Worldwide, there were roughly 573,300 cases of and 212,500 deaths from bladder cancer in 2020 (CA: Cancer J Clin 2021; https://doi.org/10.3322/caac.21660). Typically, surgery is among the first treatments for advanced bladder cancer that has grown into the muscle layer of the bladder wall. Unfortunately, relapse rates after surgery are high as some cancer cells remain left behind. These remaining cancer cells, known as molecular residual disease (MRD), increase the chances of relapse as the cells can spread and metastasize.
Moreover, it is challenging to ascertain which patients are cured after surgery and which harbor MRD. Consequently, many patients who are cured by surgery are needlessly exposed to toxicities from further treatments, while patients with MRD may not receive possibly favorable treatment until disease progression is detectable by imaging. Therefore, an unmet need remains to discover minimally invasive approaches to detect MRD after surgery to identify patients with cancer who are at risk for metastatic relapse.
Circulating tumor DNA (ctDNA) holds the potential as a biomarker for MRD and relapse. ctDNA-tumor-derived fragments of genetic material that can escape into the bloodstream-are considered to be signs of remaining cancer and can be collected non-invasively from a single blood draw. ctDNA can overcome the challenge of tissue-based biomarkers, including tumor heterogeneity, access to tissue, and use of archival samples. Additionally, recent studies have demonstrated that the presence of ctDNA precedes radiological relapse, while variations in ctDNA correlate with response to therapies (Cell 2020; doi: 10.1016/j.cell.2020.09.001).
In a new clinical study from Queen Mary University of London and Barts Health NHS Trust, researchers found that a blood test that can detect the presence or absence of ctDNA may be able to determine the risk of cancer recurrence and inform treatment in bladder cancer following surgery. The findings of the study were published in Nature (2021; https://doi.org/10.1038/s41586-021-03642-9).
The team evaluated treatment outcomes in a subgroup of patients (comprising 581 individuals) who had undergone surgery and were evaluable for ctDNA from a randomized Phase III trial evaluating the efficacy of adjuvant atezolizumab versus observation in operable urothelial cancer (IMvigor010; NCT02450331) and a Phase II study (ABACUS; NCT02662309) which investigated whether the drug atezolizumab could reduce cancer recurrence in high-risk muscle-invasive urothelial carcinoma.
The study findings revealed ctDNA as a marker for MRD and response to atezolizumab. Specifically, patients who were positive for ctDNA had improved disease-free survival (DFS) and overall survival (OS) in the atezolizumab arm versus the observation arm (DFS HR=0.58 [95% CI: 0.43-0.79]; P=0.0024, OS HR=0.59 [95% CI: 0.41-0.86]). The outcomes in patients who were ctDNA-negative did not appear to differ whether they received atezolizumab or not. Clearance of ctDNA with atezolizumab occurred in 18 percent of patients versus the observation arm (4%) (P=0.0204), suggesting that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse.
Oncology Times further discussed the study results and its implications with Bernadett E. Szabados, MD, study author and Clinical Research Fellow at Barts Cancer Institute, London. Her specialist interests are focused on urological malignancies with the goal of individualizing and improving care and treatment.
Oncology Times: Other adjuvant immunotherapy randomized studies have been positive for DFS in patients, but a positive OS signal has yet to be shown. What is the significance of the positive OS findings this study?
Szabados: "The FDA has recently approved the use of adjuvant nivolumab for patients with urothelial carcinoma who are at a high risk of recurrence following radical cystectomy. The approval was based on the results of the Phase III CheckMate 274 trial (NCT02632409), which investigated nivolumab compared with placebo. Median DFS of patients treated with nivolumab was 20.8 months (95% CI, 16.5-27.6) compared with 10.8 months (95% CI, 8.3-13.9) in the placebo cohort. Overall survival results are still awaited.
"IMvigor010 was a multicenter, randomized trial of adjuvant atezolizumab in a similar patient population. Though the trial did not meet its primary endpoint of DFS in the intention-to-treat (ITT) population (HR 0.89, 95% CI [0.74, 1.08]; P=0.245), a post-hoc biomarker analysis showed that patients who were positive for ctDNA had improved DFS and OS when receiving adjuvant atezolizumab versus observation only (DFS HR=0.58 [95%CI: 0.43-0.79]; P=0.0024, OS HR=0.59 [95% CI: 0.41-0.86]).
"IMvigor010 used the Signatera assay, which is the first custom-built ctDNA test based on individual mutations in an individual patient's tumor. By using this methodology, patients with MRD who are at high risk of relapse were successfully selected and treated rather than unselected patients as was the case in the CheckMate 274 trial. This brings a substantial change in cancer treatment and represents an important milestone in the path towards personalized cancer medicine."
Oncology Times: The study findings revealed ctDNA measurement to be more accurate and predates traditional radiology at identifying disease relapse. How much sooner can the presence of ctDNA identify relapse compared to traditional radiology?
Szabados: "ctDNA holds promise as a biomarker for MRD and relapse, which has been demonstrated in multiple tumor types. By identifying ctDNA-positive patients, we are able to select those with a high risk of recurrence, several months before the recurrence is visible on cross-sectional imaging. As new drugs are increasingly investigated in the earlier disease setting, being able to diagnose recurrence in a timely manner is crucial."
Oncology Times: What limitations of the current study remain to be addressed before this particular ctDNA measurement approach is integrated into clinical settings?
Szabados: "Approximately 30 percent of patients who were ctDNA-negative relapsed, though no difference in DFS was found between the atezolizumab and observations arms (HR=1.14 [95% CI: 0.81-1.62]; median DFS not reached). This underpins the need for further optimization in the selection of patient population, who are likely to benefit from this personalized treatment approach.
"While the ctDNA work was preplanned and within the context of a prospective randomized trial, it was not the primary endpoint. Therefore, this robust work remains exploratory. Furthermore, the sensitivity and specificity of this method are not 100 percent. Further trials with this and other methodologies are required in the future. This includes the IMvigor011 trial."
Oncology Times: Is there a potential of transferability of this adjuvant atezolizumab treatment regimen for any other types of malignancies? If so, are any such studies underway?
Szabados: "IMvigor011 is a randomized, placebo-controlled, double-blind study evaluating the efficacy of adjuvant atezolizumab compared with placebo in patients with muscle invasive bladder cancer who are ctDNA-positive and are at high risk for recurrence following cystectomy. This is the first study evaluating ctDNA-guided adjuvant therapy in a randomized setting and the next step towards personalized cancer treatment. Multiple trials are currently under way in several disease settings (e.g., neoadjuvant, treatment-naive, or treatment-refractory), which will further help patient and treatment selection."
Dibash Kumar Das is a contributing writer.