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Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma
Published on: September 8, 2021
Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial
Patricia M LoRusso1, Aleksandar Sekulic2,3, Jeffrey A Sosman4
1Yale Cancer Center, Yale University, New Haven, CT, United States of America.
Abstract:
Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.
Insights
Genomic profiling did not improve targeted therapy selection for advanced BRAFV600 wild-type melanoma. Further research is needed for effective treatments in this patient group.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Combination BRAF and MEK inhibitors are effective for BRAFV600-mutated melanoma.
- Targeted therapies have shown limited efficacy in BRAFV600 wild-type (wt) metastatic melanoma.
- Patients with BRAFV600 wt melanoma often progress on standard care, including immunotherapy.
Purpose of the Study:
- To evaluate if comprehensive genomic profiling improves the selection of molecular-based therapies for BRAFV600 wt metastatic melanoma.
- To assess treatment response in patients who had progressed on standard-of-care therapy.
Main Methods:
- A Simon two-stage optimal design was used in the SU2C Genomics-Enabled Medicine for Melanoma Trial.
- Genomic profiling guided therapy selection for the genomics-enabled arm.
- Binimetinib was the selected targeted agent for 20 patients in the genomics-enabled arm.
Main Results:
- One partial response (4%), 18 stable disease (67%), and 8 progressive disease (30%) were observed in 27 response-evaluable patients.
- The study highlighted the complexity and heterogeneity of metastatic melanomas.
- Limitations included monotherapy drug selection and a lack of available molecularly-driven therapies.
Conclusions:
- Comprehensive genomic profiling did not significantly improve outcomes for BRAFV600 wt metastatic melanoma in this trial.
- The heterogeneity of melanoma and limitations in available targeted therapies contributed to the observed lack of response.
- Future studies should explore novel drug classes and combination therapies for BRAFV600 wt melanoma.
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