Thursday, April 6, 2017
Digoxin and trametinib for BRAF wild type melanoma
With some relation to my Tuesday post....the use of older meds normally indicated for other diseases/conditions now being re-purposed for use in melanoma where I talked about mebendazole and imiquimod, here we look at the use of Digoxin. Dig, also called Lanoxin, is a cardiac glycoside that makes the heart beat more regularly and stronger. It is used to treat heart failure and arrhythmias. Given its cardiogenic effects, it is no small thing to use it in other ways and it does have its own set of possible side effects as does any other medication. I posted this abstract regarding digoxin and trametinib out of ASCO last year: See the first article -Digoxin plus trametinib therapy of BRAF wild type metastatic melanoma patients
Now there is this update:
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients. Frankel, Eskoocak, Gill, et al. Neoplasia. 2017 Mar 6.
This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy.
Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.
For what it's worth. - c