Introduction
In the past ten years, the incidence of melanoma continued to rise, accounting for 1.7% of diagnosed cancers worldwide. It is the fifth most common cancer in the United States and the annual incidence of melanoma in China has risen to about 16.83 per 10,000, while the annual death toll is about 4369. The relatively poor prognosis of melanoma also brings a great disease burden to society.[1–5] Over the past 15 years, with the improvement in our understanding of the pathophysiology of melanoma, it has been recognized that melanoma development is closely related to genetic mutations, and the emergence of targeted drugs has also changed the comprehensive treatment of melanoma. Vemurafenib was the first BRAF inhibitor that was approved by the Food and Drug Administration (FDA, in 2011) for BRAF-mutant melanoma, and since that time, the prognosis of patients with advanced melanoma has undergone continuous and significant improvement.[6] This article reviews and provides evidence on the advances in targeted therapy of melanoma.
Melanoma Subtypes and Common Gene Mutations
Based on the 2018 World Health Organization Classification of cutaneous, mucosal, and uveal melanoma, which encompasses mutational signatures, anatomical site, and epidemiology, melanoma is divided into etiologies that are related and unrelated to sun exposure. The histological degree of cumulative solar damage (CSD) of the surrounding skin, based on the level of associated solar elastosis, further categorizes melanomas on sun-exposed skin into low and high CSD. In the low-CSD group, melanomas include superficial spreading melanoma, while those in the high-CSD group include lentigo malignant and sclerosing melanomas. The "non-CSD" classification includes acral melanoma, melanoma in congenital nevus, melanoma in blue nevus, Spitz melanoma, mucosal melanoma, and uveal melanoma. Meanwhile, nodular and nevoid melanomas can occur by both routes.[7,8]
The major melanoma subtypes are associated with different mutational profiles, with frequently mutated genes, including BRAF, CDKN2A, NRAS, and TP53 in cutaneous melanoma; BRAF, NRAS, NF1, and KIT in acral melanoma (although the rate of mutation is less frequent compared with cutaneous melanoma); and SF3B1 in mucosal melanoma.[9] In all melanomas, the mutation rate of BRAF V600 is about 40–50%, NRAS is about 15–20%, and the mutation rate of KIT is only 1–2% (but the KIT mutation rate is relatively high in acral melanoma and mucosal melanoma, reaching nearly 15–20%).[10,11] Based on this, these mutations are often used as therapeutic targets.
BRAF-Mutant Melanoma
BRAF mutation is the most common mutation in melanoma and accounts for nearly 50% of all mutations.[12] The role of the MAPK (mitogen activated kinase-like protein) pathway in the proliferation of melanoma involves the activation of RAF that leads to phosphorylation of MEK (MAPK kinase) and the phosphorylation of ERK, which stimulates cell proliferation and activates mitochondrial proteins, thus promoting growth and inhibiting apoptosis.[13] Based on this, BRAF is an effective target for the treatment of melanoma with BRAF mutation, and many targeted agents are being developed. Since the approval of the BRAF inhibitor, vemurafenib, by the FDA for the treatment of advanced melanoma with BRAF V600E/K mutation, in 2011, the comprehensive treatment of melanoma has been revolutionized. A total of five BRAF and MEK inhibitors were approved by the FDA in the following years [Figure 1]. The results of several trials showed that the combination of BRAF and MEK inhibitors was more effective than BRAF inhibitor monotherapy, due to its capacity to delay the emergence of BRAF inhibitor resistance and reduce skin toxicity. Currently, regimens of BRAF inhibitors combined with MEK inhibitors are approved by the FDA and recommended as first-line therapy for advanced melanoma. These regimens include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib.[14]
;)
Figure 1: The timeline of significant clinical trials of targeted therapy and the mechanism of targeted drugs. BRIM3, BREAK3, METRIC, coBRIM, COMBI-v, COMBI-d, COLUMBUS, and IMspire150 are phase III trials. BRIM3, BREAK3, and METRIC demonstrated that vemurafenib and dabrafenib were more effective than traditional chemotherapy drug dacarbazine and had lower adverse reaction rate. coBRIM, COMBI-v, COMBI-d, and COLUMBUS demonstrated that the combination of BRAF and MEK inhibitors improved OS in melanoma patients compared with BRAF inhibitor monotherapy; besides, the combination of encorafenib and binimetinib in melanoma increases OS over 30 months for the first time. The results of IMspire150 suggested that the combination of spartalizumab with vemurafenib and cobimetinib could improve PFS and objective response and induce long-term responses in patients. TRK receptors family is composed of three receptor tyrosine kinases (RTKs): TRKA, TRKB and TRKC, also called neurotrophic tyrosine receptor kinases (NTRK1-NTRK3) that function as high affinity signaling receptors for various neurotrophins, including NGF, BDGF and NT3. BDGF: Brain-derived neurotrophic factor; ERK: extracellular regulated protein kinases; MEK: mitogen activated kinase-like protein kinase; NFI: Neurofibromin 1. NGF: Nerve growth factor NT3: Neurotrophin-3; OS: Overall survival; PFS: Progression-free survival; PLCγ: phospholipase C gamma; PI3K: phosphatidylinositol 3-kinase, putative; TRK: tropomyosin receptor kinase.
BRAF inhibitors and MEK inhibitors for advanced melanoma
A clinical trial (NCT01072175) demonstrated the efficacy and safety of the combination of dabrafenib and trametinib in patients with BRAF V600 mutations.[15,16] Based on a longer-time follow-up, the overall survival (OS) (4 years, 30%; 5 years, 28%) and progression-free survival (PFS) (4 years and 5 years, both 13%) in the case of receiving dabrafenib plus trametinib appeared to be stabilized.[17] Although NCT01072175 demonstrated the safety and efficacy of the combination of dabrafenib and trametinib, it did not compare the effects of monotherapy and combination therapy, and thus, a series of randomized controlled trials (COMBI-v, COMBI-d, coBRIM, and COLUMBUS) were carried out. The combination of dabrafenib and trametinib improved OS in patients with BRAF mutations without increasing overall toxicity (COMBI-v and COMBI-d) compared with vemurafenib or dabrafenib monotherapy.[18–21] In COMBI-v and COMBI-d, the 5-year outcomes were associated with a PFS of 21% at 4 years (95% confidence interval [CI], 17–24%) and 19% at 5 years (95% CI, 15–22%). Overall survival was 37% (95% CI, 33–42%) at 4 years and 34% (95% CI, 30–38%) at 5 years.[22] Compared with vemurafenib monotherapy, vemurafenib plus cobimetinib, encorafenib plus binimetinib, or encorafenib monotherapy could improve patients' PFS and OS. Compared with encorafenib monotherapy, encorafenib plus binimetinib could improve patient tolerability. These trials (coBRIM, COLUMBUS) supported the use of vemurafenib plus cobimetinib and encorafenib plus binimetinib as first-line treatment options for patients with advanced BRAF-mutant melanoma.[23–25] In coBRIM, the median PFS with cobimetinib and vemurafenib was 12.3 (95% CI, 9.5–13.4) months.[26] According to the updated data of COLUMBUS, the combination group reduced the risk of death by 39% compared with that of vemurafenib alone (hazard ratio [HR], 0.61). Besides, the PFS was doubled to 14.9 months (HR, 0.51).[27]
A real-world study showed that brain metastases often represented a poor prognosis.[28] A study that combined dabrafenib and trametinib suggested its efficacy and safety with a relatively short median duration of response (DoR) for patients with brain metastases. However, whether combined therapy can improve the prognosis of patients with brain metastases requires more clinical evidence.[29]
BRAF inhibitors and MEK inhibitors for adjuvant therapy
Surgery is an indispensable part of the comprehensive treatment of melanoma, but for patients with stage IIC–III, there is still a risk of recurrence and death even if R0 resection is achieved. To explore whether the use of post-surgery targeted drugs improves outcomes in patients with stage IIC and III melanoma, COMBI-AD and BRIM8 had been conducted and data from these trials showed that the use of BRAF and MEK inhibitors could reduce the risk of recurrence. From the results of COMBI-AD, patients with stage III melanoma with a BRAF V600Eor V600K mutation, who received 12 months of adjuvant dabrafenib plus trametinib after surgery, lived longer without recurrence or distant metastasis, while there was no significant long-term toxic effect compared with patients on placebo. This clinical trial suggested that dabrafenib plus trametinib adjuvant therapy might be beneficial in preventing or delaying recurrence in patients with a completely resected stage III melanoma. At 5 years, the percentage of living patients without relapse was 52% (95% CI, 48–58%) in the dabrafenib plus trametinib group and 36% (95% CI, 32–41%) in the placebo group who accepted two matched placebo (HR for recurrence or death, 0.51; 95% CI, 0.42–0.61). The percentage of living patients without distant metastases was 65% (95% CI, 61–71%) in the dabrafenib plus trametinib group and 54% (95% CI, 49–60%) in the placebo group (distant HR for metastasis or death, 0.55; 95% CI, 0.44–0.70).[30–32] In BRIM-8, the median disease-free survival was 23.1 (95% CI, 18.6–26.5) months in the vemurafenib group, compared with 15.4 (95% CI, 11.1–35.9) months in the placebo group (HR, 0.80, log-rank P = 0.26).[33]
BRAF inhibitors and MEK inhibitors for neoadjuvant therapy
Although upfront surgery and postoperative adjuvant therapy improve recurrence-free survival in stage III melanoma patients with BRAF mutation, there are still locally advanced stage III melanoma patients with BRAF mutation who are inoperable, and therefore, clinical trials of preoperative treatment with dabrafenib plus trametinib were conducted. These trials suggested that the neoadjuvant (dabrafenib plus trametinib) was beneficial for high-risk populations and could help patients with locally advanced melanoma who previously could not undergo radical tumor resection to achieve radical tumor resection after neoadjuvant therapy. Besides, these trials demonstrated the efficacy and safety of neoadjuvant therapy (dabrafenib plus trametinib). In a phase II trial of neoadjuvant plus adjuvant (NCT02231775), survival without disease progression was significantly higher in patients treated with the neoadjuvant plus adjuvants than that in patients treated with standard care (10 of 14 patients [71%] vs. none of 7 in the standard of care group; median event-free survival was 19.7 [95% CI, 16.2–not estimable] months and 2.9 [95% CI, 1.7–not estimable] months, respectively; HR, 0.016, 95% CI, 0.00012–0.14, P <0.0001). Neoadjuvant plus adjuvant was well-tolerated and without grade 4 adverse events or treatment-related deaths. The most common adverse reactions in the neoadjuvant plus adjuvant therapy group were grade 1–2 toxicities, including chills (12 of 14, 92%), headaches (12 of 14, 92%), and pyrexia (10 of 14, 77%). The most common grade 3 adverse event was diarrhea (2 of 14, 15%).[34]
In another phase II trial of neoadjuvant therapy (NeoCombi), 30 of 35 patients achieved a RECIST response, 16 patients (16 of 35, 46%; 95% CI, 29–63%) had complete responses, and 14 patients (14 of 35, 40%; 95% CI, 24–58%) had partial responses at resection. Five patients (5 of 35, 14%; 95% CI, 5–30%) had stable disease, and none had progressive disease. After resection and evaluation of the results of 18F-fluorodeoxyglucose (FDG) PET scan, all 35 patients achieved response, including 18 patients (18 of 35, 51%; 95% CI, 34–69%) with complete response and 17 patients (17 of 35, 49%; 95% CI, 31–66%) with incomplete response. Compared to traditional chemotherapy, the incidence of treatment-related adverse events (TRAEs) was relatively low, and these adverse reactions were acceptable to patients. Ten patients (10 of 35, 29%) experienced grade 3–4 adverse events, and none experienced treatment-related deaths.[35]
In a phase II study of neoadjuvant therapy, 21 patients, with unresectable BRAF mutated stage III melanoma or stage IV melanoma with ≤3 metastases, were enrolled for treatment. Surgery was performed in 18 patients (18 of 21, 86%), 17 with R0 resection and 1 with R1 resection. Patients who underwent surgery had a median recurrence-free survival of 9.9 (95% CI, 7.52–not reached) months. Through neoadjuvant therapy, 1 patient (1 of 21, 4.8%) achieved complete response, 16 (16 of 21, 76.2%) achieved partial response, and 1 (1 of 21, 4.8%) achieved stable disease, while 1 (1 of 21, 4.8%) had disease progression. Half of the patients who underwent surgery experienced recurrence (9 of 18) and most patients experienced distant recurrence (6 of 9), while 3 patients experienced local recurrence for the first time. Three patients with local recurrence underwent surgery, but all developed distant metastases.[36] Although neoadjuvant therapy can shrink and downgrade the tumor, the prognosis of patients with stage IIIC–IV melanoma is still poor, and more effective treatment options are still worth exploring.
Combination of BRAF plus MEK inhibitors with immune checkpoint inhibitors to achieve long-term response
Although treatment with BRAF plus MEK inhibitors can improve outcomes in patients with BRAF mutations, the major disadvantage of targeted therapy is that the tolerance to treatment increases with the shortening of the DoR with the patients usually relapsing within 9–12 months of treatment commencement. Patients are less responsive to immune checkpoint inhibitors than targeted therapy, but once immune memory is developed, there is a durable response to immunotherapy.[37] Based on this, several clinical trials involving the combination of targeted therapy with immunotherapy had been carried out, and the results confirmed that the combination of targeted therapy with immunotherapy could produce long-term responses in a subset of patients with BRAF mutations.
The results of IMspire150 showed that the addition of atezolizumab to patients with BRAF V600-mutant advanced melanoma, receiving vemurafenib and cobimetinib, improved PFS and was safely tolerated by the patients. PFS was significantly longer compared with that of the control group (15.1 months vs. 10.6 months; HR, 0.78; 95% CI, 0.63–0.97; P = 0.025).[38] In KEYNOTE-022 (part 3), the results suggested that pembrolizumab plus dabrafenib and trametinib improved PFS, DoR, and OS in patients with BRAF V600E/K-mutant advanced melanoma; however, the treatment-related adverse effects were higher. The median PFS was 16.9 (95% CI, 11.3–27.9) months in the pembrolizumab plus dabrafenib and trametinib group and 10.7 (95% CI, 7.2–16.8) months in the dabrafenib plus trametinib group (HR, 0.53; 95% CI, 0.34–0.83). Grade 3–5 TRAEs occurred in 35 patients (35 of 60, 58%, including one death) who received pembrolizumab plus dabrafenib and trametinib and 15 patients (15 of 60, 25%) who received dabrafenib plus trametinib.[39] The increase in the incidence of adverse reactions did not support the combination of pembrolizumab with dabrafenib and trametinib as a first-line treatment option. In COMBI-i, the results showed that the median PFS was 16.2 (95% CI, 12.7–23.9) months in the spartalizumab plus dabrafenib and trametinib group (experimental group), and 12.0 (95% CI, 10.2–15.4) months in the dabrafenib plus trametinib (control group) (HR, 0.82; P = 0.042). The objective response rates were 69% (183 of 267 patients) and 64% (170 of 265 patients), respectively. Grade 3 TRAEs occurred in 55% (146 of 267) in the experimental group and 33% (88 of 264) in the control group. It is worth noting that although the combination of spartalizumab plus dabrafenib and trametinib improved response rates, there was a corresponding increase in the incidence of adverse effects.[40] More medication regimens that can improve long-term response rates and lower TRAEs are worthy of further exploration.
KIT-Mutant Melanoma
Imatinib is a KIT inhibitor that shows effect on tumors with KIT mutation. It has a high response rate in the treatment of gastrointestinal stromal tumors and greatly improves the prognosis of patients.[41,42] Although KIT mutations account for only 1–2% of all mutations in melanoma, the KIT mutation rate is approximately 15–20% in acral and mucosal melanomas, accounting for 70% of all melanomas in Asian populations. Therefore, KIT is a reasonable therapeutic target that was tried for melanoma with KIT mutation[11,43]. Several clinical trials were conducted to explore the benefit of imatinib and confirmed that imatinib was effective for a subset of patients with KIT mutations (exon-11 or exon-13), but not for patients with KIT amplification only. In a phase II trial, 10 patients responded to imatinib, while 9 of them had exon-11 or exon-13 mutation. However, for patients who had developed resistance to imatinib, increasing the dose of imatinib to 800 mg/day in patients with disease progression did not restore disease control.[44] Meanwhile, a clinical trial showed that the emergence of imatinib resistance might be related to NRAS mutation and increase in KIT copies.[45]
Although imatinib clinical trials demonstrated the benefit of imatinib in patients with specific KIT-mutant advanced melanoma, the response rate was relatively low, and therefore, several clinical trials evaluated the efficacy of nilotinib in the treatment of advanced KIT-mutant melanoma. In a single-center phase II trial, seven patients who responded to nilotinib, and two patients who partially responded, had the KIT mutation. This result demonstrated the antitumoral effect of nilotinib in melanoma.[46] Another multicenter clinical trial further illustrated the effectiveness of nilotinib (UN10-06) by showing an overall response rate to nilotinib of 16.7% and a disease control rate of 57.1% (1 patient had complete response, 6 had a partial response, and 17 had a stable disease). Of the 7 responders, 6 patients had KIT mutations (exon-11: 5 patients; exon-17: 1 patient) and 1 patient just had a KIT amplification.[47] In a global phase II study of nilotinib, the results showed that nilotinib had a greater activity in patients with exon-11 mutation with an objective response rate of 26.2% and a median duration of overall response of 7.1 months.[48] Those trials confirmed the benefit of nilotinib in patients with KIT mutations (exon-11, exon-13, and exon-17), especially those with exon-11 mutation. The toxicity of nilotinib was also acceptable. In another phase II study, the results showed that nilotinib could achieve disease control in patients with KIT mutations and disease progression after imatinib treatment, but nilotinib had a limited efficacy in patients with brain metastases. Two partial responses were observed in patients without brain metastases (18.2%; 90% CI, 3–47%), whereas no response to nilotinib was observed in the treated patients with brain metastases. The median time to progression and OS for all treated patients were, respectively, 3.3 (90% CI, 2.1–3.9) months and 9.1 (90% CI, 4.3–14.2) months.[49]
Overall, nilotinib has a better clinical efficacy than imatinib, but only patients with specific KIT mutations can benefit from it. In a phase II study, the researchers observed decreases in the phosphorylation of the signal transducer and activator of transcription, STAT3, and its effectors (BCL-2 [BCL2 apoptosis regulator], MCL-1 [MCL1 apoptosis regulator, BCL2 family member]) in tumors during follow-up, that were significantly associated with clinical response. In the KIT-mutant melanoma cell line M230, nilotinib reduced STAT3 signaling, and STAT inhibitors were as effective as KIT inhibitors in reducing cell proliferation, demonstrating a significant association between STAT3 inhibition and response to nilotinib. These findings suggest that SATA3 may be a beneficial therapeutic target for patients with the KIT mutation and may increase the response of KIT inhibitors.[50]
At the 2021 European Society for Medical Oncology (ESMO) annual meeting, the results of a phase I study of ripretinib in KIT-mutant melanoma were presented. The data showed that in the treatment of KIT-mutant melanoma, the objective response rate (ORR) was similar to the previously reported data for other KIT inhibitors, and that the median PFS and DoR were superior. More clinical trials should be conducted to explore its efficacy and safety.[51]
NRAS-Mutant Melanoma
NRAS-mutant melanomas account for 15–20% of cutaneous melanomas.[52] So far, the first-line treatment for NRAS-mutant melanoma that is incurable by stage III/IV surgery has been immunotherapy with programed cell death protein (anti-PD-1) checkpoint inhibitors, such as nivolumab or pembrolizumab. The efficacy of immunotherapy in NRAS-mutant melanoma is controversial,[53] and a phase III trial (NEMO) suggested that binimetinib, a MEK inhibitor, might be a treatment option for patients with NRAS mutation. The median PFS in the binimetinib group was longer than that in the dacarbazine group. Median PFS was 2.8 months in the binimetinib group and 1.5 months in the dacarbazine group (HR, 0.62; 95% CI, 0.47–0.80; one-sided P <0.001).[54] Pimasertib has also demonstrated its safety and efficacy in clinical trials. In a phase II trial, the results suggested that PFS was significantly improved compared to DTIC (Dacarbazine) (median, 13 weeks and 7 weeks; HR, 0.59; 95% CI, 0.42–0.83; P = 0.002).[55] Besides, another trial of pimasertib demonstrated that pERK phosphorylated extracellular regulated protein kinases inhibition was associated with the clinical activity of pimasertib.[56] Statistically, MEK inhibitors prolong the survival period of NRAS mutant patients, but the prolongation time is relatively short, and thus, more effective targeted drugs are needed for NRAS-mutant melanoma.
NTRK-Mutant Melanoma
Fusions involving neurotrophic tyrosine receptor kinase (NTRK), a known driver of tumorigenesis, also occurs in melanoma. NTRK fusions are relatively common in spitzoid melanoma with a prevalence of 21–29%, whereas <1% are observed in cutaneous or mucosal melanoma and 2.5% in acral melanoma.[57] Therefore, NTRK is a reasonable therapeutic target for patients with advanced melanoma who have failed first-line therapy or who do not have BRAF and KIT mutations. From the results of two phase I studies of entrectinib (ALKA-372-001 and STARTRK-1), a potent oral inhibitor of the tyrosine kinases TRKA/B/C (tropomyosin receptor kinase A/B/C), ROS1, and ALK (ALK receptor tyrosine kinase), only one patient with acral melanoma responded to entrectinib. Through the evaluation of computed tomography, the patient achieved partial response without evidence of disease progression at 11 months.[58,59]
Conclusions
The emergency of targeted agents had revolutionized the treatment of advanced melanoma, especially for BRAF V600-mutant melanoma and the current major targeted agents and their indications were summarized in Table 1. The combination of encorafenib and binimetinib improved median survival to more than 30 months. Although the advance of targeted therapy has led to a decline in mortality of patients with advanced melanoma, survival rates for those diagnosed with stage IIIC or IV disease remain poor. Targeted therapy is extremely effective, but the outcome of long-term use of molecule-targeted inhibitors is the emergence of drug resistance. In melanoma, genetic mutations and cellular plasticity are mechanisms of resistance to targeted therapy.[60] To improve the prognosis of patients with advanced melanoma (the final goal is complete response), investigating the mechanism of drug resistance and identifying potential targets and treatment options (such as combination with immune checkpoint inhibitors) should be further explored.
Table 1 -
Targeted therapy approved by FDA for
melanoma.
|
Agent
|
Mechanism
|
Recommended indications
|
| Vemurafenib |
BRAF inhibitor |
As monotherapy and in combination with cobimetinib for BRAF V600E/K-mutant disease |
| Dabrafenib |
BRAF inhibitor |
As monotherapy and in combination with trametinib for BRAF V600E/K-mutant disease |
| Encorafenib |
BRAF inhibitor |
As monotherapy and in combination with binimetinib for BRAF V600E/K-mutant disease |
| Trametinib |
MEK inhibitor |
As monotherapy and in combination with dabrafenib for BRAF V600E/K-mutant disease |
| Cobimetinin |
MEK inhibitor |
In combination with vemurafenib for BRAF V600E/K-mutant disease |
| Binimetinib |
MEK inhibitor |
In combination with encorafenib for BRAF V600E/K-mutant disease |
| Imatinib |
KIT inhibitor |
As monotherapy for c-KIT-mutant disease |
| Nilotinib |
KIT inhibitor |
As monotherapy for c-KIT-mutant disease |
FDA: Food and drug administration.
Acknowledgments
We thank all the investigators who participated in preparing the present review.
Funding
This study was funded by 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Nos. ZYPY20001 and ZYPY20002).
Conflicts of interest
None.
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