Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: results from the real-world Spanish Melanoma Registry (GEM-1801).

Purpose: Most patients with BRAF-mutant melanoma eventually develop resistance to BRAF/MEK inhibitors (BRAF/MEKi) and immune-checkpoint blockade. Emerging evidence from retrospective cohorts indicates promising activity from re-exposure to BRAF/MEKi after a treatment-free interval of targeted therapy (TT), probably due to tumor regression and proliferation of sensitive clones. However, there is limited prospective evidence on this approach.

Methods/patients: GEM1801 is a prospective observational study by the Spanish Melanoma Group (GEM), including 1123 patients treated at 37 centers. We conducted a descriptive analysis of baseline characteristics, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for the 24 patients who received a second course of BRAF/MEKi, either as retreatment (after relapse following prior adjuvant TT) or rechallenge (following prior progression on TT in the metastatic setting).

Results: Five patients underwent retreatment, and 19 received rechallenge. The BRAF/MEKi median free interval for retreatment was 20.9 months (range 12.4-57.3), with an ORR of 20%, and median PFS and OS of 5.5 and 8.4 months, respectively. The median free interval of TT for rechallenge was 6.8 months, with an ORR of 31.6%, and median PFS and OS of 5.7 and 7.6 months. Patients with ECOG ≤ 1 experienced longer survival with rechallenge (8.2 vs 4.3 months; HR 9.07 [95% CI 1.37-59.8]; p = 0.022).

Conclusion: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting has shown clinical activity in patients with metastatic melanoma who lack therapeutic alternatives to prolong survival. Therefore, in our experience, it may represent a valid therapeutic strategy for selected patients.

Clinicaltrials: GOV: NCT03605771 (REGISTRATION DATE: 20-07-2018): NCT03605771.