title: Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma.
abstract: 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-naïve 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 -70%, range +9 to -100%) 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).
  
  
  CONCLUSIONS
  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. Similarly, disease progression often occurs only in a subset of the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma patients.
authors.affiliation: Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia ; Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, Australia ; Westmead Institute for Cancer Research, Westmead, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, Australia.
authors.forename: Mary W F
authors.initials: MW
authors.lastname: Azer
authors.affiliation: The University of Sydney, Sydney, Australia ; Westmead Hospital, Department of Radiology, Sydney, Australia.
authors.forename: Peter J A
authors.initials: PJ
authors.lastname: Carr
authors.affiliation: Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia ; Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, Australia ; Westmead Institute for Cancer Research, Westmead, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf