"Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.”— —Padmanee Sharma, MD, PhD, and colleagues
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As reported in The Lancet Oncology by Padmanee Sharma, MD, PhD, of MD Anderson Cancer Center, and colleagues, the phase II CheckMate 275 trial has shown that nivolumab (Opdivo) produced durable responses in patients with metastatic urothelial cancer who had received at least one prior platinum-based regimen.1 The study supported the recent Accelerated Approval by the U.S. Food and Drug Administration (FDA) of nivolumab in this setting.
Study Details
In the trial, which enrolled patients between March 2015 and October 2015, 270 patients from 63 sites in 11 countries received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons; 265 patients were evaluated for activity.
Patients had to be aged ≥ 18 years and had to have metastatic or surgically unresectable locally advanced urothelial carcinoma (involving the bladder, urethra, ureter, or renal pelvis), measurable disease on Response Evaluation Criteria in Solid Tumors (v1.1), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and available tumor samples for biomarker analysis. The primary endpoint was overall objective response on blinded independent review committee assessment in all treated patients and by tumor programmed cell death ligand 1 (PD-L1) expression of ≥ 5% and ≥ 1%. The trial is completed, and follow-up is ongoing.
Among all patients: median age was 66 years (55% ≥ 65 years); 78% were male; 86% were white and 11% Asian; ECOG performance status was 0 in 54% and 1 in 46%; sites of metastasis included the liver in 28%, visceral in 84%, lymph node only in 16%, and central nervous system in < 1%; baseline hemoglobin level was < 100 g/L in 18%; previous therapies included platinum in neo/adjuvant settings in 34%, platinum in advanced/metastatic settings in 66%, cisplatin (carboplatin)-based regimen only in advanced/metastatic settings in 39% (26%), and cisplatin and carboplatin-based regimen in advanced/metastatic settings in < 1%; and the number of previous regimens in the metastatic setting was 0 for 29%, 1 for 42%, 2 for 21%, and ≥ 3 for 8%.
Nivolumab in Metastatic Urothelial Carcinoma
Nivolumab produced response in 19.6% of patients, including 28.4%, 23.8%, and 16.1% of those with PD-L1 expression of ≥ 5%, ≥ 1%, and < 1%, respectively. The median duration of response was not reached.Responses
Median follow-up for overall survival was 7 months. A confirmed objective response was observed in 52 patients (19.6%, 95% confidence interval [CI] = 15.0%–24.9%) of 265 patients, including response in 23 of 81 patients (28.4%, 95% CI = 18.9%–39.5%) with PD-L1 expression ≥ 5%, 29 of 122 patients (23.8%, 95% CI = 16.5%–32.3%) with PD-L1 expression ≥ 1%, and 23 of 143 patients (16.1%, 95% CI 10.5%–23.1%) with PD-L1 expression < 1%. Among all patients, complete response was observed in 2%, partial response was seen in 17%, and stable disease was noted in 23%.
Median time to response was 1.9 months. Median duration of response was not reached; at the time of the last analysis, responses were ongoing in 40 of 52 patients (77%) with confirmed response.
Nivolumab was active in all predefined subgroups, including according to the site of metastasis, ECOG performance status, baseline hemoglobin level, Bellmunt risk factors, tumor origin, previous regimens in the advanced/metastatic setting, and baseline creatinine clearance, except among patients with three Bellmunt risk factors. Median progression-free survival on blinded independent review was 2 months. At median follow-up of 7 months, median overall survival was 8.7 months (95% CI = 6.1 months to not reached) among all patients, 11.3 months (95% CI = 8.7 months to not reached) in patients with PD-L1 expression ≥ 1%, and 5.9 months (95% CI = 4.30–8.08 months) in those with PD-L1 expression < 1%.
Adverse Events
Treatment-related adverse events of any grade occurred in 64% of patients. The most common of any grade was fatigue (17%). Grade 3 or 4 treatment-related adverse events occurred in 18%, with the most common being grade 3 fatigue (2%) and diarrhea (2%). Treatment was discontinued due to adverse events in 5%, including due to pneumonitis in 4 patients (1%); pemphigoid in 2 patients (1%); and dyspnea, interstitial lung disease, maculopapular rash, pruritic rash, abdominal pain, diarrhea, and circulatory collapse in 1 patient each.
The most common treatment-related potential immune-mediated adverse events of any grade were skin toxicity (17%) and endocrinopathies (14%). Most such toxicity resolved and was manageable with immune-modulating drugs, usually systemic corticosteroids. Some drug-related endocrinopathies were not considered resolved, because hormone replacement therapy was ongoing at last follow-up. Death considered related to treatment occurred in three patients, due to pneumonitis, acute respiratory failure, and cardiovascular failure.
The investigators concluded: “Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.”
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com. ■
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