ctDNA status linked to adjuvant atezolizumab benefit for muscle-invasive UC
medwireNews: Circulating tumor (ct)DNA status may help identify muscle-invasive urothelial cancer (MIUC) patients who will benefit from adjuvant treatment with atezolizumab, suggests an exploratory analysis of the IMvigor010 participants.
As reported at the ESMO Immuno-Oncology Virtual Congress 2020, MIUC patients positive for ctDNA a median of 11 weeks after cystectomy derived a significant disease-free survival (DFS) benefit from the PD-L1 inhibitor whereas no such improvement in DFS was found for the ctDNA-negative participants.
ctDNA measured using a C1D1 and C3D1 assay is “highly prognostic for both disease-free survival and overall survival [OS],” said study presenter Thomas Powles (Bart’s Cancer Institute, London, UK).
The initial IMvigor010 findings found no DFS benefit with atezolizumab 1200 mg every 3 weeks compared with observation either overall or in patient subgroups defined by tumor mutation burden (TMB) or PD-L1 status.
The current analysis involved 300 atezolizumab-treated patients, 39% of whom tested positive at baseline for ctDNA, and 281 patients who instead were under observation, 35% of whom were ctDNA-positive.
Overall, the ctDNA-positive and negative cohorts were “well balanced” for most baseline characteristics, Powles said, except that ctDNA-positive patients were significantly more likely to be node-positive than node-negative (67.3 vs 43.3%).
Patients with ctDNA had a “poor prognosis” compared with ctDNA-negative patients, the presenter said, with significant hazard ratios (HRs) for DFS and OS of 6.30 and 8.00 in favor of patients without ctDNA.
However, among ctDNA-positive patients, use of atezolizumab was associated with a significant benefit compared with observation for both DFS (HR=0.58) and OS (HR=0.59), whereas no significant difference was found for either endpoint among the two treatments arms in the ctDNA-negative cohort.
Median DFS among the ctDNA-positive patients was 5.9 months with atezolizumab versus 4.4 months with observation, and the corresponding median OS durations were 25.8 and 15.8 months.
Further analysis showed a higher rate of ctDNA clearance among the 99 ctDNA-positive patients who were treated with atezolizumab than the 79 ctDNA-positive patients who received observation.
And patients who became ctDNA-negative after atezolizumab treatment had a significantly better outcome than those who continued to test positive for ctDNA with regard to both DFS (HR=0.26) and OS (HR=0.41).
Powles and co-workers also looked at the impact of TMB status and tumor immune cell PD-L1 expression on treatment outcomes in the ctDNA-positive patients.
Among ctDNA-positive patients with a high TMB – defined as ≥10 mutations/Mb on whole exome sequencing of tumor tissue – treatment with atezolizumab achieved significantly better DFS than observation (HR=0.34). By contrast, no significant difference in DFS was detected between the treatment groups for patients with low TMB.
Similarly, ctDNA-positive patients who had high PD-L1 expression of 5% or more had significantly better DFS with atezolizumab than observation (HR=0.52), but no difference in outcome by treatment was found among the patients with lower levels of PD-L1 expression.
“This linkage of immune biomarkers and ctDNA positivity in patients who are treated with atezolizumab underpins the biology and our hypothesis,” Powles remarked.
The presenter concluded that “ctDNA positivity identified patients with high-risk MIUC likely to derive DFS and OS improvement from adjuvant atezolizumab” whereas “ctDNA-negative patients had a low risk of relapse and did not have improved outcomes with atezolizumab vs observation, suggesting they could be spared adjuvant therapy.”
He added: “This work requires further testing across different tumor types and treatments and, if validated could result in a shift in approaches to postoperative cancer treatment.”
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This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany