"There is currently no role for adjuvant atezolizumab [Tecentriq, Genentech] in muscle-invasive bladder cancer," according to Daniel Y. C. Heng, MD, MPH, who was commenting on negative results from a phase 3 clinical trial.
"So why is there a benefit in the metastatic setting but not in this adjuvant setting?" he asked. "Why is there a benefit potentially or efficacy shown in the non–muscle-invasive setting but not in this adjuvant setting in muscle-invasive disease?"
Heng is staff medical oncologist at the Tom Baker Cancer Center in Calgary and a clinical associate professor of medicine at the University of Calgary, Canada.
He was discussing results from the IMvigor 010 trial, the first phase 3 adjuvant study of a checkpoint inhibitor in muscle-invasive urothelial cancer (MIUC). The trial failed to meet its primary endpoint of disease-free survival (DFS).
The results, which were presented at the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 annual meeting, showed that the 18-month DFS rate was 51% for patients who received received atezolizumab and 49% for the observation arm.
"This was a completely negative trial with no disease-free benefit, and there was no disease-free benefit across all subgroups, including PD-L1," said Toni K. Choueiri, MD, the director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. "There was no overall survival benefit at 22 months' follow-up, despite the fact that the regimen was tolerable."
Speaking at a "Highlights of the Day" session, Choueiri explained that the significance of these data is that a single-agent checkpoint inhibitor is not advised in unselected patients for the treatment of MIUC. "And this is despite having a high-risk population, like the one here, where over 50% were PN positive," he said. "There was an interesting hazard ratio trend for pT2, pT3, pT4 favoring some benefit in high-risk T stage, but I would not recommend it in these subgroups."
Heng noted that even in a subgroup analysis of PD-L1-positive patients, there was no benefit from atezolizumab compared to observation.
"Although it wasn't shown, those patients without prior neoadjuvant chemotherapy or negative pathologic node status did not show any difference either," said Heng, who was discussant for the paper.
Heng speculated as to whether the lack of efficacy in the adjuvant setting was because the gross tumor needs to be in situ to potentiate the immune response or whether all the drugs in the class are equal. "For example, is atezolizumab not as good as some of the other agents? I'm not sure," he said.
What was interesting, he said, is that there might be a slight benefit for the T4 subset, although it wasn't statistically significant in the study. "I think that's a space to watch out for in future clinical trials of this disease to see whether or not the more higher-risk patients, the T4 disease patients, benefit from adjuvant immune checkpoint inhibitors," Heng said.
Radical surgery with or without cisplatin-based neoadjuvant chemotherapy is the standard of care for MIUC, which continues to be a deadly disease despite treatments with curative intent. There is currently no conclusive level I evidence that adjuvant chemotherapy improves overall survival.
Up to half of all patients with MIUC are eligible for cisplatin-based chemotherapy, and atezolizumab has been approved as monotherapy for patients with multiple locally advanced or metastatic urothelial carcinoma.
"We hypothesized that adjuvant atezolizumab monotherapy would reduce the risk of recurrence or death after radical surgery," said lead author Maha H. A. Hussain, MD, professor of medicine and deputy director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago, Illinois, who presented the primary analysis of the study.
A total of 809 patients were randomly assigned to receive either atezolizumab 1200 every 3 weeks for 16 cycles or 1 year of observation following radical cystectomy/nephroureterectomy with lymph node dissection within 14 weeks or less from registration.
Patients who had received neoadjuvant chemotherapy were required to have at a minimum pathologic T2 to T4a disease or node-positive disease. Others were required to have pathologic T3 or T4a disease or pathologic node-positive disease. Postsurgical radiotherapy or adjuvant chemotherapy was not permitted. If patients had not received prior neoadjuvant chemotherapy, they had to have either been ineligible for it or declined adjuvant cisplatin-based chemotherapy.
The primary endpoint was DFS; secondary endpoints included overall survival.
"In both arms, many patients came off protocol, primarily because of disease progression ― 59% of patients in the atezolizumab arm, and 77% in the observation arm," said Hussain. "However, more patients in the treatment arm came off because of adverse events ― 31%, compared to 3% in the observation arm."
Nearly half of patients had received prior neoadjuvant chemotherapy (48% of the ateozolizumab group and 47% of the observation arm). The population was considered to be at very high risk; almost 40% of patients in both arms had pathologic T3 or T4 disease, and 52% had node-positive disease.
In the intent-to-treat population, the median DFS was 19.4 months in the atezolizumab arm, compared to 16.6 months in the observation arm. This difference did not translate into a significant hazard ratio (0.89; P = .2446).
"The interim overall survival analysis is not mature at this moment, and the median overall survival has not been reached," said Hussain. "These data continue to be collected on all patients enrolled into the study in the intent-to-treat population."
Overall, the treatment was well tolerated, she noted. Treatment-related adverse events occurred in 71% of patients who received atezolizumab, and grade 3 or 4 events occurred in 16%. One grade 5 event was attributed to atezolizumab. Adverse events leading to discontinuation of atezolizumab occurred in 16% of the patients.
"IMvigor 010 did not meet its primary endpoint of disease-free survival," concluded Hussain. "There was no prespecified subgroup, including higher PD-L1 status, that showed treatment benefit with atezolizumab.”
She added that follow-up for overall survival is ongoing and that "additional exploratory biomarkers and subgroup analyses may warrant further study."
Clinical trials with atezolizumab as monotherapy and as combination treatment are underway in a variety of disease settings for patients with urothelial carcinoma.
The study was funded by F. Hoffmann-La Roche Ltd. Hussain, Heng, and Choueiri have disclosed relationships with a large number of pharmaceutical companies.
American Society of Clinical Oncology (ASCO) 2020: Abstract 5000. Presented May 31, 2020.
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Cite this: No Role for Adjv Atezolizumab in Muscle-Invasive Bladder Cancer - Medscape - Jun 04, 2020.