Combination with Higher Dose of Yervoy Shows Promise in Bladder Cancer

Patients with platinum-pretreated metastatic urothelial carcinoma who were treated with a higher dosage of Yervoy (ipilimumab) in combination with Opdivo (nivolumab) experienced improved survival and tolerable side effects, according to findings from the phase 1/2 CheckMate-032 trial.

Urothelial carcinoma is the most common type of bladder cancer, accounting for 90 percent of all cases, of which 78 percent will experience a recurrence within five years. Bladder cancer has a high mutation rate, but fortunately, immunotherapy — specifically checkpoint inhibitors like Opdivo – often work well against cancers that express mutations.

To evaluate the safety and efficacy of Opdivo as a single agent or in combination with Yervoy, the multicenter, open-label study randomized 247 patients to receive either:

• 3 mg/kg of Opdivo every two weeks (O3; 78 patients; follow up, 37.7 months);
• 3 mg/kg of Opdivo plus 1 mg/kg of Yervoy every three weeks for four cycles, followed 3 mg/kg of Opdivo every two weeks (O3:Y1; 104 patients; follow up, 38.8 months); or
• 1 mg/kg of Opdivo plus 3 mg/kg of Yervoy every three weeks for four cycles, followed by 3 mg/kg of Opdivo every two weeks until disease progression or unacceptable toxicity (O1:Y3; 92 patients; minimum follow up, 7.9 months).

All patients were heavily pretreated before enrollment — most received at least two prior treatment regimens – and patients in the O3 treatment arm could enter the O3:Y1 arm upon progression if they wished.

According to researchers, tumors were assessed every six weeks for the first 24 weeks, then every 12 weeks after that.

After the minimum follow up periods, researchers found that median progression-free survival (or the team until disease worsening) and overall survival for the O1:Y3 arm were the highest of all three arms at 4.9 and 15.3 months, respectively, compared with 2.6 and 7.4 months in the O3:Y1 arm, and 2.8 and 9.9 months among those who received Opdivo alone.

While patients treated with O1:Y3 experienced a higher rate of gastrointestinal events and hepatic toxicities, skin toxicities were not very different between each cohort.

"In general, treatment was well tolerated with the expected immune-related (side effects). There were some events that were higher in the ipilimumab arm, which we might expect,” lead study author Jonathan E. Rosenberg, M.D., a medical oncologist and chief of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center, said during a presentation on the study’s results at the European Society for Medical Oncology 2018 Congress in Munich, Germany last month.

Although overall survival data is still in the early stages, Rosenberg explained that the O1:Y3 regimen could move the field of urothelial carcinoma treatment forward if the data is confirmed in a phase 3 randomized trial.

“These results from CheckMate-032 point to the combination of nivolumab and ipilimumab as a potentially promising treatment option for patients with metastatic urothelial carcinoma who are pretreated with platinum-based chemotherapy,” he added.