Metastatic bladder Ca: High ORR seen with immunotherapy combo

Combined treatment with nivolumab (Opdivo), 1 mg/kg and ipilimumab (Yervoy), 3 mg/kg resulted in a 38% overall response rate in a study of platinum-pretreated metastatic urothelial cancer patients. That’s a higher response rate than previously reported results with any single-agent immunotherapy for metastatic bladder cancer.

“The current standard of care for patients who have failed frontline chemotherapy for metastatic bladder cancer is single-agent immunotherapy,” said study author Arlene O Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center, Houston. The study was published in the Journal of Clinical Oncology (2019; 37:1608-16).

The FDA’s approval of single-agent programmed death 1 (PD-1) checkpoint inhibitors for bladder cancer in 2017 was big news in the cancer community, Dr. Siefker-Radtke said.

Read: Cystoscopy overuse common in surveillance of low-risk bladder Ca

“We were all thrilled by having evidence of clinical activity, although the response rates are typically around 20% with a median survival of around 10 months. So, it’s clear that not all patients are benefiting from single-agent immune checkpoint inhibitor,” Dr. Siefker-Radtke said. “We need better ways of stimulating an immune response to cancer. And the combination of nivolumab with ipilimumab is showing evidence of an increase in immune response compared to what has been seen historically with single-agent immunotherapy.”

The PD-1 immune checkpoint inhibitor nivolumab, which blocks PD-1, is among the approved monotherapies for patients with locally advanced or metastatic bladder cancer who experience progression post chemotherapy. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4. Researchers studying the combination have shown benefit in several types of tumors, according to the study.

Patients in this first combination immunotherapy trial for metastatic bladder cancer, called Checkmate 032, received either single-agent nivolumab or one of two immune checkpoint inhibitor combinations. One combination was 3 mg/kg nivolumab with 1 mg/kg ipilimumab; the other, 1 mg/kg nivolumab with a higher ipilimumab dose of 3 mg/kg.

Continue to the next page for data from the study.Of the 78 patients treated with nivolumab alone, 25.6% had a response, including 10.3% who had a complete response. Median progression-free survival was 2.8 months and median overall survival 9.9 months.

Among the 104 patients who were treated with the combination of 3 mg/kg nivolumab with 1 mg/kg ipilimumab, 26.9% had a response, including 7.7% with a complete response. Median progression-free survival was 2.6 months and overall survival a mean 7.4 months.

Of the 92 patients treated with 1 mg/kg nivolumab and 3mg/kg ipilimumab, 38% had a response, including 6.5% who had complete response. Progression-free survival was a mean 4.9 months and overall survival 15.3 months.

Different tumor types may require different doses to elicit improved efficacy, study leader Padmanee Sharma, MD, PhD, of MD Anderson Cancer Center, said in a press release.

Also see: Older women who quit smoking greatly reduce bladder cancer risk

“The combination for metastatic renal cell cancer uses a lower dose of ipilimumab, but bladder cancer may require ipilimumab at the higher dose. This should be an important consideration,” Dr. Sharma said.

Serious grade 3 or life-threatening grade 4 treatment-related adverse effects occurred in 26.9% of those treated with the monotherapy, compared to 30.8% of those treated with 3 mg/kg nivolumab with 1 mg/kg ipilimumab and 39.1% treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab.

More than 80% of patients in each of the treatment arms had at least one treatment-related adverse event of any grade. And while 3.8% of patients in the nivolumab-alone group had to discontinue treatment due to treatment-related toxicity, 13% to more than 14% of patients in each of the combination treatment arms discontinued treatment due to toxicity.

“Our hope is that by pursuing these combinations that allow us to better modulate or stimulate the immune system we can improve treatment, have more patients achieve a response to therapy, and hopefully impact the lives of more of our bladder cancer patients,” Dr. Siefker-Radtke said.

These results support studying the immunotherapy combination with the higher ipilimumab dose as a first-line treatment for metastatic urothelial cancer, the authors wrote.

Dr. Siefker-Radtke is on the scientific advisory board for Bristol-Myers Squibb. Bristol-Myers Squibb funded this trial.