Adjuvant nivolumab improves outcomes in high-risk urothelial cancer
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SAN FRANCISCO — Adjuvant nivolumab improved outcomes compared with placebo for patients with high-risk muscle-invasive urothelial carcinoma, according to study results.
Extended follow-up of the randomized phase 3 CheckMate 274 trial — presented at ASCO Genitourinary Cancers Symposium — showed the agent extended DFS, non-urothelial tract recurrence-free survival and distant metastasis-free survival.
The magnitude of benefit for distant-metastasis free survival improved in both the intent-to-treat population and the subgroup with PD-L1 expression of 1% or greater compared with the primary analysis. The magnitude of benefit for the other measures improved for the PD-L1 subgroup.
“Adjuvant treatment is given for a fixed duration. We’re not treating patients until progression, as happens in the metastatic setting,” researcher Matt D. Galsky, MD, professor of medicine (hematology and medical oncology) and professor of urology at Icahn School of Medicine at Mount Sinai, told Healio. “The assumption that there will be a sustained benefit after discontinuation of treatment is an assumption until it’s proven — particularly with immune checkpoint blockade, where we don’t have as much long-term perioperative data as with chemotherapy. It’s maybe not surprising, but it’s quite important to demonstrate that the effect size across primary, secondary and exploratory endpoints is incredibly stable over time.”
Background and methodology
The double-blind CheckMate 274 included 699 patients with high-risk muscle-invasive urothelial carcinoma who underwent radical resection. All patients had pathologic evidence of urothelial carcinoma at high risk for recurrence, with ECOG performance status of 0 or 1.
Researchers randomly assigned 353 patients (PD-L1 1%, n = 140) to the anti-PD-1 inhibitor nivolumab (Opdivo, Bristol Myers Squibb) dosed at 240 mg every 2 weeks for up to 1 year. The other 346 patients (PD-L1 1%, n = 142) received placebo.
DFS in the intent-to-treat population and among patients with PD-L1 expression in at least 1% of tumor cells served as primary endpoints. OS and non-urothelial tract recurrence-free survival served as secondary endpoints. Exploratory endpoints included distant metastasis-free survival, PFS2, safety and health-related quality of life.
Initial results — based on median follow-up of 20.5 months for nivolumab and 19.5 months for placebo — showed improved DFS with nivolumab in both the intent-to-treat population (median, 21 months vs. 10.9 months; HR = 0.7; 98.22% CI, 0.55-0.9) and among those with PD-L1 expression of 1% or greater (median, not reached vs. 10.8 months; HR = 0.55; 98.72% CI, 0.35-0.85).
Based on those results, nivolumab became a standard of care in this setting.
Updated results
At this year’s ASCO GU, Galsky presented updated results based on median follow-up of 36.1 months for the nivolumab group and 33.9 months for the placebo group.
Researchers again reported improved DFS with nivolumab in the intent-to-treat population (median, 22 months vs. 10.9 months; HR = 0.71; 95% CI, 0.58-0.86) and the PD-L1 subgroup (52.6 months vs. 8.4 months; HR = 0.52; 95% CI, 0.37-0.72).
The DFS benefit persisted in most subgroups, including those evaluated by age, sex, ECOG performance status, nodal status, PD-L1 status and receipt of prior cisplatin-based chemotherapy.
Results showed improved non-urothelial tract recurrence-free survival in the intent-to-treat population (median, 25.9 months vs. 13.7 months; HR = 0.72; 95% CI, 0.59-0.88) and the PD-L1 subgroup (median, 52.6 months vs. 8.4 months; HR = 0.53; 95% CI, 0.38-0.74).
Distant metastasis-free survival outcomes also favored nivolumab in the intent-to-treat population (median, 47.1 months vs. 28.7 months; HR = 0.74; 95% CI, 0.6-0.92) and the PD-L1 subgroup (median, not reached vs. 20.7 months; HR = 0.58; 95% CI, 0.4-0.84).
Researchers also presented data on PFS2, defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic anticancer therapy or death.
Results favored nivolumab in the intent-to-treat population (median, 61.2 months vs. 47.1 months; HR = 0.79; 95% CI, 0.63-0.98) and the PD-L1 subgroup (median, not reached vs. 39.4 months; HR = 0.54; 95% CI, 0.37-0.79).
“PFS2 for an adjuvant study is an interesting concept,” Galsky told Healio. “The effect size was similar to what we have seen with all of the other endpoints. What we do in the adjuvant setting might impact the history of the disease, even in the setting of the next line of treatment, which I don’t think is obvious and is an interesting finding.”
A higher percentage of patients assigned nivolumab experienced treatment-related adverse events (any grade, 79% vs. 56%; grade 3/grade 4, 18% vs. 7%). The most common adverse events that occurred more frequently in the nivolumab arm included pruritus (23% vs. 11%), fatigue (17% vs. 12%), diarrhea (17% vs. 11%) and rash (15% vs. 6%). Researchers reported no new safety signals.
Follow-up will continue for OS.
“These results further support adjuvant nivolumab as a standard of care for patients with muscle-invasive urothelial cancer at high risk for recurrence after radical surgery,” Galsky said.
Perspective
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Scot Niglio, MD
CheckMate 274 is a practice-changing study that led to FDA approval for adjuvant nivolumab in high-risk urothelial carcinoma, the most common bladder cancer histology. For decades, there were limited to zero treatment options in the postsurgical setting for patients with urothelial cancer with high risk for recurrence, especially those who received neoadjuvant cisplatin chemotherapy or were unable to receive chemotherapy altogether. When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable — measuring life expectancy in months to a few years — making this area of research paramount.The updated results presented at ASCO GU show continued benefit in DFS, as well as non-urothelial tract RFS and distant metastasis-free survival, supporting its use as standard-of-care therapy. The OS data are still maturing but all current data remain promising. Patients with urothelial cancer who meet the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence. I will continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.
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Galsky MD, et al. LBA443. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.
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