplatin-based chemotherapy after TURBT yields a pathological complete response (pCR) at the time of cystectomy in approximately 30% of patients. Paradoxically, a pCR can be determined only after the bladder has been surgically removed.
Given the potential to achieve a pCR with TURBT followed by neoadjuvant chemotherapy, the need for cystectomy to achieve cure in all patients has been questioned. Early single centre retrospective studies reported that long-term bladder-intact disease-free survival is achievable in a select subset of patients with MIBC treated with TURBT plus systemic therapy, and contemporary retrospective series have substantiated such results.
However, challenges to the broader application of this treatment paradigm have included a paucity of prospective studies, a lack of rigorous and standardised approaches to both measure (that is, clinical restaging) and define cCR, poor understanding of the impact of later cystectomy on cancer control in patients with a cCR who develop local recurrence after a period of initial surveillance, and suboptimal systemic therapeutic regimens.
Single-agent PD-1/PD-L1 immune checkpoint blockade followed by cystectomy for the treatment of MIBC has been shown to yield a pCR in 30-40% of patients. Cisplatin may induce favourable immunomodulatory effects, providing rationale for regimens combining neoadjuvant chemotherapy plus PD-1/PD-L1 blockade. In phase II studies, neoadjuvant gemcitabine, cisplatin, plus PD-1/PD-L1 blockade has demonstrated pCR rates of 40-50%, leading to the initiation of several phase III studies.
The integration of molecular biomarkers may further improve selection of patients with MIBC who could be treated definitively with TURBT plus systemic therapy. Somatic alterations in genes encoding proteins involved in DNA damage repair (DDR) in pre-treatment TURBT tissue have been correlated with a higher pCR rate with cisplatin-based neoadjuvant chemotherapy. DDR gene alterations have also been associated with an increased likelihood of response to PD-1/PD-L1 blockade, potentially mediated by increased tumour mutational burden (TMB), raising the hypothesis that such tumours may be particularly sensitive to cisplatin plus PD-1/PD-L1 blockade combination regimens.
To further evaluate the role of TURBT plus systemic therapy as definitive treatment for MIBC, the study team designed a phase II study integrating cisplatin-based chemotherapy plus PD-1 blockade, standardised clinical restaging, and translational analyses seeking to explore genomic, radiologic, and immunologic biomarkers to refine future patient selection for this approach.
In this phase II study, patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. The primary goal was to test whether uniformly assessed and consistently defined cCR could identify patients who could safely forgo immediate cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy.
A total of 76 patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval [CI] 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anaemia, neutropenia, and nausea.
Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased TMB did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes.
The authors commented that this is among the first prospective studies to test TURBT plus cisplatin-based chemotherapy as definitive bladder-sparing treatment for MIBC, the first to define the performance characteristics of uniformly assessed and defined cCR as a tool for patient selection for this strategy, and the first to integrate immune checkpoint blockade into this approach. The study demonstrates that stringently defined cCR is associated with favourable outcomes and that prolonged bladder-intact survival is achievable in a large subset of patients with MIBC and a cCR to TURBT and gemcitabine, cisplatin, plus nivolumab.
This study was funded by Bristol Myers Squibb, and translational analyses were supported by the V Foundation for Cancer Research. Scientific and financial support for the CIMAC-CIDC Network is provided through NCI Cooperative Agreements. Study GU16-257 was additionally supported through the Foundation for the National Institutes of Health (FNIH), in partnership with Friends of Cancer Research. Scientific and financial support for the Partnership for Accelerating Cancer Therapies public–private partnership are made possible through funding support provided to the FNIH by AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Gilead, GlaxoSmithKline, Janssen, Novartis Institutes for Biomedical Research, Pfizer and Sanofi. This work used the services of the Tisch Cancer Institute Biorepository and Pathology Core.
Reference
Galsky MD, Daneshmand S, Izadmehr S, et al. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial. Nature Medicine; Published online 2 October 2023. DOI: https://doi.org/10.1038/s41591-023-02568-1
