Predictive value of ctDNA and tissue-based biomarkers with neoadjuvant atezolizumab in operable urothelial carcinoma

Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC). In the phase II ABACUS study, neoadjuvant atezolizumab was associated with clinical responses and high disease-free survival in patients with MIBC who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. At ASCO GU 2024, results of an exploratory biomarker analysis using different definitions of circulating tumour DNA response and its correlation with tissue response at time of cystectomy were presented.

Circulating tumour DNA (ctDNA) is currently being studied in the neoadjuvant setting of several prospective clinical trials. Dynamic changes in ctDNA may be a surrogate marker of a pathological complete response (pCR). Young and colleagues performed an exploratory biomarker analysis using data from the ABACUS study to assess the value of ctDNA and tissue-based biomarkers in predicting response and relapse.

Methods

ABACUS was a multicentre, single-arm phase II study investigating neoadjuvant atezolizumab (1200 mg IV Q3W, two cycles) in 95 patients with muscle-invasive urothelial cancer who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. For the current exploratory biomarker analysis, patients with baseline PD-L1, CD8, tumour mutational burden (TMB) and sequential ctDNA measurements (at baseline and at the time of cystectomy) were included. PD-L1 positivity was defined as ≥5% of immune cell staining. CD8 was measured via immunohistochemistry analyses. TMB and ctDNA were assessed using the FoundationOne CDx and Signatera assay, respectively. Two definitions of ctDNA response were used: ctDNA clearance and a ≥50% reduction in ctDNA variant allele frequency (VAF). Biomarker expression was correlated with pCR rate at the time of cystectomy and the relapse rate.

Results

In total, 40 of 95 patients had data on sequential ctDNA measurements available. Of them, 17 (43%) had pCR and 8 (20%) relapsed. At baseline, 25 patients (63%) were ctDNA+, with 10 (40%) achieving a ≥50% reduction in ctDNA VAF and 3 (8%) achieving ctDNA clearance. Furthermore, 30% (3/10) of patients who had VAF reduction experienced relapse and 40% (4/10) achieved pCR. All three patients who achieved ctDNA clearance had pCR and none of them relapsed. There was no significant association of a ≥50% reduction in ctDNA VAF with pCR (p= 0.24). Additional analysis showed no association between a ctDNA reduction of 75% (rather than 50%) and pCR (p= 0.24).

Interestingly, combining the ctDNA status with the baseline biomarkers enriches the predictive value. When ctDNA is combined with activated T-cells, this is associated with outcomes (p= 0.02) Similarly, when ctDNA is combined with PD-L1 status, this is associated with outcome (p= 0.004). However, the TMB continued to struggle as a predictive biomarker, even when combined with ctDNA status (p= 0.2). Finally, there were increased innate and adaptive immune signals in patients that were ctDNA positive at baseline and these increased immune signals appear to be associated with better outcomes with atezolizumab.

Conclusions

This exploratory biomarker analysis of data from the single-arm phase II study ABACUS shows that ctDNA clearance is rare (<10%) but appears more accurate than 75% or 50% reduction in ctDNA VAF to predict pCR and relapse. According to the researchers, this is relevant for ongoing neoadjuvant trials planning to use these endpoints. Combining tissue-based biomarkers with ctDNA seems to improve biomarker accuracy.

Reference

Young MN, et al. Predictive value of dynamic changes in ctDNA and baseline biomarkers with neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Presented at ASCO GU 2024; Abstract 534.