Immunotherapy Redefining the Treatment Strategy for Advanced Urothelial Cancer

Charles Bankhead

November 2016, Vol 7, No 10 - ESMO 2016

Copenhagen, Denmark—Two more PD-1 targeted drugs staked a claim to a role in treating advanced urothelial cancer, according to data from 2 studies that were reported at the 2016 European Society for Medical Oncology Congress.

A phase 2 clinical trial of nivolumab (Opdivo) demonstrated a 20% response rate in patients with cisplatin-eligible, untreated advanced bladder cancer. In addition, a phase 2 clinical trial of pembrolizumab (Keytruda) showed that 24% of patients with cisplatin-ineligible metastatic disease responded to the immunotherapeutic agent.

Collectively, the 2 studies reinforced the strategy of targeting PD-1/PD-L1 in the treatment of advanced urothelial cancer, which was first established with the FDA approval (in May 2016) of the PD-L1 inhibitor atezolizumab (Tecentriq) for this tumor type.

“Immune checkpoint inhibitors have started to alter the therapeutic landscape for bladder cancer,” said Maria De Santis, MD, University of Warwick, Coventry, England, who was not involved in either study. “We expect even more dramatic changes in the coming years with the use of immunotherapy in other clinical stages and as combination therapy.”

CheckMate-275: Nivolumab

The phase 2 CheckMate-275 clinical trial of nivolumab involved patients with bladder cancer that progressed during or after treatment with first-line, platinum-based chemotherapy. This single-arm clinical trial enrolled 270 patients, 265 of whom were evaluable for efficacy.

The primary end point was the objective response rate, and the efficacy analysis was stratified by PD-L1 expression (≥5%, N = 81; <5%, N = 184). The secondary end points included progression-free survival (PFS) and overall survival (OS), said Matthew Galsky, MD, Icahn School of Medicine at Mount Sinai, New York. At the time of the presentation, the study population had a median follow-up of 7 months.

The objective response rate (ORR) was 19.6%, including complete responses in 2.3% of patients. An additional 22% of patients had stable disease. Patients with ≥5% PD-L1 expression had a confirmed ORR of 28.4%, including complete responses in 4.9% of patients. Another 28.4% of the subgroup had stable disease.

The median time to response was 1.9 months, and the median duration of response had yet to be reached. The median PFS was 2 months, including 1.87 months for patients with <1% PD-L1 expression, and 3.55 months for those with ≥1% PD-L1 expression. The median OS was 8.74 months in all patients, including 11.3 months in the subgroup of patients with ≥1% PD-L1 expression.

“Although higher PD-L1 expression was associated with numerically higher objective response rate and overall survival, low to no PD-L1 expression did not preclude patients from responding,” said Dr Galsky. “On the basis of these results, the FDA has granted a breakthrough therapy designation for nivolumab, which will permit accelerated assessment for a potential indication in second-line metastatic urothelial cancer.”

KEYNOTE-052: Pembrolizumab

The phase 2 KEYNOTE-052 clinical trial evaluated pembrolizumab as first-line therapy in 374 patients with cisplatin-ineligible advanced or unresectable urothelial cancer. The primary end point was the ORR, as determined by a prespecified analysis after treatment of the first 100 patients, reported Arjun Balar, MD, NYU Langone Medical Center, New York.

The efficacy analysis showed an ORR of 24%, including complete responses in 6% of patients. Stratification by PD-L1 expression showed an ORR of 25.4% in 63 patients with ≥1% PD-L1 expression (in tumor and immune cells combined), increasing to 36.7% (13.3% complete response rate) in 30 patients with ≥10% PD-L1 expression.

“Pembrolizumab has substantial activity with a favorable safety profile as first-line therapy in cisplatin-ineligible patients with metastatic bladder cancer,” said Dr Balar. “The biomarker cut point will need to be validated in the larger study population but seems to identify patients most likely to respond to pembrolizumab.”

“Immunotherapy is rapidly redefining our treatment approach to patients facing this dreadful disease,” Dr Balar added.

Future of Immunotherapy in Urothelial Cancer

After the 2 presentations, discussants offered different perspectives on the 2 studies. Laurence Albiges, MD, PhD, Gustave Roussy Institute, Villejuif, France, said that the collective data leave little doubt that immunotherapy will be the option for advanced urothelial cancer. The only unanswered questions involve patient selection and optimal sequencing of available agents.

“PD-1/PD-L1 inhibition is a revolution in the treatment of metastatic urothelial cancer,” Dr Albiges said.

Viktor Grunwald, MD, Medical School Hannover, Germany, argued that chemotherapy will remain the backbone of treatment, explaining that long-term survival in metastatic uro­thelial cancer has been demonstrated with chemotherapy.

Intrinsic resistance to chemotherapy is uncommon. Furthermore, checkpoint inhibitors have reported failure rates as high as 48%, Dr Grunwald said.

“Molecular analysis may identify subgroups who are susceptible to chemotherapy or PD-1 blockade,” said Dr Grunwald. “PD-L1 expression alone is insufficient to guide the choice of therapy in the clinic. Chemotherapy plus PD-1 blockade may combine the best of both worlds.”