Abstract: Malignant melanoma is one kind of malignant disease which has high rates of mortality, metastasis, and poor prognosis. The therapeutic landscape is rapidly changing with the development of novel agents in recent decades, such as anti-PD-1 agents, anti-CTLA-4 agents, and BRAF inhibitors. However, since most of these novel agents are very expensive, not all patients can afford them. Apatinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) and may also be effective on Ret, c-KIT, and c-src. Temozolomide (TMZ) is a second-generation alkylating agent and a cytotoxic drug for melanoma treatment. In this work, we reported a case of metastatic melanoma with an excellent response to apatinib/TMZ combination therapy with progression-free survival for more than one year. This patient showed high expression of CD117, VEGFR-3, and KIT mutation in exon 11, suggesting that apatinib may induce clinical response via inhibiting VEGFR and c-KIT. Apatinib/TMZ combination therapy could be a new option for the treatment of advanced melanoma with KIT mutation.

Keywords: advanced melanoma, KIT mutation, apatinib, temozolomide, combination therapy 

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Malignant melanoma (MM) has characteristics of high mortality, high metastasis, and drug resistance. MM accounts for only 4% of all dermatological malignancies, but it is responsible for about 80% mortality of skin tumors. Many melanoma patients exhibited genetic mutations including BRAFNRASKITPTENGNAQGNA11, and CDKN2A mutations.1–3 Despite the fact that many novel agents (eg, anti-PD-1, anti-CTLA-4, and BRAF inhibitor) have promising effects on MM treatment while the response rate to cytotoxic agents is low in melanoma patients (<20%) and many patients eventually become resistant to chemotherapy, chemotherapy is still the main palliative treatment for advanced MM in many countries due to its lower cost and accessibility.4–6 Temozolomide (TMZ) is a novel second-generation alkylating agent and an analog of dacarbazine (DTIC). The efficacy of TMZ is similar to that of DTIC, but TMZ provides improved quality of life and better physical function for the patients.4 It is recommended as the first-line therapy for MM in many countries due to its oral route of administration with nearly 100% bioavailability and extensive tissue distribution.4,5

In addition, MM is a highly angiogenic type of tumor, suggesting anti-angiogenesis as a way of treatment.7 Previous trials indicated that the combination of anti-angiogenesis inhibitor and cytotoxic agent is a promising strategy for MM treatment, such as endostar with DTIC or bevacizumab with TMZ.8–11

Apatinib (YN968D1) is a novel potent oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), and it may also be effective on Ret, c-KIT, and c-src.12 It has been proved that apatinib showed a survival benefit in gastric cancer and non-small-cell lung cancer. In the meantime, its benefit is under investigation in multiple tumor types (eg, breast cancer and liver cancer). Due to low side effects and improved outcomes, apatinib has a substantial potential to be a new therapeutic option in a variety of tumor types. Moreover, previous studies have shown that apatinib can reverse multidrug resistance (MDR), indicating a promising landscape of apatinib/cytotoxic agent combination therapy.13

In this study, we reported a promising case of a metastatic melanoma patient treated with apatinib plus TMZ as a third-line therapy.