Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Encorafenib and Binimetinib Followed by Ipilimumab and Nivolumab in Advanced Melanoma: EBIN
PracticeUpdate: What is a sequential approach followed in the EBIN trial?
Dr. van Akkooi: In the EBIN trial, two different approaches for advanced melanoma were followed. The first approach was upfront immunotherapy in patients with a BRAF V600–mutant melanoma, where they received ipilimumab and nivolumab combination immunotherapy until progression and could then switch over to encorafenib and binimetinib, a combination of BRAF and MEK inhibitors. Interestingly, this is one of the first studies that I am aware of that used the combination of ipilimumab at 1 mg per kg and nivolumab at 3 mg per kg for advanced melanoma on such a large scale.
So, that’s one of the arms. The other arm in this randomized phase II trial was started off with a short period, 12 weeks, of the combination of encorafenib and binimetinib, followed by a planned switch after a short washout period, not only to prevent hyper-progression from occurring after ceasing the combination of BRAF/MEK inhibitors but also to prevent any additional toxicity of combining BRAF/MEK inhibitors with received ipilimumab and nivolumab. And then switching over to that same regimen of ipilimumab and nivolumab at 1 mg per kg for ipilimumab and nivolumab at 3 mg per kg. Really to see if that induction phase with a short period of 12 weeks of encorafenib and binimetinib would help achieve better responses, better durable responses, and better outcomes for these patients.
EBIN trial design
PracticeUpdate: What is the trial design and on what criteria are these patients recruited into this trial?
Dr. van Akkooi: The EBIN study is a randomized phase II trial where patients with advanced melanoma — that being unresectable stage III melanoma or metastatic stage IV melanoma — were randomized to either the approach involving a short period of 12 weeks of encorafenib and binimetinib followed by ipilimumab at the low dose of 1 mg per kg and nivolumab at 3 mg per kg or to upfront ipilimumab and nivolumab at the same dose level. Patients were allowed to have brain metastases, but stable brain metastases, not symptomatic brain metastases. Those are the major inclusion criteria for this study.
PracticeUpdate: What is the key endpoint of the study?
Dr. van Akkooi: The primary endpoint of the EBIN study is progression-free survival, but also other endpoints were looked at, such as overall survival.
Negative results overall
PracticeUpdate: And how do you foresee these results leading to a new standard treatment approach for these patients with BRAF V600 mutation–positive unresectable or metastatic melanoma?
Dr. van Akkooi: The EBIN study is a negative study because there was no difference in progression-free survival between the two arms of this trial. The arms actually crossed over at a certain point, initially showing some benefit for those patients who started on encorafenib and binimetinib, but then showing later on a seemingly superior outcome for those patients who started with immunotherapy upfront. Interestingly, if we then dive into the subgroup analyses, which were planned subgroup analyses — for example, for elevated LDH, we saw that patients who had elevated LDH seemed to benefit more by starting with a targeted therapy approach upfront.
One of the other subgroup analyses involved patients with liver metastases. This was an unplanned subgroup analysis that seemed to indicate that patients with liver metastases achieved more benefit by starting with the targeted therapy. So, we often still consider, when it is possible, starting patients with immunotherapy in cases of advanced melanoma, but we always try to consider that there are some scenarios where patients might benefit with starting with a short period of targeted therapy upfront and then having a planned switch to try to get them onto immunotherapy thereafter. This study does indicate that still might be a worthwhile approach to pursue.
Landmark PFS on low-dose IPI–NIVO
One of the other interesting findings of this study is that it had a landmark progression-free survival on the low-dose ipilimumab–nivolumab combination, which is very much in line with what was seen in the previous CheckMate 067 study, which was a randomized phase III trial that led to the approval of the full dose of ipilimumab and nivolumab. So, that too is something that is worthwhile studying further on.
Additional Info
Disclosure statements are available on the authors' profiles: