Findings from negative urothelial carcinoma trial suggest ‘chemotherapy backbone matters’
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SAN FRANCISCO — The addition of atezolizumab to platinum-based chemotherapy failed to significantly improve survival for patients with metastatic urothelial carcinoma, according to a final analysis of the randomized phase 3 IMvigor130 trial.
The findings — presented at ASCO Genitourinary Cancers Symposium — showed a trend toward improved OS with atezolizumab (Tecentriq, Genentech) but the difference did not cross the prespecified efficacy boundary.
The results prompted atezolizumab’s manufacturer last year to voluntarily withdraw the agent’s indication in the U.S. for treatment of locally advanced or metastatic urothelial carcinoma.
Despite the outcome, the trial did yield a finding that could have implications moving forward, according to researcher Matt D. Galsky, MD, professor of medicine (hematology and medical oncology) and professor of urology at Icahn School of Medicine at Mount Sinai.
“This is the first generation of trials in metastatic urothelial carcinoma in which we pooled patients who were cisplatin-eligible and cisplatin-ineligible,” Galsky told Healio. “There did seem to be a difference in the effect of combining atezolizumab with carboplatin vs. cisplatin.
“This obviously is hypothesis-generating and requires confirmation, but we now have immunologic data to support the hypothesis that the chemotherapy backbone matters,” Galsky added. “When we combine chemotherapy and immune checkpoint blockade, we tend to give whatever chemotherapy is typically given for that type of tumor. Moving forward, it’s probably worth a little more thought about how we combine chemotherapy and immune checkpoint blockade.”
Background and methodology
Atezolizumab — an anti-PD-L1 antibody — is approved in the United States for treatment of certain patients with lung cancer, liver cancer or melanoma.
The FDA had granted accelerated approval to the agent for treatment of patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or those ineligible for platinum-containing chemotherapy regardless of PD-L1 status.
The randomized phase 3 IMvigor130 trial — conducted as part of postmarketing requirements to convert the accelerated approval to regular approval — assessed the addition of atezolizumab to platinum-based chemotherapy as first-line therapy for treatment-naive advanced bladder cancer.
Researchers enrolled 1,213 adults with locally advanced or metastatic urothelial cancer treated across 221 sites in 35 countries.
Galsky and colleagues randomly assigned patients to atezolizumab plus platinum-based chemotherapy (group A; n = 451), atezolizumab monotherapy (group B; n = 362) or placebo plus platinum-based chemotherapy (group C; n = 400).
Chemotherapy consisted of IV gemcitabine dosed at 1,000 mg/m² on days 1 and 8 of each 21-day cycle plus either IV carboplatin area under the curve 4.5 mg/mL per min or IV cisplatin 70 mg/m² on day 1 of each cycle. Patients in group A and group B received IV atezolizumab dosed at 1,200 mg on day 1 of each cycle.
Investigator-assessed PFS and OS served as co-primary endpoints.
Results
As Healio previously reported, the primary analysis showed a significant PFS benefit with atezolizumab-chemotherapy vs. placebo-chemotherapy (median, 8.2 months vs. 6.3 months; HR = 0.82; 95% CI, 0.7-0.96).
However, although data from two interim analyses suggested an OS improvement with atezolizumab-chemotherapy vs. placebo-chemotherapy, the differences did not reach the prespecified threshold for statistical significance.
At ASCO GU, researchers reported the final OS analysis.
Results showed a numerical improvement in OS with the addition of atezolizumab to chemotherapy, but the difference did not reach statistical significance (median, 16.1 months vs. 13.4 months; HR = 0.85; 95% CI, 0.73-1). A higher percentage of patients assigned atezolizumab-chemotherapy remained alive at 24 months (38% vs. 32%) and 36 months (26% vs. 22%).
An analysis of OS by choice of platinum chemotherapy showed a larger survival improvement with atezolizumab among those who received a cisplatin backbone (median, 21.5 months vs. 13.4 months; HR = 0.76; 95% CI, 0.57-1.01) than a carboplatin backbone (median, 14.3 months vs. 13.4 months; HR = 0.89; 95% CI, 0.74-1.08). However, researchers emphasized this was not formally tested.
A higher percentage of patients assigned placebo-chemotherapy than atezolizumab-chemotherapy received at least one subsequent non-protocol therapy (47% vs. 33%).
A comparable percentage of patients in the atezolizumab-chemotherapy and placebo-chemotherapy groups experienced all-grade adverse events (> 99% vs. 99%), grade 3/grade 4 adverse events (84% vs. 85%), grade 5 adverse events (7% vs. 5%), treatment-related grade 5 adverse events (2% vs. 1%), serious adverse events (54% vs. 50%), adverse events leading to withdrawal from any treatment (36% vs. 34%) and adverse events leading to dose modification/interruption (81% vs. 78%).
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Galsky MD, et al. LBA440. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.
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