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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
A phase I/II study of LY3022855 with BRAF/MEK inhibition in patients with Melanoma
Elizabeth I Buchbinder1,2,3,4, Anita Giobbie-Hurder5, Rizwan Haq6,7,8
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Elizabeth_buchbinder@dfci.harvard.edu.
Abstract:
BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
Insights
Adding CSF1R inhibition to BRAF/MEK targeted therapy for advanced melanoma showed limited tolerability. While one patient achieved a complete response, the combination therapy was difficult to tolerate in this small study population.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Advanced melanoma treatments like BRAF/MEK inhibitors and immune checkpoint inhibitors improve outcomes but often lack durability.
- Resistance to BRAF/MEK inhibitors is a significant challenge, limiting long-term efficacy in melanoma patients.
- Pre-clinical studies suggest Colony-Stimulating Factor 1 Receptor (CSF1R) inhibition may overcome BRAF/MEK inhibitor resistance.
Purpose of the Study:
- To evaluate the safety and efficacy of combining CSF1R inhibition (LY3022855) with BRAF (vemurafenib) and MEK (cobimetinib) inhibitors.
- To assess the tolerability and preliminary response rates of this combination therapy in patients with BRAF V600 mutant metastatic melanoma.
Main Methods:
- Phase I/II clinical trial evaluating LY3022855, vemurafenib, and cobimetinib in BRAF V600 mutant metastatic melanoma.
- Study enrolled five patients between August 2017 and May 2018.
- Trial terminated early due to discontinuation of LY3022855 development.
Main Results:
- Three out of five patients experienced grade 3 adverse events possibly related to LY3022855; no grade 4 or 5 events occurred.
- One patient achieved a complete response (CR), while four patients had progressive disease (PD).
- Median progression-free survival was 3.9 months.
Conclusions:
- The combination of CSF1R inhibition with BRAF/MEK inhibitors was poorly tolerated in a small cohort of melanoma patients.
- Despite tolerability issues, one complete response suggests potential, warranting further investigation in optimized combinations or patient populations.
- Further exploration of CSF1R inhibition in melanoma treatment strategies may be considered, potentially with modified regimens or patient selection.
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