Jason M. Broderick
Opdivo (nivolumab) has earned an FDA breakthrough therapy designation for the treatment of patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) after the failure of a platinum-containing regimen. The designation was primarily based on findings from the phase 2 CA209-275 study (NCT02387996
), with additional supportive data also considered by the FDA.
“Urothelial cancer is a common type of bladder cancer where patients experience high rates of recurrence and remains an area where new treatment approaches are needed, further underscoring the importance of this designation for Opdivo,” Jean Viallet, from Bristol-Myers Squibb, the manufacturer of the PD-1 inhibitor, said in a statement.
“As part of our commitment to bring Opdivo to these advanced bladder cancer patients as quickly as possible, we look forward to filing a marketing application with health authorities based on results from study -275 and other supporting data in the coming months, as well as submitting the data for presentation at an upcoming medical meeting.”
Data for Opdivo in this setting from the CheckMate-032 trial were reported by Padmanee Sharma at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. In the study, single-agent Opdivo had an overall response rate (ORR) of nearly 25 percent in patients with advanced mUC. The median progression-free survival (PFS) was 2.78 months and the median overall survival (OS) was 9.72 months.
“In previously treated patients with mUC for whom there is no standard of care, [the CheckMate-032 data] provide the first evidence of substantial clinical activity with Opdivo, regardless of PD-L1 expression,” said Sharma, who is a professor of Immunology, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.
CheckMate-032 included 78 patients with locally advanced or mUC of the renal pelvis, ureter, bladder, or urethra. Patients had recurrence within one year of completing platinum-based neoadjuvant or adjuvant treatment, or progression following at least one platinum-based regimen for metastatic disease.
The median patient age was 65.5 years (ranging from 31 to 85) and 69.2 percent of patients were male. Over half of patients (53.8 percent) had received two or three prior regimens, 33.3 percent had received one, and 12.8 percent had received more than three. All patients had an ECOG performance status of 0 (53.8 percent) or 1 (46.2 percent). Metastatic disease rates at baseline included 78.2 percent, 25.6 percent and 16.7 percent, for visceral, liver, and lymph node only metastases, respectively.
As determined by by the Dako PD-L1 IHC 28-8 pharmDx kit, 67 patients had measurable PD-L1 tumor expression. Among these patients, 62.7 percent of had PD-L1 expression levels less than 1 percent, with 37.3 percent having PD-L1 expression levels at least 1 percent.
Patients received single-agent Opdivo at 3 mg/kg intravenously every two weeks. Patients could continue receiving Opdivo at progression if they had a clinical benefit and toxicity was manageable. Eligible patients also had the option to receive nivolumab combined with ipilimumab (Yervoy) at progression.
The primary endpoint was ORR. Secondary endpoints included PFS, OS, duration of response and safety.
At a minimum follow-up of nine months, the median number of doses received was 8.5 (ranging from one to 46), and 23.1 percent of patients remained on Opdivo. The ORR was 24.4 percent, including a complete response rate of 6.4 percent and a partial response rate 17.9 percent. The one-year OS rate was 45.6 percent.
Median time to response was 1.48 months and the median duration of response was not yet reached. The stable and progressive disease rates were 28.2 percent and 38.5 percent, respectively. Response status could not be determined for 9 percent of patients.
Among patients with PD-L1 levels at least 1 percent, ORR was 24 percent. Patients with PD-L1 expression less than 1 percent, had an ORR of 26.2 percent. “Basically, we saw that PD-L1 status was irrelevant for response rate and didn’t matter in this cohort of patients,” said Sharma.
The primary reasons for Opdivo discontinuation were disease progression (64.1 percent), adverse events (AEs) unrelated to treatment (5.1 percent), Opdivo-related AEs (2.6 percent), and patient request (2.6 percent). At progression, 23.1 percent of patients crossed over to combined therapy with nivolumab/ipilimumab.
The most common all-grade treatment-related AEs included fatigue (36 percent), pruritus (30 percent), elevate lipase (14 percent), rash (18 percent), nausea (13 percent), arthralgia (12 percent) and anemia (10 percent). Twenty-two percent of patients had grade 3/4 AEs, with the most common being elevated lipase (5 percent), fatigue (3 percent), rash (3 percent) and nausea (1 percent). There were two deaths related to treatment, one due to thrombocytopenia and one due to pneumonitis.
“These data indicate a favorable benefit/risk profile for Opdivo in the treatment of patients with mUC and support further development in the ongoing phase 2 -275 study,” Sharma said in her concluding remarks at ASCO.