Characterization and Outcomes of Disease Progression in 52 Patients Treated with <b><i>BRAF</i></b>-V600 + MEK Inhibitors for Advanced Melanoma

Abstract

Background: Combined treatment with BRAF-V600 and MEK inhibitors has significantly improved progression-free and overall survival of patients with BRAF-mutated melanoma. Pattern of disease progression and outcomes in patients have not been fully characterized. Methods: We conducted a single-center, retrospective, descriptive analysis of a cohort of 52 patients treated with BRAF-V600 + MEK inhibitors for advanced melanoma over a 12-month period. The aim of this study was to characterize disease progression, defined as metastatic pattern, disease kinetics, and response to subsequent therapies, in melanoma patients treated with BRAF-V600 + MEK inhibitors. Results: Disease progression was observed in 31/52 (59.6%) patients treated with BRAF-V600 + MEK inhibitors. Relapse of melanoma involved the CNS for 22/31 (70.9%) patients with disease progression, including 18/31 (58%) patients who had exclusive intracranial metastases. Sixteen patients died from disease progression. Among the 31 patients who had disease progression, the median time until a relapse was 8 months, and the median survival time after disease progression was 2 months. Conclusion: Our study shows that, for patients treated with BRAF-V600 + MEK inhibitors who lose response, disease progression was aggressive and had poor outcomes. Most patients had CNS metastases and low rates of therapeutic response to any subsequent therapy.

The Pattern of Progression to First-Line Treatment with Dabrafenib and Trametinib in Patients with Unresectable or Metastatic, BRAF-Mutated, Cutaneous Melanoma: Results of the Observational T-WIN Study

“…The Italian experience of the Managed Access Program, as presented in the retrospective study DESCRIBE in Italy, confirmed the effectiveness and safety of dabrafenib and trametinib in unselected patients [ 17 ]. Furthermore, another single-center, retrospective analysis of 52 patients treated with B-RAF and MEK inhibitors for advanced melanoma over 12 months described disease progression in 59.6% of patients, of whom 70.9% had metastasis in the CNS, and the median time until a relapse was 8 months and the median survival time after progression was 2 months [ 18 ]. The progression in both new and pre-existing metastases was described in 52% of patients treated with B-RAF inhibitors (vemurafenib 82.2% and dabrafenib 17.8%), namely, exclusive extracranial progression occurred in 50.6% of the patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%) [ 19 ]; the single-site progression and primary response to BRAF inhibitors were associated with an improved PFS [ 19 ].…”

Targeted and immunotherapies in BRAF mutant melanoma: where we stand and what to expect

“…Multiple retrospective cohort studies of relatively small sample sizes reported the ORR to be 12%-25%, the mPFS to be 2Á0-3Á0 months and the mOS to be 5Á0-8Á4 months. [53][54][55][56][57][58] In contrast, in the subgroup analysis of the Keynote 006 study, the ORR of pembro after BRAFi AE MEKi (n = 87) was 32%, the mOS was 20Á4 months, the 2-year OS rate was 46%, the 3-year OS rate was 39% and the 5-year OS rate was 31%, 10 implying a large discrepancy in and out with clinical trial settings beyond the first line. This might be partially related to the fact that many patients progressing on MAPKi had unfavourable characteristics that would have precluded entry into clinical trials.…”

“…Generally, as reported in the real‐world setting, either anti‐PD‐1 monotherapy or ipi/nivo combination (no significant difference of effectiveness observed in between) worked poorly in patients after the failure of MAPKi. Multiple retrospective cohort studies of relatively small sample sizes reported the ORR to be 12%–25%, the mPFS to be 2·0–3·0 months and the mOS to be 5·0–8·4 months 53–58 . In contrast, in the subgroup analysis of the Keynote 006 study, the ORR of pembro after BRAFi ± MEKi ( n = 87) was 32%, the mOS was 20·4 months, the 2‐year OS rate was 46%, the 3‐year OS rate was 39% and the 5‐year OS rate was 31%, 10 implying a large discrepancy in and out with clinical trial settings beyond the first line.…”