Immunotherapy Duo Trumps Single Agent in Metastatic Bladder Cancer

In a recent study, the majority of the patients with metastatic urothelial cancer who did not benefit on single-agent Opdivo (nivolumab) saw benefit from the combination of Yervoy (ipilimumab) and Opdivo, according to findings presented at the 2017 Genitourinary Cancers Symposium.

“One patient achieved a confirmed partial response and four additional patients achieved stable disease after documented progression,” Margaret K. Callahan, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues concluded in a poster presentation. “Further studies to evaluate the magnitude of clinical activity and predictors of response for this combination are needed.”

Treatments targeting PD-1/PD-L1 have a recognized role in metastatic urothelial cancer, as demonstrated by the FDA approval of the PD-1 inhibitor Opdivo and the PD-L1 inhibitor Tecentriq (atezolizumab). Nonetheless, a minority of patients with metastatic urothelial cancer respond to inhibition of the PD-1 pathway with monotherapy, and most patients eventually develop progressive disease, highlighting the need for additional treatment options, Callahan and colleagues noted.

The CTLA-4 inhibitor Yervoy has clinical activity in melanoma as a single agent or in combination with the Opdivo, establishing the paradigm for exploring the combination in urothelial carcinoma. Additionally, some evidence has suggested that Yervoy has biologic activity in urothelial cancer (N Engl J Med. 2015;374:23:34; Clin Cancer Res. 2010;28:2861-2871).

Based on the existing evidence, Callahan and colleagues hypothesized that the combination of Opdivo and Yervoy would confer additional clinical benefit for patients with metastatic urothelial cancer that had proven unresponsive to Opdivo monotherapy. They examined the hypothesis in a subgroup analysis of a prospective, single-arm trial involving patients with advanced or metastatic urothelial cancer treated with a standard dose of Opdivo.

The study involved a total of 44 patients, 42 of whom were evaluable for efficacy. Subsequently, 30 of the 42 patients had progressive disease with Opdivo monotherapy. Options for the patients with progressive disease included a trial of the Yervoy / Opdivo combination, and 10 patients received the combination, consisting of 1 mg/kg of Yervoy and 3 mg/kg of Opdivo every three weeks.

The 10 patients had a median age of 61 years, three had received two or more prior systemic regimens, two were current smokers and seven were former smokers. Duration of treatment with Opdivo monotherapy ranged from six to 30 weeks.

Eight of the 10 patients were evaluable for response to the combination therapy. Nine of the 10 had progressive disease by RECIST criteria when treated with Opdivo monotherapy, and nine had progressive disease by radiographic assessment. One patient had stable disease by RECIST criteria but radiographic progression, and one had progression by RECIST and partial response by radiographic assessment.

By radiographic assessment there was one partial response and four patients with stable disease. By RECIST criteria, four of the eight evaluable patients benefited from the Yervoy / Opdivo combination, consisting of one partial response and three patients with stable disease.

One patient had a partial response by both types of assessment criteria. The same patient had progressive disease by both criteria in response to Opdivo monotherapy. One patient had progressive disease by RECIST criteria and stable disease by radiographic assessment. During treatment with single-agent Opdivo, the patient had progressive disease by RECIST and partial response by radiography.

The patient who achieved a partial response with combination therapy maintained the response for 48 weeks. One patient with stable disease maintained the status for 24 weeks, and the other three had stable disease for six weeks.

During Opdivo monotherapy, adverse events (all grade 1/2 ) consisted of two cases each of rash, myalgia and fatigue; and one case each of arthralgia, diarrhea, dyspepsia, headache, agitation, pain and vertigo. No patient had grade 3 or higher adverse events.

During combination therapy, grade 1/2 adverse events consisted of three patients with pruritus; two each with rash, dry skin and diarrhea; and one patient each with anorexia, nausea, vomiting, fatigue, edema, weight loss, dizziness, dyspnea and mucositis. Additionally, one patient had grade 3 or higher diarrhea and one had grade 3 or higher anorexia.

“The combination of ipilimumab and nivolumab is well tolerated and may have clinical activity in patients with urothelial cancer who fail to respond to PD-1 blockade,” the investigators concluded.

A phase 3 study is planned but not yet enrolling to explore Opdivo in combination with Yervoy in comparison with standard chemotherapy for patients with untreated inoperable or metastatic urothelial carcinoma. This study, known as CheckMate-901, plans to enroll 690 patients with an estimated completion date of November 2022 (NCT03036098).