BRAF Inhibition in a Lung Transplant Recipient With Metastatic Melanoma

New treatment options like the BRAF inhibitors have been established for immunocompetent patients with metastatic melanoma, but experience in organ transplant recipients is lacking.

A female double lung transplant recipient in her 60s with a standard triple immunosuppressive regimen (cyclosporine, mycophenolate mofetil, prednisolone) and chronic lung allograft dysfunction was diagnosed with metastatic melanoma and pulmonary (Figure 1A), mediastinal, hepatic, osseous, subcutaneous, and cerebral metastases (Figure 2A). A primary tumor could not be detected, and tumor cells harbored a BRAF V600E mutation. Tumor marker S100 was elevated to 0.545 µg/L (reference value, <0.105 µg/L).

Therapy with the BRAF inhibitor vemurafenib was initiated 38 months after transplantation. Initial vemurafenib dose was 480 mg twice daily with a projected increase to the target dose of 960 mg twice daily. Because several potential interactions with her existing medication regimen were likely, itraconazole and azithromycin treatments were stopped, and the immunosuppressive regimen was changed from cyclosporine to everolimus. To reach stable levels of the immunosuppressive drugs, doses had to be monitored and adjusted frequently.

Within 3 weeks, the vemurafenib dose was increased to 960 mg twice daily, which was accompanied by a variety of well-known adverse effects, in particular joint pain, erythema, verrucalike lesions, diarrhea, and taste disturbances. Despite symptomatic treatment with loperamide and etoricoxib, vemurafenib dose reduction to 720 mg twice daily was necessary. Simultaneously, lung function continued to decrease, and laboratory tests revealed anemia that required transfusion of packed red blood cells.

After 2 months of vemurafenib treatment, the S100 marker dropped to 0.115 µg/L. Fluorodeoxyglucose–positron emission tomography, computed tomography and cerebral magnetic resonance imaging showed a partial extracerebral response but over 30 new cerebral lesions (Figures 1B, 2B). On a very low level, the graft function stayed stable, but laboratory findings showed a decline in renal function and iron deficiency anemia.

In addition to vemurafenib treatment, whole-brain radiotherapy was planned. However, our patient was hospitalized owing to progressive deterioration and died without additional tumor-specific treatments 3.5 months after initiation of vemurafenib therapy.

In immunocompetent patients, metastatic melanomas are known for their poor prognosis, which is even worse in immunocompromised organ transplant recipients.¹ New treatment options for metastatic melanoma have been established, leading to a significant improvement in recurrence-free and overall survival. These therapies, especially immunotherapies based on cytotoxic T-lymphocyte–associated protein 4 blockade with ipilimumab² and targeted therapies inhibiting BRAF V600E mutations with vemurafenib³ and dabrafenib,⁴ have not been investigated in immunocompromised patients such as lung transplant recipients. In our patient with unstable lung allograft function, we considered an immunotherapy with ipilimumab to be inappropriate. Since molecular analysis of the melanoma showed a BRAF V600E mutation, our treatment strategy consisted of adjustment of the immunosuppression (ie, switch of calcineurin to mammalian target of rapamycin [mTOR] inhibition) and BRAF inhibition with vemurafenib. Several clinical trials have shown a beneficial effect of mTOR inhibitors in organ transplant recipients, particularly with regard to the development of nonmelanoma skin cancer.⁵

In immunocompetent patients with metastatic melanoma harboring a BRAF V600E mutation (excluding patients with brain metastases), vemurafenib and dabrafenib treatment results in a response rate of 59%, with a median progression-free survival (PFS) of 6.9 months.⁴ In patients with brain metastases, the response rates to dabrafenib were lower (39%), and the PFS was shorter (median 16.1 weeks).⁶ There is a possibility that the melanoma was of donor origin, but the donor had no history of cancer.

The limiting factor in our patient was the progression of the intracerebral metastases, leading to a PFS of 9 weeks and an overall survival of 16 weeks. However, noncerebral metastases were regressing, and adverse effects were manageable. This indicates that BRAF inhibitor therapy is feasible in these patients if an intense monitoring of possible drug interactions is performed.

Corresponding Author: Kambiz Afshar, MD, Institute for General Practice, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany (Afshar.Kambiz@mh-hannover.de).

Published Online: October 21, 2015. doi:10.1001/jamadermatol.2015.2910.

Conflict of Interest Disclosures: Dr David has received funds and grants for research and fees for consultancy and speaking from Silence Therapeutics AG unrelated to the topic of this report. Dr Gutzmer has received honoraria and project, travel, and meeting support from Roche Pharmaceuticals and GlaxoSmithKline.