Promising Immunotherapy Agents on Horizon in Bladder Cancer

Thomas Powles, MD

The dramatic and often practice-changing findings demonstrated by trials of immunotherapies in melanoma and lung cancer may soon be reflected in the treatment of bladder cancer, according to a summary of ongoing studies¹ presented at the 7th European Multidisciplinary Meeting on Urological Cancers (EMUC).

“Immune therapy is a promising new treatment in transitional cell carcinoma (TCC) of the bladder,” said Thomas Powles, MD, medical oncologist, director of St Bartholomew's Cancer Centre, London. “Until recently, bladder cancer research has been somehow left behind."

Powles underscored that immune checkpoint inhibitors are active in urothelial bladder cancer (UBC) and provided an overview of the emergence of immune therapy in bladder cancer that focused on agents targeting the immune checkpoint axis, especially the programed death receptor (PD1) and its ligand (PD-L1).

“Each drug has a unique companion diagnostic but the strongest data so far are seen with blocking PD-L1 and atezolizumab,” he said.

The confirmed overall response rate (ORR) by RECIST to atezolizumab are associated with PD-L1 expression levels in the tumor. In a phase I trial of second line atezolizumab (MPDL3280A) in TCC, a response was demonstrated in patients that had previously showed only a 10% response rate to chemotherapy. The ORRs were 43% for patients with tumors expressing high levels of PD-L1 (IHC 2/3) compared to 11% in patients with tumors having low expression (IHC 0 or 1).²

PD-L1 expression on the immune cells (IC) infiltrating the tumor has also been shown to be associated with response. The PD-L1 expression on ICs was evaluated as low, medium, and high in approximately one-third each of 311 patients with locally-advanced or metastatic urothelial carcinoma (mUC) participating in the phase II IMvigor 210 trial, which corresponded to an ORR with atezolizumab of 9%, 10%, and 27% in the respective expression groups.

Overall survival (OS) at a median follow-up of 7 months (range, 0-11) also correlated with expression levels and was 6.7 months in low (IC0/1), not reached in high (IC2/3) expressing patients, and 7.9 months in overall population. However, no difference was seen in progression-free survival (PFS) according to expression levels; median PFS was 2.1 months in the overall population and in patients having both low (IC0/1) and high (IV2/3) expression levels, respectively. These data were emphasized as early response data that are expected to mature in further analyses.³

Powles commented that his team is beginning a phase III randomized trial of atezolizumab in 767 patients with locally-advanced UBC who were also chemotherapy-resistant following 1 to 2 prior lines of a platinum-based regimen. Patients have been stratified by chemotherapy regimen, PD-L1 expression, IHC status, risk factors, and the presence of liver metastasis. The primary endpoint is OS and secondary endpoints include ORR, PFS, and duration of response (DoR), safety, and tolerability. Other objectives include disease control rate and potential biomarkers.

“PD-L1 expression appears important but we need to find other biomarkers,” he remarked.

Powles moved on to discuss the KEYNOTE-012 phase Ib trial of pembrolizumab, an anti-PD1 antibody that blocks interaction with both PD-L1 and PD-L2. In KEYNOTE, pembrolizumab demonstrated anti-tumor activity in patients with recurrent or metastatic PD-L1—positive UBC in 64% of patients experiencing a decrease in target lesions from baseline.⁴

Combination and adjuvant studies are ongoing, according to Powles. A trial of atezolizumab as adjuvant therapy versus placebo is underway in patients with TCC whose tumors express PD-L1. The trial has a primary endpoint of disease-free survival (DFS).

“Next-generation combination therapy with nivolumab plus ipilimumab is a common sense approach that was tested in advanced melanoma and is now being evaluated in the Danube trial,” Powles said.

Nivolumab, a PD-1 blocking antibody, and ipilimumab, which blocks CTLA-4, will be evaluated in Danube, a randomized phase III study that will enroll 800 patients with untreated metastatic TCC. The endpoints are PFS and OS. Patients are required to have available tissue for PD-L1 testing and no contraindications for immune therapy.

The rationale for the combination was demonstrated in melanoma, where confirmed objective responses were seen in 61% of patients receiving nivolumab plus ipilimumab versus 11% in patients receiving ipilimumab and placebo (P <0.001). Complete responses were reported in 16 patients (22%) with combination compared to no patients receiving ipilimumab monotherapy.⁵

“It looks like checkpoint inhibition works particularly well in node positive patients; in the future we can see treatment with first-line immunotherapeutic agents,” said Powles.

“We hope that immune therapy will identify a subset of patients who get long-term benefits from immune therapy,” Powles said. “The future looks bright for immunotherapy in bladder cancer.”

References

1. Powles T. Update on systemic treatments in bladder cancer. Presented at: 7th European Multidisciplinary Meeting on Urological Cancers (EMUC), Barcelona, Spain, November 12—15, 2015.
2. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558-562.
3. Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 21LBA.
4. Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl; abstr 4502).
5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23-34.