Modern Perspectives in Advanced Melanoma - Episode 10
Evan J. Lipson, MD: In patients with metastatic melanoma, KEYNOTE-006 was an important study. It’s an open-label, multicenter, randomized, controlled phase 3 trial, and it was done around the world. This trial included patients with metastatic melanoma who were naïve to ipilimumab, and they were assigned to receive either pembrolizumab or ipilimumab. It assessed overall survival [OS] among other things, and the 5-year outcomes were recently published, and pembrolizumab continued to show improved overall survival vs ipilimumab in the 5-year follow-up.
There were about 43% of patients estimated to be alive at 5 years vs only 33% of patients who received ipilimumab. This is similar to some of the other outcomes we’ve discussed; this demonstrates that an anti–PD-1, in this case pembrolizumab, is superior in this way to ipilimumab in patients with advanced disease.
CheckMate 067 is one of the most often cited studies. This was a trial that randomized almost a thousand treatment-naïve patients with advanced melanoma to either ipilimumab by itself, nivolumab by itself, or the combination. It was powered to compare the nivolumab-containing arms to the ipilimumab-alone arm. It was not powered to compare both of the nivolumab-containing arms to each other.
The results of CheckMate 067 at the 5-year mark were presented at ESMO [the European Society for Medical Oncology annual meeting] in 2019, and they essentially showed that both of the arms that contained nivolumab provided significant improvements in OS and PFS [progression-free survival] over the ipilimumab by itself in this patient population. This, of course, is important information, but it leaves some of the questions unanswered.
There seems to be a durable benefit across many of the subgroups. What we don’t totally understand is whether a particular patient is in need of dual therapy with ipilimumab plus nivolumab or whether nivolumab by itself will suffice. There, the search goes on for biomarkers to better understand whether using both agents in combination is worth the increased potential toxicity signal vs using nivolumab by itself. The toxicity issue we discussed with using ipilimumab plus nivolumab together vs nivolumab alone has been a topic of a lot of further study.
One of those further trials is CheckMate 511, which is a phase 3/4 study to look at whether a different dose combination of nivolumab plus ipilimumab can improve the safety profile of the combination. This study evaluated previously untreated patients with unresectable stage III or IV melanoma, and they were randomly assigned to get either the high-dose nivolumab and low-dose ipilimumab, or the reverse. Once the patients were done getting either of those combinations, they then went on to get the nivolumab monotherapy at the standard dose of 40 mg every 4 weeks.
The primary end point of the study was a comparison of the incidence of treatment-related grade 3 to 5 adverse events. There was a secondary end point that included descriptive analyses of the objective response rate, PFS, and OS. But it was not designed to look formally at whether nivolumab 3/ipilimumab 1, which was the experimental arm, was not inferior: it was not a noninferiority study of that vs the standard dosing of nivolumab plus ipilimumab.
What it did reveal is that it met its primary end point and demonstrated a significantly lower incidence of treatment-related grade 3 to 5 adverse events when you use the nivolumab 3/ipilimumab 1, so the higher dose nivolumab and the lower dose ipilimumab vs the standard combination for melanoma, which is the lower dose nivolumab and the higher dose ipilimumab.
Some of the descriptive analyses demonstrated that there were no meaningful differences between the groups for the efficacy end points: PFS and OS. However, we need some more data to investigate some of those points further.
What this has done is that it has supported decision-making in the clinic that, in particular patients, flipping the dose can perhaps mitigate some of the adverse events that we see with the standard dose of ipilimumab plus nivolumab. I don’t know that there’s a hard and fast rule on this just yet, but it does at least introduce the possibility that, for the right patient, flipping the dose of the drugs may be a reasonable way to go.
Another interesting study that was published in the last year or so looked at the 5-year outcomes with dabrafenib plus trametinib in patients with BRAF-mutated melanoma. This was a pooled analysis of 2 different trials. The trials it looked at were the COMBI-d and the COMBI-v, and these were studies that looked at the combination of dabrafenib plus trametinib. One of them compared that combination to dabrafenib alone, and the other trial compared that combination to vemurafenib, which is another BRAF inhibitor.
In this pooled analysis, what they looked at was several factors, including performance status, age, sex, number of organ sites, and LDH [lactate dehydrogenase] level. In the multivariate analysis, several of those variables were significantly associated with progression-free survival and overall survival when you looked at the dual therapy in comparison to either of the single therapies.
The bottom line for this analysis was that frontline treatment with dabrafenib plus trametinib can lead to long-term benefits, in this case, in approximately a third of the patients with unresectable or metastatic melanoma with either a BRAF V600E or V600K mutation.
Transcript edited for clarity.