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

PLoS One. 2014 Jan 6;9(1):e85004. doi: 10.1371/journal.pone.0085004. eCollection 2014.

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).

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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Disease Progression
  • Female
  • Genetic Heterogeneity*
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / mortality
  • Melanoma / pathology
  • Middle Aged
  • Molecular Targeted Therapy*
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / genetics
  • Treatment Outcome

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf

Grant support

This work was supported by Program Grants from the National Health and Medical Research Council of Australia (NHMRC), Cancer Institute NSW, Australian Cancer Research Foundation, the Melanoma Foundation of the University of Sydney and Melanoma Institute Australia. GlaxoSmithKline funded the clinical trial from which these data were obtained. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.