Studies of Second-Line Immunotherapies in Bladder Cancer Hold Promise

Daniel Petrylak, MD

With no major advances in survival in bladder cancer in more than 30 years, interest is high in the potential to deploy immunotherapeutic approaches in this setting, according to Daniel Petrylak, MD, speaking March 14 at the 8th International Prostate Cancer Congress in New York City.

“There’s a significant unmet medical need. At this point there is no FDA-approved agent for patients who relapse after primary chemotherapy,” said Petrylak, professor of medicine and urology at the Yale Cancer Center. He went on to highlight clinical trials involving three immunotherapies—MPDL3280A, pembrolizumab, and nivolumab in bladder cancer.

The rationale for investigating immunotherapy in bladder cancer first took hold because of the positive results of bacillus Calmette-Guérin (BCG) therapy in superficial disease. The use of BCG has resulted in significantly improved outcomes for patients with non-muscle invasive bladder cancer. In addition, bladder cancer tumors appear to be immune-mediated.

“Tumors that respond to immune therapy tend to have high mutational rates and they tend to be tumors that have been exposed to external carcinogens like tobacco or other chemicals,” said Petrylak.

MPDL3280A is an anti-PD-L1 antibody that inhibits the binding of PD-L1 to PD-1 and B7.1. This effect can restore antitumor T-cell activity and enhance T-cell priming, Petrylak explained.

He noted findings of a phase I expansion trial where MPDL3280A demonstrated a 52% overall response rate (ORR) in mostly platinum-pretreated, PD-L1—positive patients with metastatic urothelial bladder cancer (UBC) and immunohistochemistry (IHC) 2/3. In patients with IHC 0/1, the ORR was 14%.

“These are the typical second-line patients,” said Petrylak, “and most of these patients were treated less than 3 months after their first chemotherapy.”¹

“This was an extremely well-tolerated drug,” he added, “exhibiting rapid and durable responses, and in patients who may have had prior cisplatin treatment, there was no renal toxicity.” The most common adverse events were fatigue (15%), decreased appetite (12%), and nausea (11%), with no treatment-related deaths.

MPDL3280A was granted breakthrough status by the FDA last year based on these phase I data, and additional studies of the agent in UBC are planned and ongoing. A phase II, multicenter, single-arm study of MPDL3280A in patients with locally advanced or metastatic urothelial bladder cancer (NCT02108652) is evaluating MPDL3280A (1200 mg) every 21 days for up to 16 cycles in 300 cisplatin-refractory patients and 100 treatment-naïve and platinum-ineligible patients.

“I think it’s going to be interesting to compare these two groups of patients because of prior chemotherapy,” said Petrylak. “We may see differences in response rates in the two groups.”

The anti-PD-1 antibody pembrolizumab is also under evaluation in this setting. In a phase Ib multi-cohort study of pembrolizumab in patients with PD-L1—positive advanced solid tumors reported at the 2014 European Society of Medical Oncology Congress in September, the agent was found to be generally well tolerated in patients with advanced urothelial cancer, demonstrating a 24.1% ORR, a complete response of 10.3%, and a partial response of 13.8% in this mostly pretreated population. Fifty-eight percent of patients were alive at 6 months, and the median overall survival was 9.3 months.²

Petrylak did caution that this trial looked at patients who were “IHC positive in either the tumor cells or stroma, so there’s a difference in the assays, making it a little difficult to compare the MPDL3280A trial that we conducted with this pembrolizumab trial directly.”

No treatment-related deaths were reported, there was one infusion reaction, and one discontinuation due to a treatment-related adverse event. “The question is can we identify these patients better,” said Petrylak, who added that the findings support the continued development of the agent in this setting, and a randomized phase III study of pembrolizumab in advanced urothelial cancer (Keynote-045) is currently recruiting patients.³

Nivolumab is also going to be evaluated as a second-line agent in a phase II trial, said Petrylak. Patients who have disease progression or recurrence after at least one platinum-containing regimen will be stratified based on their PD-L1 expression.

Checkpoint inhibition therapy demonstrates significant antitumor activity in cisplatin-treated metastatic bladder cancer, Petrylak continued, and ongoing phase II and III trials are set to confirm initial observations.

“A thorough understanding of the markers of resistance will help to design future trials in earlier stage disease. There are adjuvant trials being designed, both with cooperative groups as well as the pharmaceutical industry,” he concluded.

References

1. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). Presented at the Annual Meeting of the American Society of Clinical Oncology, May 31, 2014. J Clin Oncol. 32:5s. Abstract 5011.
2. Plimack ER, Gupta S, Bellmunt J, et al. A phase Ib study of pembrolizumab in patients with advanced urothelial tract cancer. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. LBA23A.
3. A phase III randomized clinical trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel or vinflunine in subjects with recurrent or progressive metastatic urothelial cancer. NCT02256436. https://clinicaltrials.gov/ct2/show/NCT02256436.

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