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UK Group Validating Natera ctDNA Test to Guide Therapy for Post-Operative Bladder Cancer


NEW YORK ─ Natera's Signatera circulating tumor DNA assay has shown the potential to detect the risk of bladder cancer recurrence and guide precision treatment following surgery, clinical investigators at Queen Mary University of London reported.

In a study, recently published in Nature, the researchers used the blood test to detect the risk of cancer recurrence and guide the treatment of the immunotherapy atezolizumab (Genentech's Tecentriq).

They saw that some patients who had a specific set of bladder cancer DNA biomarkers in the blood improved from treatment with atezolizumab following surgery to remove urothelial cancer tumors, and patients with ctDNA-positive results after surgery were at higher risk of cancer recurrence than those who were ctDNA-negative.

"We demonstrated that when patients were ctDNA positive, the risk of relapse was 80 percent, and when they were ctDNA negative the risk was 20 percent," Tom Powles, the lead clinical investigator for the Nature study and a professor at Queen Mary University of London and Barts Health NHS Trust, said in an interview. "That means the assay was discriminatory in its ability to identify patients at risk of relapse, which is clinically relevant."

In ctDNA-positive patients, the group also showed that atezolizumab treatment was associated with an approximately 40 percent reduction in the risk of cancer recurrence and a 40 percent reduction in the risk of dying from cancer, Powles said, adding that if the findings can be validated in additional studies, they could alter approaches to post-operative cancer care.

The Nature study, funded by Roche's Genentech and Barts Cancer Institute at Queen Mary University of London, evaluated treatment outcomes in a subgroup of 581 patients who were enrolled in a randomized Phase III trial, called IMvigor010, and a Phase II study, called ABACUS.

IMvigor010 is a multicenter trial conducted in 192 hospitals, academic centers, and community oncology practices across 24 countries or regions between 2015 and 2019. Overall, it enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Meanwhile, ABACUS investigated the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer.

"We know that immune checkpoint inhibitors work well in some but not all patients with metastatic disease," Powles said. "Because cancer often grows quickly, an immunotherapy may not have time to get it under control. As a result, we thought that post-operatively, the cancer might be less complex and treatments might work better."

The results of the IMvigor010 and ABACUS studies showed that atezolizumab was not significantly better than supportive care when patients were not selected with the help of an assay. "There was about a 15 percent reduction in the time to progression [of bladder cancer recurrence] and about a 15 percent improvement in overall patient survival, but these results were not particularly significant or practice changing," Powles said.

On the other hand, in the 581-patient subgroup, the investigators saw clinically significant effects from treating selected patients with atezolizumab following ctDNA testing, he said.

Before they initiated the IMvigor010 and ABACUS studies, the group ran a series of analyses to diagnose molecular residual disease, or MRD, that involved detecting DNA biomarkers in cancer tissue that had been removed from the patients.

Whole-exome sequencing on tumor and normal samples enabled the investigators to identify 16 patient-specific clonal tumor mutations that they used to design the Signatera ctDNA PCR assay. They then tested plasma samples at baseline on the first day following surgery and six weeks later.

Though surgery is often among the first treatments for advanced cancer in the muscle layer of the bladder wall, relapse rates after surgery are high because some cancer cells can be left behind. Such molecular residual disease increases the chances of a patient's cancer reoccurring.

Powles said that the use of ctDNA testing enabled him and his colleagues to detect molecular residual disease that is untraceable by viewing patients' X-rays and CT scans.

According to Natera, Signatera is a personalized assay for detecting circulating tumor DNA for MRD assessment and recurrence monitoring for patients previously diagnosed with cancers. Analytical studies of the assay have demonstrated a more than 95 percent sensitivity at 0.01 percent variant allele frequency with high specificity.

The turnaround time for the assay was two to three weeks for the first plasma sample, including tissue whole-exome sequencing, assay design, and plasma ctDNA analysis and reporting, and one week for all subsequent plasma processing and ctDNA analysis and reporting, the Queen Mary University group said.

"We believe this study clearly lays out a use case for Signatera in early stage [muscle invasive bladder cancer] to stratify patients after cystectomy as either lower or higher risk for recurrence and help inform adjuvant treatment decisions," Alexey Aleshin, Natera’s vice president of medical affairs, oncology, said in an email, referring to the Nature study. "CtDNA dynamics at six weeks on treatment identified patients who were benefiting from atezolizumab, allowing for real-time treatment response monitoring even in the adjuvant setting."

Meanwhile, the UK investigators have started a follow-up randomized study, Imvigor011, to further validate their findings. The new trial involves testing of bladder cancer patients with the Signatera ctDNA assay six months after surgery.

Patients who test ctDNA positive without their CT scans showing bladder cancer relapse will be randomly selected to receive atezolizumab or best supportive care, Powles said.

The group will screen about 1,000 patients overall to recruit about 650 patients that are needed for the study, and enrolling them is expected to take up to three years.

"Ongoing prospective studies [such as Imvigor011] will further help refine optimal treatment algorithms utilizing ctDNA in the perioperative setting," Aleshin said.