Dr. Gschwend starts by highlighting the potential utility of ctDNA throughout a patient’s clinical journey – from patient identification through monitoring for resistance, as seen below.
With regards to surgery, ctDNA can be used to determine risk and determine the need for treatment intensification – specifically the need for perioperative therapy.
Indeed, it has previously been established that the presence of ctDNA after surgery in the bladder cancer setting indicates molecular disease progression that precedes clinical relapse.
The IMvigor010 has been previously presented (a summary can be found here:
https://www.urotoday.com/conference-highlights/asco-2020/asco-2020-bladder-cancer/121831-asco-2020-imvigor010-primary-analysis-from-a-phase-iii-randomized-study-of-adjuvant-atezolizumab-atezo-versus-observation-obs-in-high-risk-muscle-invasive-urothelial-carcinoma-miuc.html
The study evaluated the utility of adjuvant atezolizumab (anti-PD-L1) for patients with muscle-invasive bladder cancer (MIBC) following surgery. The control arm was best supportive care or observation. However, included in the study was a ctDNA exploratory analysis – which was collected prospectively.
The authors hypothesized that plasma ctDNA positivity is associated with a worse prognosis, atezolizumab provides disease-free survival (DFS) or overall survival (OS) benefit in these patients, and ctDNA clearance occurs at a higher rate with adjuvant therapy.
The study design is below:
Below is the breakdown of the ctDNA analyzed cohort:
Of the 809 patients included in the study, only 581 had biomarker-evaluable tissue (72% of the population). Of these 281 were in the observation arm (98 were ctDNA positive) and 300 were in the intervention arm (116 were ctDNA positive).
The groups were evenly matched, similar to the total intention-to-treat (ITT) cohort.
DFS and OS data of the overall ITT cohort and the reduced biomarker-evaluable population (BEP) was similar – no significant difference was identified.
However, below is the key slide:
ctDNA status clearly had prognostic value – patients who were ctDNA positive had worse DFS and OS outcomes compared to patients who were ctDNA negative. But it was also predictive because ctDNA positive patients who received adjuvant atezo did better than patients who were on BSC/surveillance.
Indeed, when they further looked at tumor mutational burden (TMB) status (high defined as >10 mut/Mb), they found that patients who were TMB high and ctDNA(+) had better DFS and OS than patients who were patients who were observed.
Changes in ctDNA status were also associated with treatment arm and survival. Patients treated with atezo were more likely to clear the ctDNA if they were positive to start (18% vs. 3%), and clearance was associated with improved DFS and OS. Seen below:
Based on this, they have moved on to the IMvigor010 study, which is ctDNA based.
Dr. Stenzl then provided a discussion of the study results and some commentary. I highlight his main points below.
First, when it comes to adjuvant therapy for bladder cancer, our data has never been as strong as the neoadjuvant therapy approach.
Secondly, he addresses the reliability of ctDNA in bladder cancer – and notes that data by Dr. Powles himself (Nature 2021) demonstrates that node-positive rates in patients who were ctDNA positive and ctDNA negative were not much different (67% vs. 43%), which suggests that many patients with metastatic disease may not have ctDNA evident.
He also addressed the significant genomic heterogeneity in bladder cancer, which arises from numerous sources: interpatient, intratumoral, temporal (changes over time), intertumoral (between different lesions), and circulation (location). This makes liquid biopsy a little more challenging and perhaps not as reliable as we would like.
Faltas et al. (Nature Genetics, 2016) demonstrated this in a single patient -
The mutational burden from ctDNA assays varied significantly depending on the source of tissue.
He also touched on the discrepancy in outcomes from different adjuvant IO phase 3 trials in bladder cancer. The differential response may be due to patient selection and different inclusion criteria.
Overall, he also looks forward to the IMvigor011 study to provide more information regarding the potential impact of ctDNA on patient selection.
Presented by: Jürgen E. Gschwend, MD, Professor and Chairman, Department of Urology at the Technical University of Munich (TUM) School of Medicine in Munich, Germany
Discussant: Arnulf Stenzl, MD, Medical Director of the Department of Urology at the University of Tübingen in Germanyubingen, Germany
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.