Two recent studies have offered new insights into the treatment of muscle-invasive urothelial carcinoma following cystectomy, according to findings presented by Powles et al and Galsky et al at the European Association of Urology Congress 2024. The research could allow physicians to target treatments more effectively to patients who need it and spare those in whom further treatment is unnecessary.
Background
Muscle-invasive urothelial carcinoma is an advanced form of bladder cancer in which the tumor has spread into the bladder wall. Although the disease is often treated with cystectomy, around 50% of patients may see cancer recurrence in the lungs within 2 to 3 years. All patients who undergo cystectomy are currently offered follow-up treatments such as chemotherapy or immunotherapy to prevent recurrence; however, the side effects can be severe.
Findings From IMvigor011 Trial
In the screening phase of the phase III IMvigor011 trial, researchers recruited patients with high-risk muscle-invasive urothelial carcinoma and tested them for circulating tumor DNA (ctDNA) postcystectomy. The researchers then randomly assigned the patients who exhibited positive ctDNA test results to receive either the immunotherapy atezolizumab or placebo. Those with negative ctDNA test results were given no further treatment but were followed up with scans and further ctDNA tests for up to 2 years. They noted that 171 patients with negative ctDNA results were included in the new analysis—and follow-up continued on 115 of them.
The researchers found that 90.1% (n = 154) of the patients with negative ctDNA results did not experience disease relapse, and 9.9% (n = 17) of the patients saw their cancer return within 2 years. These outcomes were irrespective of the stage their tumor was at or whether it showed elevated levels of PD-L1. The researchers highlighted that the use of a ctDNA test could allow some patients to be spared further treatment with minimal risk.
Findings From CheckMate 274 Trial
In the phase III CheckMate 274 trial, researchers randomly assigned 700 patients with high-risk muscle-invasive urothelial carcinoma to receive either the immunotherapy nivolumab or placebo every 2 weeks for 12 months following cystectomy. The patients were also tested to see if their cancer had elevated PD-L1 levels, which nivolumab specifically targets.
The CheckMate 274 trial has already reported that nivolumab can successfully reduce cancer recurrence—particularly for patients with higher PD-L1 levels—but these interim results are the first to show the potential overall survival benefit in these patients.
Among all of the patients, the patients who received nivolumab experienced recurrence-free survival of 22 months vs 10 months among those who received placebo. Among the patients in the PD-L1 group, the patients who received nivolumab experienced recurrence-free survival of over 4 years vs 8 months among those who received placebo. Additionally, compared with those who received placebo, the patients who received nivolumab experienced an average overall survival of 69.5 months vs 50.1 months. The researchers noted that they don’t yet have enough follow-up data to separate out the PD-L1 patients, but the analysis has demonstrated that the overall survival benefit may be greater in this group when treated with nivolumab.
Conclusions
The researchers involved in the IMvigor011 trial emphasized that testing for ctDNA in the blood may successfully identify patients with advanced urothelial carcinoma who may not relapse following surgery.
“These results are even better than we were hoping. The risk of relapse in this ctDNA group of patients is just one in 10. It appears this test can effectively filter patients into two groups: those who are likely to relapse and those at much lower risk. Focusing treatment on those at risk and sparing the very low risk group potentially life-altering treatment-related side effects is attractive. Hopefully these data will allow patients to remain treatment free with the reassurance they need, that they’re unlikely to see their cancer return,” suggested lead study author Thomas Powles, MD, of the Barts Cancer Institute.
“We know that patients with high-risk [muscle-invasive urothelial carcinoma] are at highest risk for recurrence within the first 3 years after surgery. We’ve now followed a substantial subset of patients for longer than that on this study without recurrence. It looks as if the improvement in disease-free survival is ultimately going to translate into improvement in overall survival—and that’s for all patients, but particularly patients with the PD-L1 biomarker. Our hope is that this improvement will then translate into an increased likelihood of curing cancer in these patients,” underscored lead study author Matthew Galsky, MD, of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.
“Although we already knew that nivolumab improved disease-free survival in patients [with muscle-invasive urothelial carcinoma] who received radical surgery, overall survival is what really matters following local treatment such as radical surgery. These interim findings, which show that overall survival also improves, are very encouraging, particularly as this hasn’t been the case in other recent immunotherapy trials,” underlined Joost Boormans, MD, PhD, Professor of Urology at the Erasmus University Medical Centre in the Netherlands and a member of the European Association of Urology Scientific Congress Office.
“The question for regulators and health-care authorities is whether the improvement in overall survival is enough to justify licensing or prescribing the drug for all patients in the knowledge that some of these patients would have been cured of their cancer by surgery alone. This is where the findings from the IMvigor011 trial could really make a difference, by allowing us to select patients at highest risk who will benefit the most from treatment while sparing others for whom it isn’t needed. At a time when health-care resources are under pressure, this kind of innovation is really needed,” he concluded.
Disclosure: The IMvigor011 trial was sponsored by F. Hoffmann-La Roche. The CheckMate 274 trial was funded by Bristol Myers Squibb and Ono Pharmaceutical.
