Ipilimumab Broadens Nivolumab Activity in Urothelial Cancer

Margaret K. Callahan, MD, PhD

Five of 8 evaluable patients with metastatic urothelial cancer benefited from the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) after having no response to single-agent nivolumab, according to findings reported at the 2017 Genitourinary Cancers Symposium. The combination was associated with a modest increase in toxicity, but was generally well tolerated.

“One patient achieved a confirmed partial response and four additional patients achieved stable disease after documented progression,” Margaret K. Callahan, MD, 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 nivolumab and the PD-L1 inhibitor atezolizumab (Tecentriq). 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 ipilimumab has clinical activity in melanoma as a single agent or in combination with the nivolumab, establishing the paradigm for exploring the combination in urothelial carcinoma. Additionally, some evidence has suggested that ipilimumab 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 nivolumab and ipilimumab would confer additional clinical benefit for patients with metastatic urothelial cancer that had proven unresponsive to nivolumab 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 nivolumab.

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 nivolumab monotherapy. Options for the patients with progressive disease included a trial of the ipilimumab/nivolumab combination, and 10 patients received the combination, consisting of 1 mg/kg of ipilimumab and 3 mg/kg of nivolumab every 3 weeks.

The 10 patients had a median age of 61 years, 3 had received 2 or more prior systemic regimens, 2 were current smokers, and 7 were former smokers. Duration of treatment with nivolumab monotherapy ranged from 6 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 nivolumab monotherapy, and 9 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 1 partial response and 4 patients with stable disease. By RECIST criteria, 4 of the 8 evaluable patients benefited from the ipilimumab/nivolumab combination, consisting of 1 partial response and 3 patients with stable disease.

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 3 had stable disease for 6 weeks.

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

During combination therapy, grade 1/2 adverse events consisted of 3 patients with pruritus; 2 each with rash, dry skin, and diarrhea; and 1 patient each with anorexia, nausea, vomiting, fatigue, edema, weight loss, dizziness, dyspnea, and mucositis. Additionally, 1 patient had grade ≥3 diarrhea and 1 had grade ≥3 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 III study is planned but not yet enrolling to explore nivolumab in combination with ipilimumab 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).

Callahan MK, Kania BE, Iyer G, et al. Evaluation of the clinical activity of ipilimumab (IPI) plus nivolumab (NIVO) in patients (pts) with NIVO-refractory metastatic urothelial cancer (UC). J Clin Oncol. 2017;35 (suppl 6S; abstract 384).

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