An immunotherapy combination with a higher dose of ipilimumab produced a 38 percent overall response rate for patients with metastatic bladder cancer in a clinical trial led by investigators at The University of Texas MD Anderson Cancer Center that examined single-agent nivolumab and two combinations of the immune checkpoint inhibitors.

Progression-free survival and overall survival also were higher for patients given the combination with the higher-dose of ipilimumab.

Study results were published online by the Journal of Clinical Oncology.

“The approval of single-agent PD-1 checkpoint inhibitors for bladder cancer in 2017 was an important step forward, but it will take combination therapies to extend the impact of these drugs to more of our patients,” said study leader Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at MD Anderson.

The 38 percent overall response rate is higher than any previously reported in studies of single-agent immunotherapies, which ranged from 13.4 to 21.1 percent for metastatic bladder cancer, the investigators note.

The clinical trial, called Checkmate 032, was the first combination immunotherapy trial for metastatic bladder cancer.

The two combination dosages were 3mg/kg nivolumab with 1mg/kg ipilimumab (NIVO3 IPI1) and 1mg/kg nivolumab with 3mg/kg ipilimumab (NIVO1 IPI3).

“The durable higher response rate with NIVO1 IPI3 found in this study is most encouraging and also indicates that different tumour types may require different doses to elicit improved efficacy,” Sharma said. “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.”

Sharma and colleagues note the results are promising for patients that had been heavily pretreated and had limited treatment options.

But they also write that a larger trial with direct comparison of outcomes and arms that represent standard of care are needed to confirm these findings.

In this trial, outcomes for single-agent nivolumab and NIVO3 IPI1 were similar.

Objective response rate is confirmed complete response (disappearance of tumours) plus confirmed partial response (at least 30 percent shrinkage).

Response rates and survival

Therapy, dosage, objective response rate (ORR), complete response rate (CR), progression-free survival (PFS) and overall survival (OS) are:

- Nivolumab alone, 3mg/kg, 20 out of 78 patients (25.6 percent) had a response; 8 (10.3 percent) complete response; median progression-free    survival 2.8 months; median overall survival 9.9 months.
- NIVO3 IPI1: ORR 28 of 104 patients (26.9 percent); CR 8 (7.7 percent); PFS 2.6 months; OS 7.4 months.
- NIVO1 IPI3: ORR 35 of 92 patients (38 percent); CR 6 (6.5 percent); PFS 4.9 months; OS 15.3 months.

The two drugs target different proteins on T cells, white blood cells that act as the targeted soldiers of the immune system.

Programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) each act as brakes on T cells, working in different ways to shut down immune response.

Nivolumab blocks PD-1, ipilimumab blocks CTLA-4, freeing T cells to attack cancer.

Nivolumab was approved by the Food and Drug Administration as a single agent for advanced bladder cancer in 2017.

The NIVO1 IPI3 cohort was based on Sharma’s immune-monitoring research that showed higher frequency of effector ICOS-positive CD4 helper T cells and ICOS-positive CD8 cytotoxic T cells in bladder cancer tumours after treatment with 3 mg/kg of ipilimumab compared to 1 mg/kg.

Side effects

The side effect profiles of the two combinations were similar, with the NIVO1 IPI3 regimen causing slightly more frequent grade 3 (serious) or grade 4 (life-threatening) adverse events.

- NIVO1 IPI3: 80.4 percent had at least one treatment-related adverse event of any grade, 39.1 percent had grade 3-4 events, and 13 percent    discontinued treatment due to study drug toxicity.
- NIVO3 IPI1, 84.6 percent had an event, 30.8 had grade 3-4 events and 14.4 percent stopped treatment due to study drug toxicity.

For nivolumab alone, 84.6 percent of patients had events, 26.9 percent had grade 3-4 events, and 3.8 percent had to discontinue treatment.

Minimum follow-up was 37.7 months for the nivolumab cohort, 38.8 for NIVO3 IPI1 and 7.9 months for the NIVO1 IPI3 cohort.

Sponsor Bristol-Myers Squibb opened the trial with a small, 26-person cohort of patients in NIVO1 IPI3 with anticipated cohorts of 60-100 patients in the other two arms.

Later in the trial, NIVO1 IPI3 was expanded to 92 patients, so that arm accumulated more slowly than the other two.

Bristol-Myers has opened CheckMate 901, an 897-patient Phase III clinical trial comparing the NIVO1 IPI3 combination to chemotherapy combinations and a combination of nivolumab and chemotherapy.

Source: The University of Texas MD Anderson Cancer Center