Ipilimumab plus nivolumab demonstrated encouraging activity in advanced melanoma

CHICAGO — The combination of the immunotherapy agents ipilimumab and nivolumab induced extensive and durable tumor shrinkage in patients with advanced melanoma, according to long-term study results presented at the ASCO Annual Meeting.

“These are two distinct immune checkpoint inhibitors, so it makes sense to combine them together,” researcher Mario Sznol, MD, a professor of medical oncology at Yale School of Medicine, said during a press conference. “They both produce very significant clinical activity as monotherapy in advanced melanoma.”

Sznol and colleagues evaluated data from 94 patients with inoperable stage III or IV melanoma who received ipilimumab (Yervoy, Bristol-Myers Squibb) — a monoclonal antibody that targets CTLA-4 — and nivolumab (BMS-936558, Bristol-Myers Squibb), a fully human IgG4 monoclonal antibody that targets the programmed cell death 1 (PD-1) receptor. Fifty-five percent of patients had not received prior systemic therapy.

The current analysis includes long-term follow-up data from 53 of these patients. Patients received the ipilimumab–nivolumab combination every 3 weeks for four doses. They subsequently received nivolumab alone every 3 weeks for four doses. Nivolumab doses ranged from 0.3 mg/kg to 3 mg/kg, and ipilimumab doses ranged from 1 mg/kg to 3 mg/kg.

Patients who achieved disease control at week 24 with no disease-limiting toxicity went on to receive the combination every 12 weeks for another eight doses.

Overall, 85% of patients from all dosing schedules achieved 1-year OS, and 79% achieved 2-year OS.

“This was a small trial, so this very impressive 2-year OS data,” Sznol said.

Researchers observed responses in 22 patients (41%), including complete responses in nine patients (17%). Responses in 18 of these patients were still ongoing at the time of the analysis, and the median duration of responses had not yet been reached.

The responses were rapid, Sznol said. Forty-two percent of patients demonstrated ≥80% tumor reduction by week 36.

The combination demonstrated activity regardless of BRAF mutation status. The aggregate clinical activity rate among patients with mutated BRAF was 60%, and the rate among patients with wild-type BRAF was 73%.

Researchers also noted the combination was effective regardless of PD-L1 status; however, patients with PD-L1–negative disease demonstrated higher rates of response with the combination than what has been previously reported with nivolumab alone.

“This suggests that we’re picking up activity in patients who might not have responded to anti-PD-1 therapy alone,” Sznol said.

Sznol and colleagues enrolled 41 additional patients on a phase 2/phase 3 trial evaluating 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for four doses, followed by 3 mg/kg nivolumab every other week.

Initial analyses indicated 94% of patients achieved 1-year OS, and 88% achieved 2-year OS. The objective response rate for this cohort was 43%.

“This was very similar to what we saw with the first cohorts of patients, so we feel very confident that the activity of this combination is real,” Sznol said. 

More than half of patients (62%) experienced a grade 3 to grade 4 adverse event, the most common of which were elevated lipase and aspartate aminotransferase. There was one death from treatment-related colitis.

“The concurrent therapy produced unprecedented 1- and 2-year OS rates; of course, these are small cohorts of patients and this needs to be verified in phase 3 trials,” Sznol said. “At least in our preliminary experience, it did appear that OS looked a little bit better in the higher-dose cohorts, but again this needs to be confirmed. The increased rate of adverse events is real but manageable with algorithms, and I think the adverse events are justified by the increased activity.”

For more information:

Sznol M. Abstract #LBA9003. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Disclosure: The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. The researchers report consultant/advisory roles or employment/leadership positions with; research funding, honoraria or other remuneration from; and stock ownership in Amgen, Anaeropharma,