ctDNA Identifies Patients Who Benefit From Immunotherapy in MIUC

Among patients with muscle-invasive urothelial carcinoma (MIUC), the presence of detectable circulating tumor DNA (ctDNA) after surgery may identify those who are likely to benefit from adjuvant immunotherapy with the immune checkpoint inhibitor atezolizumab (Tecentriq).

The finding comes from a new analysis of data from the ImVigor010 trial, which had failed to reach its primary endpoint.

“If these results are confirmed by the prospective ImVigor011 study, this may change our understanding of postsurgical care in bladder cancer patients,” commented lead author Jürgen E. Gschwend, MD, PhD, from Technical University Munich, Munich, Germany

He presented the new data, which were published recently in Nature, at a “game-changing” research session of the European Association of Urology 2021 Annual Meeting (EAU 2021).

“Adjuvant treatment in these high-risk, non–organ confined patients is needed, as well as optimization of the primary tumor characterization,” commented invited discussant Arnulf Stenzl, MD, from the University of Tübingen, in Tübingen, Germany.

“Changes due to previous systemic therapy must be taken into consideration. We also have to further characterize and define the control group, and apart from deep sequencing, blood samples dependent on the timeline of possible changes in ctDNA should be considered,” he said.

Details of the New Analysis

As previously reported by Medscape Medical News, the phase 3 ImVigor010 trial failed to reach its primary endpoint of showing a clinical benefit for postsurgical therapy with atezolizumab compared with observation for patients with high-risk MIUC. When these results were reported, an expert not involved in the trial concluded that “there is currently no role for adjuvant atezolizumab in muscle-invasive bladder cancer.”

However, the new analysis, which was preplanned, showed that for patients who tested positive for ctDNA at the time of randomization to adjuvant atezolizumab, disease-free survival (DFS) and overall survival (OS) were significantly better than for those patients in the atezolizumab arm who tested negative for ctDNA.

This planned exploratory analysis took some doing: the investigators sequenced tumor tissues to identify unique tumor mutational signatures, chose 16 of the mutations, and for each patient, they custom-designed and manufactured personalized multiplex polymerase chain reaction assays that targeted clonal mutations found in each tumor. They then used the personalized assays to test for the presence of ctDNA. ctDNA positivity was defined as the presence of two or more mutations in plasma.

A total of 581 patients in the original intention-to-treat population (ITT) were evaluable for biomarkers. Of these patients, 281 were assigned to undergo observation, and 300 were assigned to receive atezolizumab. In each arm, approximately one third of patients tested positive for ctDNA.

Although in the overall trial results, there were no significant differences in DFS or OS between the ITT and biomarker-evaluable populations, DFS and OS were significantly better for the ctDNA-positive patients who received atezolizumab compared to those who underwent observation.

The median DFS for patients assigned to atezolizumab was 5.9 months, compared with 4.4 months for those assigned to observation (hazard ratio [HR], 0.58; P = .0005).

Median OS was 25.8 months in the atezolizumab arm and 15.8 months in the observation arm (HR for death with atezolizumab, 0.59; P = .0059).

“The combination of ctDNA-positivity and high tumor mutational burden [TMB] translated into an even more pronounced benefit in regard of disease-free survival and survival compared to TMB-negative patients,” Gschwend said.

In addition, OS was better for patients in the atezolizumab arm who were free of ctDNA by the first day of cycle 3 compared with those who were not (HR for death with early clearance, 0.14; 95% CI, 0.03 – 0.59).

Why the Worse ctDNA Outcomes?

“Clearly, patients with positive ctDNA had a poor prognosis, regardless of whether they were treated or not. But what is surprising is the relatively poor outcome of those patients that had no ctDNA after cystectomy,” commented Stenzl.

The finding of worse outcomes among ctDNA-negative patients, who presumably did not have minimal residual disease, is puzzling and runs counter to results reported in other clinical trials. The explanation may lie in inter-patient heterogeneity “but also the time-specific, intratumoral, temporal, individual, or circulation heterogeneity,” he said.

Stenzl raised the question of why one immune checkpoint inhibitor directed against programmed cell death protein–1 (PD-1), nivolumab (Opdivo), was superior to placebo at improving DFS among patients with high-risk MIUC regardless of ctDNA in the Checkmate 274 trial, whereas the efficacy of an agent directed against programmed cell death–ligand-1 (PD-L1), atezolizumab, was dependent on ctDNA status, as seen in ImVigor010.

“Was it the PD-L1 or the PD-1? Or is it the study design, which provided a structured, clearly unmistakable placebo in the Checkmate 274 study vs an undefined surveillance in the ImVigor 010 study, the reason why the study was so different from Checkmate 274?,” he asked.

Stenzl noted that the ongoing ImVigor011 study, which is still recruiting, is designed to focus on the potential benefits of atezolizumab for patients with high-risk MIUC who are ctDNA positive after cystectomy.

In this ongoing trial, patients are enrolled a minimum of 6 weeks after cystectomy. They are followed with serial plasma collections and imaging. ctDNA positivity is determined within 21 months of surgery, after which ctDNA-positive patients are randomly assigned on a 2:1 basis to receive either atezolizumab or a placebo.

“If ctDNA is a valuable marker, is it now ethical to do a placebo in one third of these patients, and [considering] the 21 months time lag between the cystectomy for the screening and the actual inclusion, is that an adjuvant treatment? We have to doubt that, and we’ll have to see how this will come out,” he said.

The study was funded by F. Hoffmann–La Roche. Gschwend and Stenzl have relationships with multiple pharmaceutical companies.

European Association of Urology 2021 Annual Meeting (EAU 2021): Presented July 10, 2021.

Nature. Published online June 16, 2021. Abstract

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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