Simultaneous targeted therapy for metastatic melanoma and hepatitis C

Abstract

Combined therapy of advanced melanoma with BRAF/MEK inhibitors leads to an improvement of overall survival [1–6]. In 2014, the combined HCV-NS5A/nucleotide polymerase inhibitor Harvoni® was approved for the treatment of chronic hepatitis C and demonstrated to be highly effective in previously untreated patients [7]. However, active hepatitis C was a common exclusion criterion in registration trials for metastasized melanoma and was also valid in the Combi-V and Combi-D trials [8, 9]. We describe a patient with an advanced nodular melanoma (pT3bN3M1b, stage IV) with a proven BRAF-V600E mutation. Clinical and radiological examination revealed the presence of pulmonary metastases as well as unresectable, painful, locoregional metastases. A chronic hepatitis C infection was known for some years but was not treated. Laboratory testing showed 42.400 IU HCV RNA/ml serum using a quantitative PCR (COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test, version 2.0; Roche Diagnostics Deutschland, Mannheim, Germany) as well as evidence of anti-hepatitis C antibodies. Based upon a recommendation of our interdisciplinary tumor board, targeted hepatitis C-therapy with ledipasvir 90 mg and sofosbuvir 400 mg (Harvoni®) was initiated for twelve consecutive weeks. Simultaneously, we started a combined targeted melanoma treatment with dabrafenib 300 mg (Tafinlar®) and trametinib 2 mg (Mekinist®). The tumor board recommended targeted melanoma therapy due to painful locoregional metastases, since a more rapid treatment could be expected than for checkpoint inhibitors. Initially, trametinib as well as ledipasvir/sofosbuvir were taken at the same time in the morning. At the first follow-up visit, the patient reported nocturnal chills and intermittent diarrhea. We excluded an infectious cause for these symptoms. As ledipasvir/sofosbuvir and trametinib are eliminated by the breast cancer resistant protein (BCRP), which is an efflux transport protein strongly expressed in barrier tissues, a competitive drug interaction may be assumed to underlie these adverse reactions [10]. We could not exclude an interaction via hepatic OATP1B3 uptake, which would result in higher BRAF/MEK-inhibitor plasma-levels [11]. Therefore, an interval of two hours after intake of BRAF/MEK inhibitors was recommended for ledipasvir/sofosbuvir, resulting in complete resolution of the symptoms. No further side effects have been reported by the patient so far. At a follow-up visit three months after completing the treatment with ledipasvir/sofosbuvir, HCV-RNA-PCR remained negative. We observed complete response of the melanoma metastases. The targeted therapy with dabrafenib and trametinib is currently continuing. Various side effects have been described for BRAF/MEK inhibitors, including diarrhea and chills. Therefore, careful clinical examination and a detailed anamnesis is of great importance. Good safety profiles for patients with hepatitis C have already been reported for anti-PD-1 therapy [12, 13]. Serial application of the anti-PD-1 mAb nivolumab and ledipasvir has also been described in a patient with advanced melanoma and hepatitis C [14]. However, simultaneous combined targeted therapies for melanoma with dabrafenib/ trametinib and chronic hepatitis C with ledipasvir/sofosbuvir in a single patient have not been described before. In case of pronounced side effects related to BRAF/ MEK inhibitors during co-administration of direct antiviral agents, a time interval of at least two hours between drug administrations is advised in order to avoid any competition with transmembrane influx or efflux pumps. A competitive drug interaction between ledipasvir/sofosbuvir as well as trametinib seems to be the most likely explanation for the mentioned side effects, as all of these drugs are eliminated by the efflux transport protein BCRP. Competitive inhibition of BRCP is minimized if a sufficient time interval is ensured after the administration of trametinib; this reduces side effects due to accumulation. Our case demonstrates that the simultaneous application of dabrafenib and trametinib in combination with ledipasvir and sofosbuvir is feasible and can be safely performed under close monitoring.