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Updated: May 4, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma
Alexander M Menzies1, Lauren E Haydu1, Matteo S Carlino2
1Melanoma Institute Australia, Sydney, Australia ; The University of Sydney, Sydney, Australia.
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.
Insights
Melanoma patients treated with MAPK inhibitors show varied responses, with most metastases shrinking but few patients achieving complete remission. Disease progression often involves new tumors, highlighting treatment heterogeneity.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- BRAF-mutant metastatic melanoma patients treated with MAPK inhibitors (MAPKi) exhibit variable responses and progression-free survival (PFS).
- Complete responses are infrequent in patients receiving MAPKi therapy for metastatic melanoma.
Purpose of the Study:
- To investigate response and progression patterns in metastatic melanoma patients undergoing targeted therapy with combined dabrafenib and trametinib.
- To analyze the heterogeneity of tumor response and disease progression in BRAF-mutant melanoma.
Main Methods:
- MAPKi-naïve patients with BRAF-mutant metastatic melanoma were treated with combined dabrafenib and trametinib.
- Tumor metastases visible on computed tomography were measured at baseline and throughout treatment to assess response and progression.
Main Results:
- A significant heterogeneity in best response (median -70% change) and time to best response was observed among 24 patients.
- While 53% of metastases achieved complete response (CR), only 17% of patients attained an overall CR. Metastases achieving CR were smaller (median 11 mm) than non-CR metastases (median 20 mm).
- Progression-free survival (PFS) varied (median 8.2 months), with 50% of patients progressing in new metastases. Twelve-month overall survival was poorer in patients with heterogeneous initial responses.
Conclusions:
- Melanoma response and progression to MAPKi therapy demonstrate substantial inter- and intra-patient heterogeneity.
- Despite high rates of complete response in individual metastases, overall patient CR is low, and progression often occurs in new metastatic sites.
- Clinical heterogeneity, potentially driven by molecular differences, presents a significant challenge in effectively treating metastatic melanoma patients with targeted therapies.
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