medwireNews: Early trial findings indicate that adding atezolizumab to neoadjuvant gemcitabine plus cisplatin might improve the outcome of patients with muscle-invasive bladder cancer (MIBC) scheduled to undergo radical cystectomy.
The primary endpoint of non-muscle-invasive downstaging to below pT2N0 was achieved by 69% of patients given the PD-L1 inhibitor combination, which the investigators say “compares favorably with historical data” for use of gemcitabine plus cisplatin alone, where 36–49% of MIBC patients have achieved this target.
The phase II trial included 39 evaluable patients (84.6% men, median age 65 years) with cT2–T4aN0M0 muscle-invasive bladder cancer. The majority (79.5%) had clinical stage T2 disease and pure urothelial carcinoma not otherwise specified (61.5%), and 89.7% had PD-L1-negative tumors, defined as less than 5% of tumor-infiltrating immune cells staining positive.
The participants were given atezolizumab 1200 mg every 3 weeks, including a lead-in dose 2 weeks before beginning four 21-day cycles of gemcitabine plus cisplatin, and a final atezolizumab dose 2 weeks after chemotherapy ended, followed by surgery 2–4 weeks later.
Of the 39 patients, 23.1% had pT2N0 or more advanced disease at the time of radical cystectomy and 7.7% refused surgery or did not undergo the procedure because of metastatic disease. The majority (69.2%) of patients responded to atezolizumab and chemotherapy and had downstaging below T2N0, while 41.0% achieved a pathologic complete response (pT0N0).
After a median of 16.5 months, none of the patients who underwent surgery and had downstaging below pT2N0 had relapsed, whereas relapse occurred in four patients who had not responded to treatment.
This translated to a significant improvement in relapse-free survival among patients who had responded to neoadjuvant atezolizumab plus chemotherapy versus nonresponders, say Samuel Funt, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors in the Journal of Clinical Oncology.
They note, however, that the duration of follow-up “may be insufficient to capture all recurrences.”
All four of the patients with PD-L1-positive tumors achieved less than pT2N0 status, as did 67.6% of patients with a PD-L1 low or negative status, indicating that “PD-L1 positivity was not predictive of non-muscle-invasive downstaging,” the team observes.
Safety analysis in the full study population of 44 patients showed that the most common treatment-related adverse events (TRAEs) at any grade were neutropenia (59%), fatigue (55%), anemia (55%), and nausea (50%).
Grade 3 or more severe TRAEs occurred in 59%, most commonly neutropenia (36%), and grade 3 immune-related AEs were reported in 11%, with individual cases of hepatitis, lipase elevation plus nephritis, pancreatitis, rash, and asymptomatic amylase plus lipase elevations.
TRAEs led to dose alterations in 67% of 39 evaluable patients but these were primarily related to chemotherapy and did not delay surgery; 92% of patients completed four cycles of chemotherapy and 74% received all six planned doses of atezolizumab.
Funt et al conclude that the combination of atezolizumab with gemcitabine plus cisplatin is “worthy of further investigation” alongside studies of other immunotherapy/chemotherapy options in muscle-invasive and metastatic bladder cancer.
Nevertheless, they emphasize the need for biomarkers to identify patients who will benefit from novel treatment combinations for “preserving efficacy and minimizing toxicity.”
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