Adjuvant Immunotherapy Best for ctDNA⁺ Bladder Cancer

A liquid biopsy may help identify patients with operable urothelial cancer who stand to benefit from adjuvant therapy with a checkpoint inhibitor.

According to a prospective but exploratory endpoint analysis from the phase III IMvigor010 study, patients with muscle-invasive carcinomas of the bladder or upper tract who underwent surgery and then tested positive for circulating tumor DNA (ctDNA) showed improvements in both disease-free survival (DFS) and overall survival (OS) if they received the anti–PD-L1 agent atezolizumab (Tecentriq; Genentech) rather than observation (Nature 2021 Jun 16 [Epub ahead of print]).

No such differences were noted among trial participants who were negative for ctDNA in their blood, a sign of minimal residual disease (MRD)—or, as previously reported, in the overall study population (Lancet Oncol 2021;22:525–37).

The finding “tells you that adjuvant immunotherapy works. It's just a matter of patient selection,” says Matthew Galsky, MD, of the Icahn School of Medicine at Mount Sinai in New York, NY, who was not involved in the study.

Yet in the phase III CheckMate 274 study, which Galsky co-led, unselected patients who received the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) did show significant improvement in DFS compared with those given placebo (N Engl J Med 2021;384:2102–14).

That result might seem to undermine the need for patients to have ctDNA testing. However, methodologic differences—for example, open-label versus double-blind—could account for the divergent findings, with more people in the observation arm dropping out of the IMvigor010 study than did placebo recipients in the CheckMate 274 trial. And according to Alexey Aleshin, MD, senior medical director of oncology at Natera, the company behind the ctDNA assays used in IMvigor010, and a coauthor of the Nature article, “We believe that identifying MRD-positive patients will enrich for benefit, really regardless of the type of drug you use.”

In IMvigor010, 37% of the 581 patients who were evaluable for ctDNA status proved to be MRD positive, with lingering cancer cells putting them at high risk of disease progression and relapse if left untreated. In that group, patients given atezolizumab had a median DFS of 5.9 months and a median OS of 25.8 months, compared with 4.4 months and 15.8 months, respectively, among patients assigned to observation. No other established biomarkers, including PD-L1 expression and tumor mutational burden, predicted response.

In the entire study population of CheckMate 274, which did not include MRD testing, the median DFS was 20.8 months with nivolumab and 10.8 months with placebo. At the last data cutoff, median OS had not yet been reached, so it is unclear whether nivolumab use in unselected patients offers a lifespan-extending advantage as well.

Many clinicians are waiting on that OS analysis before deciding if it is worth exposing all patients with operable urothelial cancer to the toxicity of checkpoint blockade. A similar phase III trial involving pembrolizumab (Keytruda; Merck) could inform that answer, too.

Meanwhile, Genentech and Natera hope to validate the OS benefit of atezolizumab in a ctDNA-based stratified cohort through the IMvigor011 study, a 495-person trial launched earlier this year for patients with muscle-invasive bladder cancer who show MRD positivity within 20 weeks of surgery. If successful, “I think in a few years' time, we'll all be using this ctDNA technology much more broadly,” says principal investigator Thomas Powles, MD, of Barts Cancer Institute in London, UK.

Whether with atezolizumab or some other checkpoint-directed agent, when it comes to adjuvant immunotherapy in urothelial carcinoma, Powles predicts, “We won't be treating unselected patients.” –Elie Dolgin