Adjuvant nivolumab significantly extends DFS in high-risk bladder cancer
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Adjuvant nivolumab extended DFS compared with placebo among patients with high-risk, muscle invasive urothelial carcinoma, according to results of the phase 3 CheckMate 274 trial presented at Genitourinary Cancers Symposium.
Researchers observed “a statistically significant and clinically meaningful improvement in outcomes,” Dean F. Bajorin, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation.
“These results support nivolumab [Opdivo, Bristol Myers Squibb] monotherapy as a new standard of care in the adjuvant setting for patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, regardless of PD-L1 status and prior neoadjuvant chemotherapy,” he added.
Cisplatin-based neoadjuvant therapy followed by radical surgery is the standard of care for patients with high-risk muscle-invasive urothelial carcinoma, and adjuvant therapy is not recommended for patients who receive neoadjuvant therapy, according to study background. No immune checkpoint inhibitor has demonstrated efficacy as adjuvant therapy among patients at high risk for recurrence following radical surgery, Bajorin said.
Bajorin and colleagues conducted the randomized, double-blind, multicenter CheckMate 274 study to evaluate the safety and efficacy of adjuvant nivolumab vs. placebo for this patient population.
The analysis included 709 patients with muscle-invasive urothelial carcinoma following radical surgery with or without neoadjuvant cisplatin-based chemotherapy. Researchers randomly assigned 353 patients (mean age, 65.3 years; 75.1% men) to 240 mg nivolumab every 2 weeks and 356 patients (mean age, 65.9 years; 77.2% men) to placebo every 2 weeks as adjuvant therapy for no more than 1 year.
Patients in the nivolumab and placebo groups had similar baseline characteristics, including tumor origin at first diagnosis (urinary bladder, 79% vs. 78.9%; upper tract, 21% vs. 21.1%), PD-L1 expression of 1% or greater (39.7% vs. 39.9%) and use of neoadjuvant cisplatin (43.3% vs. 43.5%).
DFS among all randomly assigned patients and among those with PD-L1 expression of 1% or greater served as the study’s primary endpoint. Researchers stratified DFS by nodal status, previous neoadjuvant cisplatin and PD-L1 status.
Secondary endpoints included nonurothelial tract RFS, with safety as an exploratory endpoint.
Median follow-up was 20.9 months in the nivolumab group and 19.5 months in the placebo group.
During the study, 53.3% of patients in the nivolumab group and 56.3% of patients in the placebo group discontinued treatment, mostly due to disease recurrence (25.6% nivolumab vs. 42.2% placebo).
Results showed improved DFS with nivolumab vs. placebo in both the intention-to-treat population (median, 21 months vs. 10.9 months; HR = 0.7; 98% CI, 0.54-0.89) and among patients with PD-L1 expression of 1% or greater (median, not reached vs. 10.8 months; HR = 0.53; 98.87% CI, 0.34-0.84).
“Both of these findings were highly statistically significant,” Bajorin said.
The DFS benefit with nivolumab appeared consistent across subgroups, with no differences according to age, sex, region or performance status, he added.
Grade 3 or worse treatment-related adverse events occurred more often in the nivolumab group than the placebo group (17.9% vs. 7.2%). These included increased lipase (5.1% vs. 2.6%) and increased amylase (3.7% vs. 1.4%). Grade 3 or worse treatment-related “select” adverse events, which researchers identified as those with a possible inflammatory mechanism that could warrant more frequent monitoring or a specific intervention, included diarrhea (0.9%), colitis (0.9%) and pneumonitis (0.9%) in the nivolumab group and colitis (0.6%), diarrhea (0.3%), increased gamma-glutamyl transpeptidase (0.3%) and hepatitis (0.3%) in the placebo group.
Researchers observed no deterioration in health-related quality of life with nivolumab vs. placebo.
Longer follow-up is needed to examine the impact of nivolumab on OS and cancer-specific survival, Bajorin said.
Perspective
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Yung Lyou, MD, PhD
Many patients with muscle-invasive urothelial carcinoma are ineligible for or refuse cisplatin-based neoadjuvant chemotherapy prior to their radical cystectomy. Several studies have attempted to see if there is clinical benefit in preventing disease recurrence by giving adjuvant treatment in the form of chemotherapy, radiation or immune checkpoint inhibitors. Unfortunately, with the exception of upper tract urothelial carcinoma, there is only a low level of evidence supporting clinical benefit for adjuvant cisplatin-based chemotherapy. Current National Comprehensive Cancer Network guidelines categorize the recommendation for adjuvant chemotherapy or radiation treatment as 2B, which is below the categories that indicate uniform NCCN consensus that the intervention is appropriate. Further, many patients often are not candidates for cisplatin-based chemotherapy due to poor renal function or performance status.
Previously, the IMvigor010 study attempted to answer the question of whether adjuvant treatment could confer clinical benefit using the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) among patients with muscle-invasive urothelial carcinoma who had undergone radical cystectomy. This large, phase 3 clinical trial showed no difference in PFS or OS between the treatment or observation group.
CheckMate 274 is significant in that it is the first clinical trial to show clinical benefit of an immune checkpoint inhibitor (nivolumab) for adjuvant treatment of muscle-invasive urothelial carcinoma by meeting its primary endpoint of DFS. It is unclear why CheckMate 274 achieved positive results whereas IMvigor010 was a negative study. It could be a difference in trial design (placebo vs. observation) or mechanism of action (anti-PD-1 vs. anti-PD-L1) of the immune checkpoint inhibitor.
Overall, these first results of CheckMate 274 are quite exciting given they have the potential to change current practice. We eagerly await more clinical outcomes data, especially OS, to be presented in the future.
Reference:
Hussain MHA, et al. Abstract 5000. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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Bajorin DF, et al. Abstract 391. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
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