Inter- and Intra-Patient Heterogeneity of Response and Progression to Targeted Therapy in Metastatic

Background: MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic melanoma patients, but the extent of response and progression-free survival (PFS) is variable, and complete responses are rare. We sought to examine the patterns of response and progression in patients treated with targeted therapy. Methods: MAPKi-naı̈ve patients treated with combined dabrafenib and trametinib had all metastases$5 mm (lymph nodes $15 mm in short axis) visible on computed tomography measured at baseline and throughout treatment. Results: 24 patients had 135 measured metastases (median 4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7–20.1 mo), and the degree of best response (median 270%, range +9 to 2100%) varied amongst patients. 17 % of patients achieved complete response (CR), whereas 53 % of metastases underwent CR, including 42% $10 mm. Metastases that underwent CR were smaller than non-CR metastases (median 11 vs 20 mm, P,0.001). PFS was variable among patients (median 8.2 mo, range 2.6–18.3 mo), and 50 % of patients had disease progression in new metastases only. Only 1 % (1/71) of CR-metastases subsequently progressed. Twelve-month overall survival was poorer in those with a more heterogeneous initial response to therapy than less heterogeneous (67 % vs 93%, P = 0.009). Conclusion: Melanoma response and progression with MAPKi displays marked inter- and intra-patient heterogeneity. Most metastases undergo complete response, yet only a small proportion of patients achieve an overall complete response