Masanori Noguchi, MD, PhD
The prognosis for patients with bladder cancer who have progressed after platinum-based chemotherapy is poor, but the results of a phase II study involving an immunotherapy hold promise.
Eighty patients were randomized to receive either an investigational personalized peptide vaccine (PPV) plus best supportive care (n = 39) or best supportive care alone (n = 41). Best supportive care included palliative radiotherapy, antibiotics, and pain relief. Results were published in Clinical Cancer Research
, a journal of the American Association for Cancer Research.
“We assessed whether a novel immunotherapeutic approach could improve outcomes for patients who have advanced bladder cancer that has progressed after platinum-based chemotherapy,” said Masanori Noguchi, MD, PhD, a professor in the Clinical Research Division of the Kurume University Research Center for Innovative Cancer Therapy in Japan.
Eligible patients had histologically proven metastatic urothelial carcinoma of the bladder and had progressed within 12 months after receiving first-line platinum based chemotherapy. Patients were also required to have measurable disease and a life expectancy of at least 12 weeks.
Patients in the treatment arm received a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen (HLA) types and peptide-reactive IgG titers, in 12 subcutaneous injections. Eight injections were given weekly, followed by four biweekly injections. The peptides selected for each patient were determined by which form of HLA class IA was expressed by the patient and whether there were signs of an existing immune response to the peptides in the patient’s blood. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS), immune response, and toxicity.
“Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of advanced cancer,” said Noguchi. Typically, median survival for advanced bladder cancer is just 13 to 15 months from the time of starting platinum-based chemotherapy.
Nine patients assigned PPV and best supportive care had a partial response, as determined by RECIST 1.1 criteria. In the control arm, no patients had a partial response. Two of the patients who had a partial response were alive with no disease progression at the time of data cutoff, which was April 20, 2014. Almost three-quarters of patients overall had died from their disease. However, risk of death was reduced by 42% in the experimental arm compared with the control arm (HR, 0.58, 95% CI 0.34-0.99; P
The median OS for patients assigned personalized peptide vaccine and best supportive care was almost twice as long as that for patients assigned best supportive care: 7.9 months versus 4.1 months. The median PFS was not significantly different between the two groups.
The findings suggest that “this immunotherapeutic approach might become a treatment option for advanced bladder cancer after failure of platinum-based regimens. However, large-scale, randomized clinical trials are needed to confirm our results,” said Noguchi.
The researchers reported that the onset of clinical benefit from the PPV strategy was slow, with both overall and progression-free survival (PFS) curves diverging between the two arms relatively late in follow-up. Some patients randomized to additional PPV initially experienced disease progression following randomization.
In contrast to chemotherapy or small molecules, PPV may take time to induce an effective immune response, Noguchi and colleagues wrote. Delayed clinical benefit has also been noted for other immunotherapeutic approaches such as ipilimumab and sipuleucel-T.
No immune-related serious adverse events were observed in patients who received the additional PPV strategy and treatment was extremely well tolerated.
Major limitations of the study include its small size and that the clinical trial did not have a blinded study design. To address this concern, Nogouchi said that they are planning a double-blinded, placebo-controlled, randomized phase II study in patients with advanced metastatic urothelial cancer after platinum-based chemotherapy.
Noguchi M, Matsumoto K, Uemura H, et al. An open-label, randomized phase II trial of personalized peptide vaccination in patients with bladder cancer that progressed after platinum-based chemotherapy. [published online November 18, 2015]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-15-1265.