Long-term data continue to show sustained improvements in overall survival with nivolumab alone or in combination with ipilimumab as a frontline treatment for patients with advanced melanoma.
Victoria Atkinson, MD
Long-term data continue to show sustained improvements in overall survival (OS) with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) as a frontline treatment for patients with advanced melanoma, according to two presentations at the 2015 Society for Melanoma Research Congress.
In the phase III CheckMate-066 trial, the 2-year OS rate with frontline nivolumab was 57.7% compared with 26.7% for dacarbazine.1 Additionally, in a phase Ib study, the combination of nivolumab and ipilimumab showed an OS rate of 68% at a median follow-up of 32.7 months.2
“This trial is the longest follow-up that we have for patients from a phase III trial for a PD-1 antibody. It shows the highest 2-year survival for any PD-1 therapy in advanced melanoma,” study author Victoria Atkinson, MD, of Princess Alexandra Hospital and Gallipoli Medical Research Foundation, Queensland, Australia, told OncLive at the conference. “Nivolumab is a highly effective treatment, which is significantly improving overall survival for patients with good quality of life.”
The FDA is currently reviewing an application for nivolumab as frontline therapy for patients with advanced melanoma, based on the CheckMate-066 trial. The agency is scheduled to make a decision regarding the application by November 27, 2015.
In the phase III trial, 418 untreated patients were randomized in a 1:1 ratio to receive nivolumab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1000 mg/m2 every 3 weeks (n = 208). Of the patients enrolled, 61% had stage M1c disease and 36.6% had an elevated lactate dehydrogenase level. The primary endpoint of the study was OS. Secondary endpoints included progression-free survival (PFS), objective response rates (ORR), and quality of life.
After a minimum follow-up of 15.1 months, median OS was not yet reached for patients receiving nivolumab compared with 11.2 months in the dacarbazine arm (HR, 0.43; 95% CI, 0.33-0.57; P <.001). The 1-year OS rates were 70.7% and 46.3%, for nivolumab and dacarbazine, respectively. Additionally, following progression in the dacarbazine arm, 13% of patients (n = 27) went on to receive nivolumab.
Median PFS was 5.4 months with nivolumab versus 2.2 months for dacarbazine (HR, 0.42; 95% CI, 0.32-0.53; P <.001). With nivolumab, the 1- and 2-year PFS rates were consistent, at 44.3% and 39.2%, respectively.
The ORR was 42.9% with nivolumab versus 14.4% with dacarbazine. A complete response was achieved by 11% of patients with nivolumab compared with 1% for dacarbazine. At the analysis, 81% of responses in the nivolumab arm remained ongoing.
“This data reassures us that the responses are maintained. Those who do obtain a response with nivolumab have a maintained response,” Atkinson said. “With the two year overall survival being so high, we’re seeing a plateauing of the curve. We hope that with further follow-up we will see maintained responses.”
All-grade adverse events (AEs) were similar between each arm but grade ≥3 AEs were less common with nivolumab (13% vs 17%). The most frequently reported all-grade AEs in patients treated with nivolumab were pruritus (22%), diarrhea (18%), and rash (18%). Altogether, AEs led to discontinuation in just 6% of patients in the nivolumab arm.
“The highest toxicities with nivolumab were fatigue and arthralgias,” said Atkinson. “These are very easily managed side effects, and we see that the toxicity profile is better than chemotherapy,”
Patient characteristics, such as disease burden, should be utilized to tailor treatment for patients with advanced melanoma, according to Atkinson. Those with a lower burden of disease who are frail are ideal candidates for nivolumab monotherapy. However, patients with high-risk characteristics, for which a rapid response is needed, should receive a combination of nivolumab and ipilimumab. In either scenario, PD-L1 expression did not seem to play a significant role, Atkinson advised.
“For melanoma, PD-L1 shouldn’t determine whether we give nivolumab monotherapy,” she said. “Regardless of PD-L1 status, you live longer with nivolumab.”
In the smaller phase Ib study, labeled Study 004, the combination of nivolumab and ipilimumab was explored at various dosing schedules for patients with unresectable or metastatic melanoma. In 3 cohorts that received similar treatment schedules (n = 53), the ORR with the combination was 42% and the median duration of response was 22.3 months. Complete responses were seen in 21% of patients treated with the combination.
In another cohort that received the combination every 3 weeks for 12 weeks followed by nivolumab alone every 3 weeks for 12 weeks (n = 41), the 18-month OS rate was 68%. The ORR was 44%, with complete responses in 17% of patients. The median duration of response was 13.7 months.
This phase Ib study laid the groundwork for a phase II study, which was instrumental in an accelerated approval for the combination of nivolumab and ipilimumab as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma. This accelerated approval marked the first for an immunotherapy combination for patients with cancer.
In the pivotal phase II trial, known as CheckMate-069,3 the combination reduced the risk of progression or death by 60% compared with ipilimumab alone (HR, 0.40; 95% CI, 0.22-0.71; P <.002). Among patients with BRAF wild-type tumors, median PFS was 8.9 months in the nivolumab plus ipilimumab group versus 4.7 months in the ipilimumab arm. The ORR was 60% with the combination versus 11% with ipilimumab alone.
Under the FDA's accelerated program, full approval for the combination is contingent upon findings from a confirmatory study. Supporting data are usually available years after an accelerated approval; however, in this circumstance, the FDA is already considering phase III data for the combination of nivolumab and ipilimumab. The agency is scheduled to make a decision regarding these data by January 23, 2016.
The application for full approval was based on the phase III CheckMate-067 study,4 which showed a 59% reduction in the risk of progression or death with the combination versus ipilimumab alone (HR, 0.41; 95% CI, 0.32-0.53). Median PFS with nivolumab/ipilimumab was 11.5 months versus 2.9 months with ipilimumab alone (HR, 0.42; 95% CI, 0.31-0.57; P <.001).
“I think immunotherapy is going to have a PD-1 backbone, but it will be combined with other things to see if we can improve that response rate,” said Atkinson. “Even with ipilimumab, we’re still only looking at response rate of around 55%. We need to look at other therapies to see if we can improve that, so that all patients are achieving a clinically significant response from immuno-oncology.”
A number of studies are assessing nivolumab in various combinations for patients with melanoma and other types of cancer. A phase I/II study is looking at nivolumab with the anti-CD27 antibody varlilumab (NCT02335918). Additionally, a phase II/III study is exploring nivolumab and ipilimumab with the GM-CSF agent sargramostim (NCT02339571).
In addition to melanoma, the FDA has approved has nivolumab as a treatment for patients with metastatic non-small cell lung cancer (NSCLC) following a platinum-based chemotherapy regardless of histology or PD-L1 status. Additionally, the agency is currently reviewing an application for the PD-1 inhibitor for patients with renal cell carcinoma following frontline antiangiogenic therapy.