Adjuvant Nivolumab for High-Risk Bladder Cancer

Published - Written by Roma Bhatia, MD

A 65-year-old man visited his oncologist to discuss follow-up treatment for high-risk muscle-invasive urothelial cancer after completing neoadjuvant chemotherapy with cisplatin and undergoing a cystectomy. The patient asked if there was anything else he could do to reduce his risk of experiencing a recurrence of bladder cancer.

Although several immune checkpoint inhibitors are approved for use in advanced bladder cancer based on results of phase 2 and 3 trials, until now, none have shown efficacy as adjuvant therapy in patients with urothelial carcinoma who are at high risk for metastatic recurrence after surgery. Results from a recent phase 3, randomized, placebo-controlled study published in NEJM suggest that the immune checkpoint inhibitor nivolumab might lengthen disease-free survival in such patients.

Researchers randomized patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive treatment (every 2 weeks for up to 1 year) with nivolumab or placebo. In patients who received nivolumab, median disease-free survival was nearly double that of placebo (20.8 months vs. 10.8 months) and the rate of disease-free survival at 6 months was higher (75% vs. 60%). In patients with PD-L1 expression >1%, disease-free survival at 6 months was 75% with nivolumab versus 56% with placebo. Similar trends in disease-free survival were seen at 12 months.

Patients in the nivolumab group also had longer distant metastasis-free survival (40.5 months vs. 29.5 months. At 6 months, 82% of the participants in the nivolumab group were alive and free from distant metastases, versus 70% in the placebo group.  

More patients treated with nivolumab experienced any treatment-related adverse events (78% vs. 56%) as well as grade 3 or higher adverse events (18% vs. 7%). The most common adverse events associated with nivolumab were pruritus, fatigue, and diarrhea. The most common grade 3 or higher adverse effects were elevated lipase or amylase levels, colitis, and pneumonitis. PD-L1 status did not affect frequency or intensity of adverse effects.

Based on these results, the oncologist used principles of shared decision making to explain to this patient that although adjuvant nivolumab might reduce the risk of bladder cancer recurrence, it is associated with a high rate of treatment-related adverse effects that could affect the patients quality of life.

The following NEJM Journal Watch summary further explains details of the study:


Adjuvant Immunotherapy for High-Risk Bladder Cancer

Robert Dreicer, MD, MS, MACP, FASCO, reviewing Bajorin DF et al. N Engl J Med 2021 Jun 3

Disease-free survival was improved with adjuvant nivolumab compared with placebo.

Although level 1 evidence supports the use of neoadjuvant cisplatin-based chemotherapy before radical cystectomy in patients with muscle-invasive bladder cancer, uptake in clinical practice has been uneven and impact on overall survival remains very modest. Several immune checkpoint inhibitors are approved for use in advanced urothelial cancer based on phase 2 and 3 trials.

Investigators conducted an industry-supported international phase 3 trial of adjuvant nivolumab in high-risk urothelial cancer. Patients who underwent radical surgery (cystectomy or nephroureterectomy) with pathologic evidence of high-risk disease, with or without neoadjuvant cisplatin-based chemotherapy, were randomized to nivolumab or placebo every 2 weeks for up to 1 year. Dual primary endpoints were disease-free survival in the intent-to-treat population and in patients with tumor PD-L1 expression ≥1%.

Of 709 patients, median age was 65 years, 79% had primary bladder tumors, and 43% had received neoadjuvant chemotherapy. Median follow-up was approximately 20 months, and median duration of drug exposure was 8.8 and 8.2 months in the nivolumab and placebo arms, respectively. At 6 months, the disease-free survival rate was 74.9% in the nivolumab group versus 60.3% in the placebo group (hazard ratio, 0.70; P<0.001). In PD-L1+ patients, rates were 74.5% versus 55.7% (HR, 0.55; P<0.001).

Treatment-related adverse events occurred in 77.5% of the nivolumab arm and 55.5% of the placebo arm. There were two treatment-related deaths in the nivolumab arm.

Comment: At the time of this analysis the addition of adjuvant nivolumab had not yet resulted in an overall survival benefit in the intent-to-treat population; however, the difference in median disease-free survival with nivolumab (20.8 months) versus placebo (10.8 months) is clinically meaningful. Although it is important to place these findings into context with a recent negative study of adjuvant atezolizumab (Lancet 2021; 22:525), they are provocative and will be evaluated by the FDA in the coming months.


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 Roma is a 2021–2022 NEJM Editorial Fellow.

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