MPDL3280A, an Anti-PD-L1 Monoclonal Antibody, in Metastatic Bladder Cancer

Conference Correspondent - ASCO 2014 - Immuno-Oncology


Metastatic transitional cell or urothelial bladder cancer (UBC) is associated with a poor prognosis and limited treatment options.1 Approximately 70% to 80% of patients with newly diagnosed bladder cancer present with superficial bladder tumors in which prognosis varies based on tumor grade.1 Patients with progressive or recurrent invasive bladder cancer have a poor prognosis.1 Because many of these patients are elderly with comorbidities, management is not standardized.2 PD-L1 expression is prevalent in this disease and may protect UBC cells from immune-mediated destruction.3

To explore the clinical relevance of immunotherapy in metastatic UBC, Powles et al presented results of a phase 1 study of MPDL3280A, a human anti-PD-L1 monoclonal antibody that has recently obtained breakthrough therapy designation by the US Food and Drug Administration (ASCO 2104; Abstract 5011). A total of 67 patients with metastatic UBC received MPDL3280A given at a dose of 15 mg/kg every 3 weeks for up to 1 year. The primary endpoint was objective response rate (ORR), including unconfirmed responses as assessed by RECIST v1.1. Tumor and circulating biomarkers were evaluated to study MPDL3280A immune correlates.

Patients in this trial were 72% male and had a median age of 65 years. The majority had visceral metastases (75%), received prior cisplatin-based chemotherapy (79%), and progressed within 3 months of their prior treatment (42%). MPDL3280A was administered for a median duration of 43 days (1-153 days), and the majority of patients were on treatment as of the data cutoff date.

The most common adverse events (AEs) related to treatment with MPDL3280A were decreased appetite, fatigue, nausea, pyrexia, and asthenia. Related grade 3/4 AEs occurred in 4% of patients. MPDL3280A was not associated with renal toxicity. No investigator-assessed immune-related AEs were observed.

Sixty-five patients with UBC were evaluable for efficacy. As shown in the Table, the ORR was higher in patients whose tumor highly expressed PD-L1 (immunohistochemistry [IHC] 2 and 3) compared with those with low (IHC 1) or no PD-L1 expression. The median time to response was 42 days. Two of these responses were complete responses. Sixteen of 17 responding patients continued to respond at the time of data cutoff. Dr Powles noted that responders to MPDL3280A included UBC patients with visceral metastases at baseline.

Table: Efficacy Outcomes of MPDL3280A in Patients with RCC by PD-L1 Expression (n = 53)

PD-L1 IHC
Tumor-infiltrating immune cells
ORR
% (95% CI)
PD-L1 (+) vs PD-L1 (–) ORR
% (95% CI)
IHC 3 (n = 10) 50 (22, 78) 43 (26, 63)
IHC 2 (n = 20) 40 (21, 64)
IHC 1 (n = 23) 13 (4, 32) 11 (4, 26)
IHC 0 (n = 12) 8 (0.4, 35)

Powles and colleagues concluded that MPDL3280A has noteworthy activity in heavily pretreated patients with metastatic UBC. The agent was well tolerated, with only 4% of patients experiencing grade 3/4 treatment-related AEs and no evidence of renal toxicity. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to MPDL3280A therapy. Further study of MPDL3280A in patients with UBC is planned and ongoing.

References

  1. National Cancer Institute website. Bladder Cancer Treatment: PDQ®. General Information about Bladder Cancer. Last modified: February 21, 2014. www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page1. Accessed June 1, 2014.
  2. National Cancer Institute website. Bladder Cancer Treatment: PDQ®. Recurrent Bladder Cancer Treatment. Last modified: February 21, 2014. http://www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page9. Accessed June 1, 2014.
  3. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007; 109(8):1499-1505.