Question: What do we know about the benefit of ipilimumab in the second-line setting after using anti–PD-1 therapy in the frontline setting?
Answer: Multiple prospective phase III studies have demonstrated the superiority of anti–PD-1 agents over ipilimumab in patients with metastatic melanoma.1,2 In the first study, KEYNOTE-006, previously untreated patients with metastatic melanoma were randomly assigned to either two different doses of pembrolizumab or ipilimumab.1 Patients who received pembrolizumab had improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). In the second study, CheckMate 067, previously untreated patients with metastatic melanoma were randomly assigned to nivolumab, ipilimumab, or ipilimumab and nivolumab. The patients assigned to the nivolumab or the ipilimumab/nivolumab arms had superior ORR, PFS, and OS compared with those in the ipilimumab arm. Based on the results of both of these studies, single-agent ipilimumab is no longer a recommended frontline agent for patients with metastatic melanoma.
In the frontline, approximately 40% or more of patients with metastatic melanoma will achieve a partial or complete response with anti–PD-1 agents, which, unfortunately, leaves the majority of patients in need of an option in the second line. At present, there are no prospective data published on the efficacy of ipilimumab in patients whose disease progressed during anti–PD-1 therapy. A review of the literature identified three peer-reviewed retrospective case series and one presentation at an annual meeting reporting on the use of ipilimumab in patients with melanoma whose disease had progressed during anti–PD-1 treatment.
In the first retrospective study, Jacobsoone-Ulrich et al. reported on eight patients with metastatic melanoma whose disease progressed during anti–PD-1 treatment.3 In this series, four out of eight (50%) patients achieved a response. In the second retrospective study, Bowyer et al. reviewed a cohort of 40 patients treated with ipilimumab as the next treatment after progression with anti–PD-1 agents, demonstrating an ORR of 10%, with 8% of patients with stable disease for more than 6 months.4 In the third retrospective study, Aya et al. reported on nine patients who received ipilimumab after progression with anti–PD-1 agents, with a response occurring in two out of nine (22%) patients.5
At the 13th Society for Melanoma Research Congress, Long et al. presented the largest retrospective study of the efficacy of ipilimumab after progression during frontline treatment with pembrolizumab.6 This presentation reviewed the experience of patients enrolled in the KEYNOTE-006 trial, which was a frontline study of patients with metastatic melanoma who were randomly assigned to receive either pembrolizumab at two different doses or ipilimumab.1 In this study, patients who received either dose of pembrolizumab had improved OS, PFS, and ORR compared with patients who received ipilimumab, thus establishing pembrolizumab as the new standard of care in frontline metastatic melanoma. Despite the clinical success in patients treated with frontline pembrolizumab (555 patients), approximately 40% (219 patients) of patients who received pembrolizumab went on to receive additional treatments. Of these patients, approximately 59% (129 patients) received ipilimumab, with 75% (97 patients) receiving ipilimumab in the second line immediately following progression during pembrolizumab. In this cohort of 97 patients who received ipilimumab as the next therapy after progression during frontline pembrolizumab, there were 3% with complete remissions, 10% with partial remissions, 32% with stable disease, 32% with progressive disease, and 23% unknown. Of the 57 patients for whom survival data are known, the median OS from the time of random assignment was 19.0 months.
In summary, although there are no prospective trials to assess the efficacy of ipilimumab in patients with metastatic melanoma whose disease progressed during frontline treatment with an anti–PD-1 agent, we can surmise that approximately 10% to 20% of patients will achieve a response to second-line ipilimumab. Given this information, we believe ipilimumab is a reasonable option in patients whose disease progressed during frontline treatment with anti–PD-1 agents.