Adjuvant nivolumab (Opdivo) is FDA-approved for patients with urothelial carcinoma, so it’s integral for clinicians to understand the optimal use of this treatment.
A study presented at the 2021 Society of Urologic Oncology Annual Meeting investigated adjuvant nivolumab in a population of patients with high risk of disease recurrence after radical surgery.1 Matthew D. Galsky, MD, and co-authors found promising outcomes in this population. Galsky is a Professor of Medicine and Director of Genitourinary Medical Oncology at the Icahn School of Medicine, Mount Sinai, and the Co-director of the Center of Excellence for Bladder Cancer and Associate Director for Translational Research at the Tisch Cancer Institute in New York City, New York.
Checkmate 274 is a large, randomized, phase 3 study assessing the potential benefit of adjuvant immune checkpoint blockade in patients with muscle-invasive urothelial cancer at high risk for recurrence after radical surgery. So, this trial enrolled 2 groups of patients: patients who had received neoadjuvant chemotherapy but had residual T2 or higher disease at the time of radical surgery, or patients who hadn't received neoadjuvant cisplatin-based chemotherapy [and] had T3 or higher disease at the time of surgery but were cisplatin-ineligible or declined cisplatin-based adjuvant chemotherapy.
The results of the trial were initially presented at ASCO GU last year, and that was with a minimum of 5.9 months of follow up. At the time, the co-primary end point of disease-free survival in the all-comer population and in the subset of patients with tumors harboring high levels of PDL-1 expression were reported, and both of those endpoints were met in terms of an improvement in disease-free survival with adjuvant nivolumab. Those results were not necessarily surprising in terms of our hypotheses when we designed this study but were somewhat surprising in the context of another study exploring immune checkpoint blockade, which had been reported a little bit earlier and had not shown a benefit.
At the SUO meeting this year, we reported the extended follow-up of the co-primary end point of disease-free survival. Now, there's a minimum follow-up of 11 months, and the intent-to-treat population demonstrated an improvement in disease-free survival with adjuvant nivolumab versus placebo with a hazard ratio of 0.7. That's very consistent with what we saw in the initial report of the data. And the subset of patients with tumors harboring high levels of PDL-1 expression, the improvement in disease free survival with adjuvant nivolumab was associated with a hazard ratio of 0.53. It was 0.55 in the initial report of the data last year, and so very consistent maintenance of the benefit with adjuvant nivolumab now with extended follow up now.
Adjuvant nivolumab has become a standard of care approved by the FDA for the treatment of patients with muscle-invasive urothelial cancer at high risk for recurrence after surgery. There's a number of attempts to further improve upon the use of perioperative immune checkpoint blockade. Several ongoing studies are evaluating the role of neoadjuvant immune checkpoint blockade in combination with chemotherapy, in combination with other drugs, or actually just by itself for the treatment of patients who are cisplatin-ineligible. So, immune checkpoint blockade has really transformed the treatment of patients with metastatic urothelial cancer. It is now transforming the treatment of patients with muscle-invasive urothelial cancer and will likely continue to do so as regiments are moved to the neoadjuvant setting, including novel combinations.
The take-home message here is that adjuvant nivolumab improves disease-free survival in patients with muscle-invasive urothelial cancer at high risk for recurrence after surgery. This includes patients who received neoadjuvant chemotherapy but have residual disease at the time of surgery, or patients who didn't receive neoadjuvant chemotherapy but are at higher risk for recurrence after surgery and are cisplatin-ineligible. And remember, these are 2 patient populations for whom we have not had adjuvant therapies available in the past. So, these are 2 unmet need populations, and it's important to remember these criteria in terms of referring patients to medical oncologist for consideration of adjuvant immune checkpoint blockade.
The secondary end points of this study included non-urothelial tract recurrence-free survival [and] distant metastasis-free survival. All of those end points are going in the same exact direction as the primary endpoints with a very similar effect size. So, [it’s] important to see all of these clinically important end points going in the same direction. Overall survival is also a secondary end point of this study that hasn't been reported yet because it's an event-driven analysis and the number of events [has] not been reached yet to perform that analysis.
1. Galsky MD, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the phase 3 Checkmate 274 trial of adjuvant nivolumab in patients who underwent surgery for high-risk muscle-invasive urothelial carcinoma. Paper presented at: 2021 Society of Urologic Oncology Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster #175