Combining Yervoy (ipilimumab) with Opdivo (nivolumab) appears to lengthen survival and trigger a stronger response against tumors than Opdivo alone in patients with metastatic bladder cancer who were already treated with chemotherapy, Phase 1/2 results show.
The data support a Phase 3 trial, now underway and enrolling, that is evaluating the efficacy of a Yervoy-Opdivo combination (both marketed by Bristol-Myers Squibb) plus standard of care chemotherapy as a first-line treatment in patients with inoperable or metastatic urothelial (bladder) cancer.
The findings, “Nivolumab (N) Alone or in Combination With Ipilimumab (I) in Patients (pts) With Platinum-Pretreated Metastatic Urothelial Carcinoma (mUC), Including the Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Expansion From CheckMate 032,” were presented last month at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany. They were also the focus of an ESMO news article.
CheckMate 032 (NCT01928394) was a multicenter, open-label Phase 1/2 study evaluating Opdivo alone in comparison to an Opdivo-Yervoy combo in treating locally advanced or metastatic urothelial cancer (the cause of 90% of all bladder cancers). All enrolled had received at least one prior line of platinum-based chemotherapy, and most were heavily pre-treated.
Patients were divided in three groups: 78 received 3 mg/kg Opdivo alone every two weeks; 104 were given Opdivo at 3 mg/kg plus 1 mg/kg of Yervoy every three weeks for up to four doses, followed by Opdivo alone; 92 patients received 1 mg/kg Opdivo plus 3 mg/kg Yervoy every three weeks up for to four doses, followed by Opdivo.
Minimum follow-up was 37.7, 38.8 and 7.9 months for each group, respectively.
The overall response rate — the proportion of patients whose tumor was either smaller or disappeared — was 26%, 27%, and 38%, suggesting that combo with Yervoy at the highest dose (3 mg/kg) was most effective.
Progression-free survival, or the median time patients lived without cancer progression, was also consistently longer in the high-dose combo group, at 4.9 months. It was 2.8 months in those treated with Opdivo alone, and 2.6 in the Yervoy at 1 mg/kg combination.
Likewise, overall survival was longest in the Yervoy 3 mg/kg combination group at 15.3 months, compared to 7.4 months in the lower-dose combination group and 9.9 months in those receiving Opdivo alone.
Researchers noted a more favorable response in patients with PD-L1 positive tumors (1% or higher expression), particularly if patients were given the higher Yervoy dose (3 mg/kg). In this patient group, the response rate was 58%.
In contrast, those with PD-L1 negative tumors showed lesser benefit and lower response rates regardless of the treatment regimen. Patients given the combination with Yervoy at 3 mg/kg had a response rate of 24%, versus 26% for Opdivo alone.
A Opdivo-Yervoy combo treatment was considered to have a “manageable safety profile.” Severe or life-threatening treatment-related reactions were reported 27% (Opdivo only), 31% (lower-dose combo), and 39% (higher-dose combo) of patients.
“The combination of [Yervoy at 3 mg/kg] demonstrated higher ORR [objective response rate] and longer PFS [progression-free survival] and OS [overall survival] than previous reports of PD-1/PD-L1 monotherapies,” the researchers wrote.
These results, they added, support the Phase 3 trial (NCT03036098), called CheckMate901, now evaluating Opdivo-Yervoy plus chemotherapy as a first-line treatment for previously untreated patients whose urothelial cancer is inoperable or metastatic. This study plans to enroll 897 adults at sites across the U.S., Canada, Europe, Asia and South America; information is available here.
“The response rate of 38% is encouraging,” but we need to wait for Phase 3 results with longer-term outcomes, Cora Sternberg, MD, chief of the department of Medical Oncology at San Camillo and Forlanini Hospitals in Italy, said in a study discussion at the ESMO 2018 congress.
Sternberg also noted a need for a more detailed characterization of patient tumors, partly to show if PD-L1 positive or negative status was a “good biomarker” of likely treatment response, and to examine markers other than PD-L1.