Advances in Treatment for Patients with Unresectable or Metastatic BRAF V600 Mutated Melanoma
ACH Ying
Hong Kong J Radiol 2013;16(Suppl):S34-8
Melanoma is widely prevalent among western populations and is a relatively rare malignancy in the local Chinese population. In local Chinese patients, clinicians should be wary of suspicious pigmented lesions over the extremities, such as the soles, palms, nail beds, or mucous membrane because up to 60% of cases of melanoma in Chinese people are of acral lentiginous type, compared with only 2% in Caucasians. The pigmented type of basal cell carcinoma is the most common subtype of basal cell carcinoma in Hong Kong. Thus, differential diagnoses of pigmented skin lesions in local Chinese should include pigmented basal cell carcinoma in addition to melanoma. The standard treatment of advanced and metastatic disease is chemotherapy with agents such as dacarbazine, with immunotherapy (e.g. interleukin-2) providing an alternative option. However, both treatment modalities are associated with modest effectiveness in terms of response and survival, and with potentially serious side-effects. A phase III clinical trial in patients with metastatic melanoma showed that treatment with the novel immunotherapy ipilimumab — an intravenous, fully humanised immunoglobulin monoclonal antibody — was associated with a response rate of 10.9% and median overall survival of approximately 10 months; however, there were marked immune side-effects. Recently, advances in the knowledge of cell signalling pathways in melanoma — particularly with regard to the role of the serine/threonine kinase v-raf murine sarcoma viral oncogene homolog B1 (BRAF) — have led to the development of targeted biological agents. Vemurafenib is a potent oral small molecule that inhibits the activated form of the oncogenic BRAF V600E mutant. In a recent phase III clinical trial comparing vemurafenib with dacarbazine, treatment with vemurafenib was associated with improved overall survival (median, 13.6 months vs. 9.7 months with dacarbazine), progression-free survival (median, 5.3 months vs. 1.6 months with dacarbazine), and confirmed objective response rate (57.0% vs. 8.6% with dacarbazine) in patients with advanced melanoma at a median follow-up of 12.5 months. This article provides an overview of the features of melanoma in Chinese patients, and the current treatment options for advanced metastatic melanoma. At the time of crossover in 2012, subjects receiving vemurafenib showed higher objective response rate (57.0% vs. 8.6%), complete remission rate (5.6% vs. 1.2% ), and partial response rate (51.3% vs. 7.4%), versus those receiving dacarbazine.
中文摘要
不能切除或轉移性帶BRAF V600E突變黑色素瘤的治療發展
應志浩
黑色素瘤在西方人口中較普遍，而在華籍人口當中則仍屬相對罕見的惡性腫瘤。與白種人的2%相比，華籍人口中有60%的黑色素瘤病例屬肢端雀斑樣痣（acral lentiginous）型，因此在本港的華籍患者中，臨床醫生應對出現於四肢 如腳底、手掌、指甲床，或黏膜的可疑色素病變加以警惕。在香港，最常見的基底細胞癌亞型是色素型基底細胞癌。因此，對本地華籍人皮膚色素病變的鑑別診斷，除黑色素瘤外，亦應包括色素型基底細胞癌。在晚期和轉移性疾病的治療方面，採用例如達卡巴（dacarbazine）的化療藥物是標準治療，而免疫治療（例如白細胞介素-2）則是另一選擇。然而，這兩種治療方案在治療反應及存活方面的療效只屬一般，並有嚴重的潛在副作用。一項轉移性黑色素瘤三期臨床試驗採用了新型的免療治療ipilimumab，一種靜脈注射完全人源化免疫球蛋白單克隆抗體，相關的反應率為10.9%、總存活中位數約10個月，但有顯著的免疫副作用。最近在黑色素瘤細胞信號傳導途徑——尤其對於絲氨酸-蘇氨酸激酶（serine/threonine kinase）v-raf鼠肉瘤病毒癌基因同源物B1（BRAF）的知識進展——造成了標靶生物製劑的研發。一項近期的三期臨床試驗在晚期黑色素瘤患者中，採用了一種抑制致癌BRAF V600E突變活化形的強效口服小分子藥物vemurafenib；在跟進12.5個月（中位數）後，與達卡巴相比，vemurafenib改善了相關的總存活率（中位數為13.6個月比9.7個月）、無惡化存活率（中位數為5.3個月比1.6個月）及客觀反應率（57.0%比8.6%）。本文概述了華籍患者黑色素瘤的特點，以及目前對晚期轉移性黑色素瘤的治療選擇。2012年的數據顯示，與達卡巴相比，vemurafenib有較高的客觀反應率（57.0%比8.6%）、完全緩解率（5.6%比1.2%）和部分反應率（51.3%比7.4%）。