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Anti-PD-1 immunotherapy after radical surgery in high-risk muscle-invasive urothelial cancer improved disease-free survival (DFS), regardless of PD-L1 status, a randomized phase III trial showed.

In the intent-to-treat (ITT) population of the CheckMate 274 study, DFS reached 21 months in patients who received nivolumab (Opdivo) versus 10.9 months for those assigned to placebo (HR 0.70, 98.31% CI 0.54-0.89, P<0.001), reported Dean Bajorin, MD, of Memorial Sloan Kettering Cancer Center in New York City.

In the PD-L1-positive (≥1%) population, the DFS benefit with nivolumab was even more pronounced, with a median not reached compared to 10.8 months with placebo (HR 0.53, 98.87% CI 0.34-0.84, P<0.001), according to the findings presented at the virtual Genitourinary Cancers Symposium.

"Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma," said Bajorin. "These results support nivolumab monotherapy as a new standard of care in the adjuvant setting."

A previous phase III trial in high-risk muscle-invasive urothelial cancer, IMvigor010, with adjuvant atezolizumab (Tecentriq), an anti-PD-L1 checkpoint inhibitor, over surveillance.

Radical cystectomy is the standard of care in muscle-invasive urothelial cancer of the bladder, ureter, and renal pelvis. Neoadjuvant cisplatin is an option but many are ineligible or refuse this option, and adjuvant therapy is not currently recommended for patients who have already received neoadjuvant therapy, Bajorin explained. Some patients who did not receive neoadjuvant therapy may be offered adjuvant cisplatin-based therapy, but evidence for this approach is low outside of upper tract disease.

While overall survival (OS) data are immature in the current study, Bajorin noted that the DFS curves are clearly separate for both the ITT and PD-L1-positive populations.

"We think, based on those curves, it will translate into an overall survival benefit," he said.

Guru Sonpavde, MD, of Dana-Farber Cancer Institute in Boston, told 名媛直播 that nivolumab will likely become a new standard in this setting.

"In my opinion, this is potentially practice-changing since the co-primary endpoints were met for DFS overall and the PD-L1-positive group," he said. "I also think a DFS benefit with an immune checkpoint inhibitor is highly likely to translate to improved OS."

Sonpavde pointed out that the testing adjuvant pembrolizumab (Keytruda) in this setting has co-primary endpoints of OS and DFS in the ITT population, but the trial is not placebo-controlled and the benefit in the PD-L1-positive subgroup is a secondary endpoint.

"So while data from AMBASSADOR may be thought of as the tie-breaker given the negative adjuvant atezolizumab data (IMvigor010), CheckMate 274 may be the strongest evidence we have for the PD-L1-positive group," said Sonpavde.

He added that post-operative circulating tumor DNA (ctDNA)-guided adjuvant therapy, to assess minimal residual disease, "appeared promising in an , but requires validation."

Study Details

CheckMate 274 was a multicenter phase III trial that randomized 709 patients with high-risk muscle-invasive urothelial cancer to either nivolumab (240 mg every 2 weeks) or placebo for up to a year. Stratification factors included PD-L1 status (<1% or ≥1%), prior neoadjuvant cisplatin-based chemotherapy, and nodal status. DFS in the ITT and PD-L1 populations were the co-primary endpoints.

Most patients had bladder tumors (79%), with the remaining having tumors of the upper tract, 40% had PD-L1 positive disease, and 43% had previously received neoadjuvant therapy.

Subgroup analyses of the ITT group showed benefit was driven by patients with tumors of the urinary bladder (HR 0.62, 95% CI 0.49-0.78), with no benefit seen among those with renal pelvis or ureter tumors. Patients who had already received neoadjuvant therapy fared better with nivolumab than those without pre-operative chemotherapy. Treatment still favored nivolumab in the PD-L1-negative (<1%) population (HR 0.82, 95% CI 0.63-1.06).

Nivolumab also improved non-urothelial tract recurrence-free survival, a secondary endpoint, in both populations, with a median 24.6 months compared to 13.7 months with placebo in the ITT population (HR 0.72, 95% CI 0.58-0.89) and a median not reached versus 10.9 months, respectively, in the PD-L1-positive group (HR 0.54, 95% CI 0.38-0.77).

For the exploratory endpoint of distant metastasis-free survival, nivolumab improved outcomes in both the ITT (35 vs 29 months; HR 0.74, 95% CI 0.58-0.93) and PD-L1 populations (not reached vs 21.2 months; HR 0.60, 95% CI 0.41-0.88).

Toxicity was slightly worse in the nivolumab arm, with the most common adverse events (AEs) with nivolumab including pruritis, fatigue, diarrhea, and rash.

Overall, grade ≥3 AEs occurred in 42.7% of nivolumab-treated patients versus 36.8% with placebo, but treatment-related grade ≥3 AEs occurred in 17.9% versus 7.2%, respectively. Discontinuation for toxicity occurred in 14% of patients in the nivolumab arm compared with 2.3% of those on placebo.

Quality of life outcomes, as measured by the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30), were similar between the two study arms in both the ITT/PD-L1 populations, said Bajorin.

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