Gemcitabine/Cisplatin/Nivolumab as Bladder Sparing Therapy in MIBC


A phase 2 study of neoadjuvant gemcitabine, cisplatin, plus nivolumab met its co-primary end point with a positive predictive value of clinical complete response of 0.97 among patients with muscle-invasive bladder cancer.

Bladder Cancer : © SciePro -

Bladder Cancer : © SciePro -

Neoadjuvant gemcitabine, cisplatin, plus nivolumab (Opdivo) following treatment with transurethral resection of bladder tumor (TURBT) was associated with a positive clinical complete response (cCR) rate among patients with muscle-invasive bladder cancer (MIBC) who otherwise would have undergone surgery, according to findings from the phase 2 HCRN GU 16–257 trial (NCT03451331).1

A total of 33 patients achieved a cCR (43%; 95% CI, 32%-55%) and 32 of these patients who achieved a cCR opted to forgo immediate cystectomy. The study met its co-primary end point with a positive predictive value of cCR of 0.97 (95% CI, 0.91-1), with the lower bound of the 95% CI exceeding the pre-specified threshold of 80%.

Somatic alterations in pre-specified genes, including ATM, RB1, FANCC, and ERCC2, or increased tumor mutational burden did not improve the positive predictive value of cCR. Additionally, clinical response assessment identified patients with particularly favorable outcomes and facilitated bladder sparing in the phase 2 trial.

“Genomic, imaging, and immunological biomarkers have the potential to refine this treatment paradigm, but they require further investigation. These findings may help advance a more personalized approach to the management of MIBC,” wrote study authors in findings published in Nature Medicine.

In the investigator-initiated, multicenter, phase 2 study, patients with MIBC were given 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) were offered to proceed without cystectomy vs retain their bladder and receive 8 additional doses of nivolumab, which were administered every 2 weeks, followed by surveillance. Patients who did not achieve a cCR were recommended to proceed with cystectomy.

Patients aged ≥18 years at the time of consent with an ECOG performance status of ≤1 within 28 days before registration, histological evidence of clinically localized muscle-invasive urothelial carcinoma of the bladder, and those who had adequate organ function were eligible for enrollment in the study.2 Patients must have also been a candidate for cystectomy as per treating physician and have adequate archival tissue identified at screening.

Investigators assessed the co-primary end points of cCR rate, defined as cT0 or cTa disease, and the positive predictive value of cCR for a composite outcome for either 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy.1

A total of 76 patients were enrolled, and 72 underwent clinical restaging. One patient did not undergo restaging due to the development of metastatic disease, and 3 patients developed adverse events (AEs), including cerebrovascular accident, deep venous thrombosis, and increase in creatinine. These patients proceeded with cystectomy.

The majority of patients were male (79%), White (76%), and had a UC histology (75%). The median age of patients enrolled was 69 years (range, 39-85), and 57% of patients had a clinically staged cT2N0M0 carcinoma.

Additional findings showed that the median follow-up for patients achieving a cCR was 30 months (range, 18–42 months). Lower baseline clinical T stage correlated with a higher likelihood of a cCR, although cCRs were observed in patients with cT2-T4 disease.

For the secondary end points of median metastasis-free survival (MFS) and overall survival (OS), rates were not reached at the time of the data lock. To further evaluate the prognostic impact of achieving a cCR as related to MFS and OS, a post hoc landmark analysis was performed using the time of clinical restaging as “time 0” and showed that patients who had a cCR experienced significantly longer MFS and OS vs patients who did not achieve a cCR.

For safety, AEs which were most commonly observed included fatigue, anemia, neutropenia, and nausea, including those which were grade ≥3 treatment-emergent adverse events (TEAEs). These TEAEs were seen in 75% of patients and the most common grade ≥3 TEAEs were anemia, neutropenia, and urinary tract infections. Additionally, 1 patient died due to sepsis subsequent to a bowel perforation occurring at the time of cystectomy. This was not attributed to systemic therapy.

“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,” concluded the study authors.


  1. 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 [published online ahead of print, 2023 Oct 2]. Nat Med. 2023;10.1038/s41591-023-02568-1. doi:10.1038/s41591-023-02568-1
  2. Gemcitabine + carboplatin + nivolumab versus gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer. Updated August 14, 2023. Accessed October 24, 2023.
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