Editor's note: In Asian populations, mucosal melanoma (MM) accounts for 9.5% to 22.6% of all melanomas [1-4], second only to acral melanoma. With the advent of targeted therapy and immunotherapy, progress has been made in the treatment of cutaneous melanoma, but the benefits for MM patients are limited. This article reviews the current status of the treatment of MM and proposes potential treatment strategies for MM.
Professor Wu Di of the First Hospital of Jilin University is the executive editor-in-chief of this issue of "Expert Group Draft", and Dr. Zhang Yiqun, Department of Medical Oncology, First Hospital of Jilin University, shared the current status and prospects of the treatment of advanced mucosal melanoma, providing more references for doctors and patients.
Expert presentation
Wu Zhao
Cancer Center, The First Hospital of Jilin University
Doctoral supervisor, chief physician and professor
Director of the Comprehensive Oncology Treatment Area of the First Hospital of Jilin University
Director of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman of CSCO Melanoma Expert Committee
Member of the CSCO Small Cell Lung Cancer Expert Committee
Member of the CSCO Bone and Soft Tissue Sarcoma Expert Committee
He is a member of the Tumor Metastasis Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of CSCO Oncology and Cardiology Expert Committee
Zhang Yiqun
He is a doctoral student in the Department of Medical Oncology of the First Hospital of Jilin University
Main research directions: targeted, immunological, chemotherapy and other comprehensive treatments for melanoma
Title: Current status and prospects of treatment of advanced mucosal melanoma
◾ Author: Wu Di and Zhang Yiqun
Current status of treatment
1. Chemotherapy
For advanced melanoma, dacarbazine has been one of the most commonly used chemotherapy drugs. Dacarbazine-based chemotherapy has been associated with objective response rate (ORR) of 36 to 47 percent, median PFS of 3 to 10 months, and median OS of 9.6 to 22 months for advanced MM [5-8]. In Asia, where the proportion of MM is higher, dacarbazine-based chemotherapy remains a first-line option.
2. Immunotherapy
Ipilimumab, as the first immune checkpoint inhibitor proven to prolong the survival of melanoma patients, is not as effective as metastatic MM. As a first-line treatment for advanced MM, it had an ORR of 8.2 percent, a median PFS of three months, and a median OS of 12 months, compared with an ORR of 6.7 to 12.0 percent, a median PFS of 4.3 months, and a median OS of 6.4 months for the subsequent treatment [9-12].
Compared with ipilimumab, PD-1 inhibitors have achieved better efficacy in patients with advanced MM, but they are still not satisfactory. PD-1 inhibitors were associated with ORRs of 20.0 to 26.0 percent, median PFS of 5.9 to 6.2 months, and median OS of 15.9 to 20.4 months for first-line treatment of advanced MM [13-15], compared with 13.3 to 19.0 percent, median PFS of 2.6 to 2.8 months, and median OS of 7.4 to 11.5 months for second-line treatment of advanced MM [16-19].
3. Molecularly targeted therapy
3.1 BRAF inhibitors The frequency of BRAF mutations in MM is only 6 to 17 percent [20-24], which limits the use of BRAF inhibitors in patients with MM. In only one retrospective study, patients with metastatic/unresectable MM with BRAF mutations treated with BRAF inhibitors had an ORR of 20 percent, a median PFS of 4.4 months, and a median OS of 8.2 months [25].
3.2 KIT inhibitors KIT mutations and amplifications occur in 15 to 39 percent of MM [22,26]. Among the common KIT inhibitors, only imatinib and nilotinib have shown some efficacy in advanced MM. Hodi et al. found that imatinib had an ORR of 64 percent in patients with advanced MM with KIT mutations, but was less effective in patients with KIT amplification alone [27].
For advanced MM with KIT mutations that have progressed after imatinib treatment, we can try nilotinib treatment. Nilotinib has an ORR of 25 percent in patients with advanced melanoma who have progressed on treatment with other KIT inhibitors [28].
4. Combination therapy
4.1 Immunotherapy combination therapy CTLA-4 and PD-1 inhibit anti-tumor immune responses through different mechanisms [29]. Unfortunately, the CheckMate067 study showed no advantage over nivolumab, although nivolumab plus ipilimumab was superior to ipilimumab in patients with advanced MM.
4.2 Immunotherapy combined with chemotherapy Paclitaxel can induce immunogenic cell death and tumor cell surface PD-L1 expression through a variety of pathways [30-33]. According to Li JJ et al., PD-1 inhibitors combined with nab-paclitaxel were associated with an ORR of 33.3 percent, a DCR of 63.3 percent, and a median PFS of 4.9 months in patients with advanced MM [34].
4.3 Immunotherapy combined with anti-angiogenic therapy Anti-angiogenic drugs can improve patient response to ICIs by promoting anti-tumor immunity [35]. In a phase Ib clinical trial, toripalimab in combination with axitinib was associated with an ORR of 48.3 percent, a median PFS of 7.5 months, and a median OS of 20.7 months in patients with metastatic MM who were naïve with chemotherapy [36]. In another phase II clinical study, atezolizumab in combination with bevacizumab was associated with an ORR of 45.0 percent, a median PFS of 8.2 months, and median OS not reached in patients with unresectable/advanced MM who had not been previously immunotherapeutic. No studies have shown that PD-1 and PD-L1 inhibitors differ in efficacy in combination with antiangiogenic agents in the treatment of advanced MM.
4.4 Chemotherapy combined with immunotherapy combined with anti-angiogenic therapy With the publication of data on many combination treatments, the combination of chemotherapy, immunotherapy and targeted therapy is being considered for the treatment of advanced MM. As reported at the 2023 ASCO meeting, a single-arm, multicenter exploratory study of camrelizumab in combination with anlotinib and nab-paclitaxel in the first-line treatment of advanced MM is underway (NCT04979585), with results expected to be published.
Future outlook
1. Immunotherapy
1.1. Novel intratumoral immunotherapy BO-112 is a nanocomposite formulation complexed with poly I:C (an analogue of double-stranded viral RNA) and polyethylenimine, which increases T cell-mediated immune responses and causes apoptosis in tumor cells upon release within tumors [38,39]. As reported at the 2022 AACR Annual Meeting, the ORR of BO-112 in combination with pembrolizumab was 66 percent in patients with advanced MM [40].
1.2. Novel cytokine Nemvaleukin alfa is a new engineered cytokine that activates CD8+ T cells and natural killer cells and reduces the proliferation of regulatory T cells [41]. Nemvaleukin has been granted orphan drug approval by the US FDA for the treatment of MM. The ARTISTRY-1 study (NCT02799095) showed that nemvaleukin alfa had an ORR of 33.3% for patients with advanced MM who failed ICIs.
1.3. TIL cell therapy Lifileucel, as an autologous tumor-infiltrating lymphocyte (TIL) therapy cell therapy, uses a centralized manufacturing process to prepare polyclonal patient-specific TILs using TIL recovered from patient tumor tissue [42]. In the C-144-01 study, a subset of patients with advanced MM who had been treated with immune checkpoint inhibitors and BRAF/MEK inhibitors achieved sustained clinical remission after Lifileucel [43].
2. DNA damage repair after immunotherapy failure
Tumour cells are often deficient in DNA damage response (DDR). Alterations in the DDR gene can promote PD-L1 expression, increase the number of tumor-infiltrating lymphocytes [44], increase tumor mutational burden, and enhance immunogenicity by increasing neoantigen burden [45], which are all potential determinants of response to ICIs therapy.
RAD3-related protein kinase (ATR) is key to the DDR pathway [46], and its inhibitors are promising for MM therapy. In a phase II clinical trial, durvalumab in combination with the ATR inhibitor ceralasertib demonstrated an ORR of 40 percent in patients with advanced MM after PD-1 inhibitor failure [47]. In another phase I study, ceralasertib in combination with paclitaxel in patients with advanced MM who were resistant to anti-PD-1 therapy had an ORR of 45.5 percent [48].
MDM2 inhibits DDR by inhibiting p53 function [49], and MDM2 amplification may lead to a worse response to ICIs in advanced MM [50]. Zhou R et al. observed MDM2 amplification in 50% of MM samples [51]. These make MDM2 a potential therapeutic target for MM. Alrizomadlin, as a novel small molecule MDM2 inhibitor, can restore antitumor activity in tumor patients with PD-1/PD-L1 blockade failure [52]. As reported at the 2021 ASCO Annual Meeting, the combination of alrizomadlin and pembrolizumab in patients with advanced MM who have failed immunotherapy has an ORR of 40% (NCT03611868).
summary
MM's unique genomic profile and tumor immune microenvironment lead to poor response to current immunotherapies as well as other systemic therapies, and ICIs-centric combination therapy is more likely to benefit patients. With a better understanding of the genomic characteristics of MM and the tumor immune microenvironment, it will be possible to develop new drugs and combination treatment regimens to improve the survival of patients with advanced MM.
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