• EBIN
• Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K-mutated melanoma: The primary analysis of an EORTC randomized phase II study (EBIN).

Background: The benefit of an induction treatment with targeted therapy (TT) with BRAF+MEK inhibitors prior to a combined immunotherapy (IT) with ipilimumab (ipi) + nivolumab (nivo) in patients (pts) with advanced BRAF-V600E/K mutant melanoma is still unclear. Methods: EBIN is an international randomized controlled phase II trial comparing upfront IT (arm A: nivo [3mg/kg] + ipi [1mg/kg] q3w x4 followed by nivo 480 mg q4w) with the sequential approach (arm B: 3 months induction with TT with encorafenib 450 mg QD + binimetinib 45 mg BID orally, followed by IT using the same regimen as in arm A), total treatment [Tx] duration in both arms: 2 years. In arm B, pts were allowed to be rechallenged with TT after progression. Pts with measurable BRAF-V600E/K unresectable stage III/IV melanoma, except pts with uveal melanoma, untreated or symptomatic brain or leptomeningeal involvement were randomly assigned 1:1 to arm A or B. Prior Tx for advanced melanoma was not allowed but adjuvant Tx completed at least 6 months before randomization was permitted. The primary objective was to show superiority of arm B in progression-free survival (PFS) using the log-rank test stratified by stage and lactate dehydrogenase (LDH) with a 1-sided alpha error set at 5%. The study had a power of 80% to detect a HR of 0.65. The study planned to randomize 135 pts in each arm. Results: All 136 pts randomized to arm B and 131 out of 135 in arm A started protocol Tx. At baseline, 170 (63%) pts had stage M1c, 129 (48%) had LDH above upper limit normal (ULN), 74 (27%) had a liver metastasis, and 19 (7%) received adjuvant therapy. The median follow-up was 21 months. In arm B, 135 (99%) pts were free of progression at week 12, when the end of TT was scheduled. In the intention-to-treat population, there was no evidence of a longer PFS in arm B (HR = 0.87, 90% confidence interval [CI] 0.67-1.12, p = 0.36). In a prespecified subgroup analysis, the HR for arm B vs arm A was 2.09 (95% CI 0.96-4.53), 0.74 (95% CI 0.43-1.29), 0.86 (95% CI 0.54-1.37), and 0.46 (95% CI 0.21-1.03) in pts with stage III with LDH≤ULN or M1a, M1b/M1c with LDH≤ULN, ULN 2ULN, respectively (p-value for interaction 0.045). In a post-hoc subgroup analysis, pts with ≥3 metastatic sites or a sum of target lesions ≥10cm at baseline did not have a longer PFS in arm B but in pts with liver metastasis the Tx HR was 0.48 (95% CI 0.28-0.80, p-value for interaction 0.008). The objective response rate was 53% in arm B and 45% in arm A. Complete response rate was 12% in arm B and 10% in arm A. Grade ≥3 adverse events occurred in 58% of pts in arm B and 51% in arm A. Conclusion: The EBIN trial shows there is no difference in PFS between the two treatment arms for unselected patients but supports the hypothesis that patients with very high LDH and those with liver metastases benefit from the sequential approach. Clinical trial information: NCT03235245.