1. Fuerst, Mark L.

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Adjuvant nivolumab should be considered the new standard of care for patients with muscle-invasive urothelial carcinoma with high risk for recurrence despite neoadjuvant chemotherapy or for those who are ineligible for or decline cisplatin-based chemotherapy. These results are from the Phase III CheckMate 274 trial presented at the 2021 ASCO Genitourinary Cancers Symposium (Abstract 391).

Urothelial Carcinoma... - Click to enlarge in new windowUrothelial Carcinoma. Urothelial Carcinoma

The current standard-of-care treatment for muscle-invasive urothelial carcinoma is cisplatin-based neoadjuvant therapy followed by radical surgery. However, some patients may be ineligible to receive cisplatin due to factors such as inadequate kidney function.


"People with muscle-invasive urothelial carcinoma often undergo major surgery to remove their bladders as a life-saving measure, but still face a probability of about 50 percent that their cancer will recur," said lead author Dean F. Bajorin, MD, a genitourinary oncologist at Memorial Sloan Kettering Cancer Center, who presented the study results.


"In the CheckMate 274 trial, patients who received nivolumab lived almost twice as long without their disease recurring compared to those treated with placebo. These clinically meaningful results have the potential to change the way physicians treat muscle-invasive urothelial carcinoma, helping address the pressing unmet need for efficacious, tolerable therapies following surgery."

Dean F. Bajorin, MD.... - Click to enlarge in new windowDean F. Bajorin, MD. Dean F. Bajorin, MD

Nivolumab is an immunotherapy that works by blocking the protein PD-L1 from binding to another protein, PD-1, found on T cells. When PD-L1 and PD-1 bind, T cells are prevented from killing cancer cells. By blocking PD-L1, nivolumab allows T cells to kill cancer cells.


About the Study

Treatment with the immunotherapy nivolumab following radical surgery with or without cisplatin-based chemotherapy significantly improved disease-free survival (DFS) in patients with muscle-invasive urothelial carcinoma.


The randomized, double-blind, multi-center CheckMate 274 study compared nivolumab to placebo in 709 patients with muscle-invasive urothelial cancer of the bladder, ureter, or renal pelvis at a high risk of recurrence after radical surgery. Patients had radical surgery with or without neoadjuvant cisplatin-based chemotherapy and were at high risk for recurrence based on the tumor stage at surgery. They were randomized to receive nivolumab 240 mg every 2 weeks or placebo for up to 1 year. The primary endpoints of the trial are DFS in all randomized patients and in the subset of patients whose tumors express PD-L1 >=1 percent.


Key Findings

Across all randomized patients, nivolumab nearly doubled the average length of time patients lived without disease recurrence, demonstrating a median DFS of 21 months compared to 10.9 months with placebo, a risk reduction of 30 percent. In patients whose tumors express PD-L1 >=1 percent, nivolumab reduced the risk of disease recurrence or death by 47 percent, with the median DFS not reached for nivolumab versus 10.8 months for placebo.


Nivolumab also demonstrated improvements in key secondary endpoints, including non-urothelial tract recurrence-free survival (NUTRFS), defined as the time that patients lived without disease recurrence outside of the bladder, ureters, or renal pelvis. In all randomized patients, those treated with nivolumab showed a median NUTRFS of more than 2 years (24.6 months) compared to 13.7 months for placebo. In patients whose tumors express PD-L1 >=1 percent, median NUTRFS was not reached with nivolumab versus 10.9 months with placebo.


The safety profile of nivolumab was consistent with previously reported studies in patients with solid tumors. Treatment-related adverse events (TRAEs) occurred in 77.5 percent of patients who received nivolumab versus 55.5 percent of patients who received placebo, while Grade 3 or 4 TRAEs were observed in 17.9 percent versus 7.2 percent of patients, respectively. The most common grade 3 or higher treatment-related side effects were diarrhea, colitis, and pneumonitis in the nivolumab arm and colitis, diarrhea, gamma-glutamyl transferase increase, and hepatitis in the placebo arm.


"Nivolumab is the first immune therapy to be used in the adjuvant setting that provides a statistically significant and clinically meaningful improvement in disease-free survival for patients with high-risk muscle-invasive urothelial carcinoma after radical surgery with curative intent, irrespective of PD-L1 status," said Bajorin.


In order to examine the impact of nivolumab on overall survival and cancer-specific survival, longer follow-up is needed, he said.


ASCO expert Robert Dreicer, MD, MS, Deputy Director of the UVA Cancer Center, commented: "Even with the current standard of care-surgery with or without pre-surgery chemotherapy-muscle-invasive urothelial carcinoma has a high risk of recurring. These new findings show that treating patients at highest risk of recurrence with an immunotherapy after surgery can help extend the time until the disease returns."


Mark L. Fuerst is a contributing writer.