DISCUSSION


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Gene mutation plays a pivotal role in melanoma. Reported mutated genes include BRAFNRAS, and KITKIT mutations occur in about 3% of patients with melanoma, especially in acral, mucosal, and chronic sun damage melanoma. The most common KIT mutation identified in MM is located in exons 11 (~70%), 13 (13% or so), and 17 (9% or so). As mentioned above, the patient with acral melanoma reported in this work had KIT mutation in exon 11, which may account for melanoma developing. KIT is found to be dispensable for growth, differentiation, migration, and proliferation in melanocytes systems. Besides, data show that abnormal activation of KIT signaling leads to increased growth and survival behavior and increased oncogenic potential in melanoma cells, indicating the reason why this patient progressed.14,15

Regimens in melanoma treatment include checkpoint immunotherapy, BRAF-targeted therapy, high-dose interleukin-2, chemotherapy, biochemotherapy, and clinical trials. For those who have KITmutation, imatinib is also a good option. Results from one trial of imatinib in Chinese patients harboring KIT mutation or amplification showed the median PFS of 3.5 months, and the median PFS for patients who had PR or SD versus PD was 9.0 versus 1.5 months.16 Apart from the regimens mentioned above, the landscape of anti-angiogenesis agents in MM treatment has aroused increasing attention. Results from a Phase II trial led by Chinese Professor Guo showed that median PFS in the endostar/DTIC arm was 4.5 months versus 1.5 months in placebo/DTIC arm (p=0.013).8 There were statistically significant improvements in median overall survival (OS; 12.0 vs 8.0 months, p=0.005) in favor of endostar/DTIC arm. Based on this trial, the Chinese Society of Clinical Oncology recommends endostar plus DTIC as the first-line setting for advanced MM treatment. Besides, a number of Phase II clinical trials have shown the efficacy of bevacizumab/cytotoxic agent combination therapy in melanoma treatment.9–11 For example, SAKK50/07 trial evaluated the efficacy of bevacizumab/TMZ combination therapy in 62 patients, and the results showed that overall response rate was 16.1% (complete response: 1 patient and PR: 9 patients), and median PFS and OS were 4.2 and 9.6 months, respectively.11 All the information gave us a hint that the combination of anti-angiogenesis inhibitor and cytotoxic agent could be effective on MM treatment.

Apatinib is an anti-angiogenesis agent that preferably targets VEGFR-2. Besides, one previous study has shown that apatinib could also potently inhibit the activities of Ret, c-KIT, and c-src.12 Multiple clinical trials have shown the survival benefit of apatinib in tumors such as gastric cancer and non-small-cell lung cancer. Apart from the ongoing trials, some case reports also showed the promising landscape of apatinib in various solid tumors such as advanced angiosarcoma and myxoid/round cell liposarcoma.17,18 It is also worth noticing that some preclinical studies show that apatinib can reverse MDR with other conventional antineoplastic drugs by inhibiting the efflux function of ABC transporters such as P-gp (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), suggesting that the combination of apatinib and chemotherapeutic agents may be a promising strategy in clinic.13

In this case, the patient with advanced melanoma failed two lines of chemotherapy, and he refused to accept expensive novel drugs. Therefore, after getting a written informed consent from the patient, we gave him a combination regiment of an anti-angiogenesis apatinib and one alkylating agent TMZ. Surprisingly, he showed a longer PFS of >1 year. Compared with the results of therapies mentioned above such as endostar plus DTIC, bevacizumab plus TMZ, and imatinib, our combination regiment showed better efficacy than TMZ or imatinib monotherapy or TMZ combination therapy reported previously. Besides, this treatment is also convenient for patients since both of them are oral drugs. In addition, the main adverse events were tolerable with mild hand-foot syndrome and aphthous stomatitis.

Considering that many melanoma patients have gene mutations and apatinib not only targets VEGFR but also works on Ret, c-KIT, and c-src, some tests were done to see whether there were any abnormalities in this patient. Because the sample of his right planta pedis was poorly stored and it took time to test every piece of the inguinal lymph node sample, we preferentially tested the patient’s blood first hoping to find something. The patient’s NGS analysis revealed only KIT mutation in exon 11. It was really surprising to find KIT mutation since it was even rare in tumors with high prevalence of KITmutation like gastrointestinal stromal tumor, let alone in melanoma with <3% mutation rate of KIT. The reason why KIT mutation could be detected in blood was that tumor cells entered into the vessels and then released DNA, which explained how the patient developed metastasis. The excellent response in this patient with a KIT-mutant melanoma suggests that routine screening of acral melanoma for KITmutation may be critical in identifying patients who may benefit from apatinib. Besides, tests of the inguinal lymph node sample were done later and revealed high expression of CD117 and VEGFR-3, suggesting that apatinib may work for the patient by inhibiting VEGFR and c-KIT. However, it still needs more large prospective trials to verify the efficacy and safety of this treatment.