Adjuvant atezolizumab fails to extend DFS in high-risk urothelial carcinoma
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Adjuvant atezolizumab failed to extend DFS compared with observation for patients with high-risk muscle-invasive urothelial carcinoma, according to randomized phase 3 study results presented during the ASCO20 Virtual Scientific Program.
“The results of this study will not change the way we treat this disease in the adjuvant setting,” Petros Grivas, MD, PhD, medical oncologist at Seattle Cancer Care Alliance, clinical director of the genitourinary cancers program at University of Washington School of Medicine and associate member of the clinical research division at Fred Hutchinson Cancer Research Center, told Healio. “However, despite the fact it did not meet its primary endpoint, this is still a very important trial, and hopefully we can learn a lot from it.”
Standard treatment for muscle-invasive urothelial carcinoma consists of radical surgery — cystectomy for those with bladder cancer or nephroureterectomy for those with upper tract urothelial carcinoma — with or without cisplatin-based neoadjuvant chemotherapy. However, no conclusive level one evidence exists to support use of adjuvant chemotherapy after radical cystectomy in bladder cancer, according to study background.
Atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor, is approved in the United States for treatment of certain adults with locally advanced/unresectable or metastatic urothelial carcinoma.
The global, open-label, multicenter IMvigor010 study — led by Maha Hussain, MD, FACP, FASCO, deputy director of Robert H. Lurie Comprehensive Cancer Center at Northwestern University and a HemOnc Today Editorial Board Member — assessed adjuvant atezolizumab for patients with muscle-invasive urothelial carcinoma at high risk for recurrence after primary resection.
The study included 809 patients with muscle-invasive urothelial carcinoma who had undergone radical cystectomy/nephroureterectomy with lymph node dissection within 14 weeks of study enrollment.
All patients had ECOG performance status of 0 to 2 and had resected tissue for PD-L1 testing on immune cells.
Pathologic stages were ypT2-4a or ypN+ for patients who received neoadjuvant chemotherapy; they were pT3-4a or pN+ for those who did not have neoadjuvant chemotherapy.
Patients were not allowed to have had postsurgical radiation or adjuvant chemotherapy. If patients did not receive neoadjuvant chemotherapy, they must have either declined or been ineligible for cisplatin-based adjuvant chemotherapy.
Researchers randomly assigned 406 patients to atezolizumab dosed at 1,200 mg via IV every 3 weeks for 16 cycles. The other 403 patients underwent observation for 1 year.
“This patient population overall was at significant risk for recurrence based on pathologic stage,” Grivas said. “The rationale was that the anti-PD-L1 therapy could eradicate any residual microscopic disease that was present after radical surgery.”
Investigators stratified patients by number of lymph nodes resected, pathologic nodal status, pathologic tumor stage, PD-L1 status and prior neoadjuvant chemotherapy.
The atezolizumab and observation groups were balanced with regard to median age (67 years vs. 66 years), sex (male, 79% vs. 78%), neoadjuvant chemotherapy receipt (48% vs. 47%), percentage of patients with upper tract urothelial carcinoma as primary disease (7% vs. 6%) and lymph node-positive disease (48% each).
DFS served as the primary endpoint. OS served as a secondary endpoint.
Median follow-up for the intention-to-treat population as 21.9 months.
Results showed no statistically significant difference in DFS between the atezolizumab and observation groups (median, 19.4 months vs. 16.6 months; HR = 0.89; 95% CI, 0.74-1.08).
DFS analysis by PD-L1 expression showed stratified HRs of 0.81 (95% CI, 0.63-1.05) among patients with PD-L1 expression less than 5%, and 1.01 (95% CI, 0.75-1.35) among those with PD-L1 expression of 5% or greater.
The first interim OS analysis also showed no significant difference between the atezolizumab and observation groups (median, not reached in either group; HR = 0.85; 95% CI, 0.66-1.09).
OS follow-up is ongoing, and additional exploratory biomarker and subgroup analyses may warrant further study, according to the researchers.
Atezolizumab exhibited a safety profile generally consistent with that observed in prior studies.
Seventy-one percent of atezolizumab-treated patients experienced treatment-related adverse events, 16% of which were grade 3 or grade 4. Researchers reported 41 (11%) treatment-related serious adverse events and one treatment-related grade 5 adverse event.
Sixteen percent of patients assigned atezolizumab discontinued treatment due to adverse events — primarily skin and gastrointestinal toxicities — and 33% required dose interruptions due to adverse events.
The IMvigor010 study was the first large randomized phase 3 trial to report outcomes of checkpoint inhibition in the adjuvant setting for this patient population.
At least two other clinical trials assessing checkpoint inhibitors in the adjuvant setting have not yet reported results, Grivas said. One is evaluating nivolumab (Opdivo, Bristol-Myers Squibb) vs. placebo. Another — the Ambassador trial, which is still accruing patients — will evaluate pembrolizumab (Keytruda, Merck) vs. observation.
“These studies will report in the future, so we will see whether this is a ‘class effect’ or there are different results among checkpoint inhibitor trials, but we don’t know the answer to that question,” Grivas told Healio. “The other question is whether there is impact with immunotherapy in this context of minimal residual/microscopic disease in the adjuvant setting, or there should have been visible metastatic disease to see a benefit. We don’t have a good answer yet. We are also waiting for another adjuvant trial to accrue — PROOF-302 — comparing infigratinib (QED Therapeutics) to placebo [for] patients with activating FGFR3 mutation or fusion” – by Mark Leiser
Reference:
Hussain MHA, et al. Abstract 5000. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosures: F. Hoffmann-La Roche funded this study. Grivas reports research funding to his institution from Bavarian Nordic, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Immunomedics, Merck and Pfizer, as well as consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Driver Inc., EMD Serono, Exelixis, Foundation Medicine, Genzyme, GlaxoSmithKline, Heron, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Roche and Seattle Genetics. Please see the abstract for all other researchers’ relevant financial disclosures.
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