Dear Editor, Treatment with BRAF inhibitors leads to objective responses in the majority of patients with metastatic melanomas harbouring BRAF V600 mutations. However, BRAF inhibition may be limited by side-effects; among the most common are the development of secondary cutaneous neoplasms (grade 3 in 4–18%),[1, 2] rash (grade 3 in 8%),[1] arthralgia (grade 3 in < 1–3%)[1, 2] and fatigue (grade 3 in 2%),[1, 2] which can lead to dose modification or interruption of the treatment in 28–38%[1, 2] of the patients. Therapy resistance usually occurs after a median progression-free survival (PFS) of approximately 6 months[1, 2] due to several mitogen-activated protein kinase signalling-dependent and -independent mechanisms,[3, 4] while the development of new BRAF mutations or loss of the BRAF V600 mutation is extremely rare.[5, 6]

Thus, strategies to ameliorate side-effects and to prolong PFS during BRAF inhibition are needed.[7] One strategy that yielded promising results in a phase II study is the combination of BRAF and MEK inhibitors. The combination of dabrafenib and trametinib reduced some side-effects such as the development of secondary cutaneous neoplasms and prolonged the median PFS from 5·8 with dabrafenib alone to 9·2–9·4 months.[8]

Another potential strategy to reduce side-effects and to prolong PFS could be an intermittent dosing regimen. Recently published data from a human melanoma xenograft model in mice showed that intermittent dosing compared with continuous administration of vemurafenib delayed drug resistance and improved survival of mice from 100 to 200 days.[9] Two recently reported patients benefited from rechallenge of BRAF inhibitors. They developed resistance to dabrafenib or the combination of dabrafenib plus trametinib, and were treated with immunotherapies for 4 or 8 months, respectively. After progression, the first patient received vemurafenib, leading to a partial response that was ongoing after 4 months of therapy. The second patient received the combination of dabrafenib and trametinib, resulting in a mixed response with a markedly improved performance status that was ongoing after 5 months of therapy.[10]

To the best of our knowledge we report the first patient who successfully underwent an intermittent treatment with vemurafenib for metastatic BRAF V600E-mutated melanoma. The patient is an 85-year-old man with known atrial fibrillation under phenprocoumon medication, Parkinson disease and monoclonal gammopathy of unknown significance. Melanoma of unknown primary was diagnosed in March 2003 after resection of one cutaneous metastasis on the left thigh. From 2007 to 2008 multiple cutaneous, subcutaneous and lymph node metastases on the left leg and inguinal region were resected. In January 2010, the patient was included in a clinical study on tumour vaccination for inoperable cutaneous metastases on the leg. While on the experimental treatment, the patient had slowly progressive disease, and resection of painful cutaneous metastases was performed where needed. In February 2012, the therapeutic regimen was switched to single-agent chemotherapy (four cycles of dacarbazine 850 mg m−2 every 4 weeks); however, this treatment was ineffective (Fig. 1; day 0). In June 2012, therapy with vemurafenib 960 mg twice daily was initiated and led to rapid reduction in size of the cutaneous metastases within a few weeks. The patient suffered from vemurafenib adverse events, including acanthoma on the trunk, photosensitivity, loss of taste and intolerable fatigue [according to common toxicity criteria (CTC), National Cancer Institute Common Terminology Criteria for Adverse Events version 4.02, grade 2]. Therefore, the patient requested an interruption of vemurafenib therapy after 6 weeks of treatment (day 1 until day 39) when a partial remission (almost complete remission of cutaneous metastases) was reached (Fig. 1; day 17). A follow-up visit 5 weeks after the last vemurafenib dose showed maintained partial remission, while vemurafenib side-effects had completely resolved. After 12 weeks (day 40 until day 162), progressive cutaneous metastases appeared on the left leg (Fig. 1; day 162) and vemurafenib 960 mg twice daily was reintroduced. Again an almost complete remission with disappearance of all metastases was seen by clinical examination after 7 weeks (day 162 until day 213) of treatment (Fig. 1; day 213). Side-effects were less incisive, but fatigue (CTC grade 2) and loss of taste led to the patient's request for interruption after 8 weeks of treatment with vemurafenib. After pausing therapy over 11 weeks, cutaneous metastases reoccurred (Fig. 1; day 281) and vemurafenib was reintroduced. The third therapy cycle led to a mixed response where all but one lesion on the lower left leg showed size reduction (Fig. 1; day 333). Therapy was again interrupted after 6 weeks at the patient's request because of fatigue (CTC grade 2). Irradiation therapy was initiated for progressive metastasis. Regular re-examinations with computed tomography scans and ultrasound have revealed no evidence of distant metastases to date. In conclusion, our patient shows that intermittent vemurafenib therapy is feasible. It resulted in amelioration of side-effects during periods of drug holidays and repeated antitumour responses in treatment intervals. Therefore, this case reinforces previous data and encourages clinical studies on intermittent BRAF-inhibitor regimens.


Figure 1. Results of intermittent treatment with vemurafenib for metastatic BRAF V600E-mutated melanoma. Day 0, dacarbazine therapy was ineffective; day 17, partial remission seen during treatment with vemurafenib; day 162, progressive cutaneous metastases appeared on the left leg following interruption of vemurafenib therapy; day 213, almost complete remission seen after reintroduction of vemurafenib therapy; day 281, after a pause in vemurafenib therapy cutaneous metastases recurred; day 333, during the third cycle of vemurafenib one lesion did not respond (circle).

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