Written by: Alex Huynh
Melanoma is deadliest of three major skin cancers due to high proliferation rates and molecular properties that allow for immune evasion. Of the two main treatment approaches viable against metastatic melanoma, targeted MAPK therapy offers poor durability with rapid development of resistance and immunotherapy demonstrates slow responses. A novel treatment option that combines MAPK inhibitors and immune checkpoint inhibitors shows promise due to higher response rates from synergistic effects.
Cutaneous malignant melanoma is a melanocyte-based skin cancer characterized by elevated asymmetric lesions greater than 6 mm in diameter often with colour variations.1 Under normal conditions, melanocytes produce the skin pigment melanin at the basal layer of the epidermis.1 Malignant transformation of melanocytes follows an accumulation of mutations on tumour-intrinsic and immune-related factors that trigger uncontrolled growth.2 The traditional number staging system couples information on the depth of the lesion with TNM (Tumor, Node, Metastases) staging to diagnose melanoma histopathologically and informs treatment plans based on risk calculation.2 Whereas early stages of cutaneous melanoma are confined to their primary site, advanced stages of melanoma can spread to lymph nodes and distant tissues in metastasis.2 Past treatment strategies emphasized early detection of melanoma before lymph nodal or distant metastases occur as traditional therapeutics or resection could not address the mass proliferation of a tumor.3 However, new drug discoveries targeting immune checkpoints and specific oncogenes demonstrates new hope on the prognosis of metastatic melanoma (MM). This following review will discuss pathophysiology of metastatic melanoma, the current applications of targeted therapy and immunotherapeutics as treatments, and insights into the use of novel combination therapies as a treatment option.
The etiology of MM follows genetic transformation similar to other cancers to gain constitutive activity in oncogenic signal transduction.2 Melanoma occurs in several variants due to differences in mutational frequencies but there are recurrent somatic mutations that are shared among melanoma types.4 Regular mutations in melanoma are typically associated with signaling pathways that allow for apoptosis evasion (TF53), uncontrolled proliferation and survival (NRAS, BRAF, PTEN and c-KIT), and metastasis (CDKN2A and ARID2) (Figure 1).1,2,4 Early oncogenic events involved in the transition from primary melanoma to MM is associated with the overstimulation of the mitogen-activated-protein-kinase (MAPK) pathway.1,2 MAPK phosphorylation cascade includes RAS, RAF, MEK, and ERK kinases which are responsible for cell survival, proliferation, and differentiation.5 BRAF mutation at the amino acid position 600 (BRAFV600) forms an active kinase conformation that facilitates constitutive activity of the MAPK pathway independent of stimulation and is found in 50-60% of melanoma variants.2,4,6
Figure 1: Common oncogenic pathways in melanoma. Mutations in NRAS or BRAF trigger constitutive MAPK signaling leading to malignant transformation involving uncontrolled proliferations. Mutations in PTEN or TP53 inhibit tumor suppressing factors that enable malignant growth. Mutations in CDKN2A are responsible for the invasive potential of melanoma as it controls the cell-cycle.2,4 Image from Schadendorf et al. as “Selected key signalling pathways and therapeutic targets in melanoma”.
MM reinforce immune checkpoints that allow malignant cells to physiologically evade immune responses.2 In healthy melanoma cells, the release of interferons upregulates the expression of programmed cell death-ligand 1 (PD-L1) and PD-L2 on the cell surface. When PD-L1/2 binds to programmed cell death protein 1 (PD-1) on T cells, a signal deescalates the immune system to prevent autoimmunity.2,4 MM exploits the intrinsic PD-L1 expression upon antigen recognition of T cells to inhibit the antitumor response and enhance tumorigenicity. 2,7 Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a immune checkpoint found on T cells receptor which functions similarly to PD-1. Inhibition of immune checkpoint presents a compelling target to treat MM by increasing the agency of natural immune cells to suppress further proliferation.7
CURRENT TREATMENT APPROACHES
Immunotherapy: Immune Checkpoint Inhibitors
As a broad spectrum treatment for MM, immunotherapeutics employ antibodies to block inhibitory receptors on immune cells or the malignant tumor (CTLA-4, PD-1 or PD-L1).8 The immune checkpoint blockade prevents malignant cells from evading the immune system and in turn assists T cell effector activity in anti-tumor responses.8 As monotherapies, PD-1 inhibitors (nivolumab and pembrolizumab) demonstrate higher overall progression-free survival (PFS; length of time without worsening symptoms) and overall survival (OS) and response rate (RR) than the previous chemotherapeutic alternatives and CTLA-4 inhibitors (ipilimumab) with notable decreased toxicity rates.2,9 In practice, PD-1 inhibitors are used in conjunction with CTLA-4 Inhibitors against MM after a more rapid and durable response was found in clinical trials.8,9 In one phase III clinical trial with and randomized, stratified population, the combination of nivolumab and ipilimumab as non-redundant immune checkpoint inhibitors yielded an objective RR of 58% and PFS of 11.5 months.9 Nivolumab and ipilimumab monotherapy showed 44% RR, 6.9 month PFS and 11% RR, 2.9 month PFS respectively.9 Results are supported by a Bayesian network meta-analysis in which nivolumab plus ipilimumab demonstrated the the most effective response in terms of PFS.10 However, the synergistic effects compound adverse side-effects as well, causing around 30% of patients to discontinue combination immunotherapy treatment. 9,10
Targeted Therapy: MAPK (BRAF-MEK) Inhibitors
In MM patients with BRAF V600 mutations (50-60%), the current treatment standard calls for the administration of BRAF plus MEK inhibitors.11 Commercially, three regimens of BRAF-MEK Targeted therapy drugs have been approved by the FDA: vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib plus binimetinib.11 Down regulating BRAF and MEK, and consequently the MAPK signalling pathway, is an attractive target to reduce malignant cell proliferation.5 In multiple phases of multiple randomized controlled trials, vemurafenib and dabrafenib, as BRAF monotherapies, demonstrates improved PFS, OS and RR of 50% or greater.11 Response rates increase to around 70% in combination with MEK inhibitors.2 A Baysian network analysis found BRAF-MEK inhibitor targeted therapy outperforms other current treatments for BRAF-mutated patients with a 55.8% posterior probability of outperforming the next best treatment (PD-1 immunotherapy) in OS and a 97.1% posterior probability of outperforming any other treatment in ORR (chemotherapy or immunotherapy).12
Evidently, MM mutation patterns will vary among different melanoma subtypes. The appropriate treatment response will depend on the specific type of variant (e.g. BRAFv600 variant v.s. BRAF wild-type variant), the rate of adverse side-effects, and potential innate resistance to treatment. It Is noteworthy that the presence of a BRAFv600 mutation does not automatically presume targeted therapy as the first-line treatment as cross-study analysis suggests that anti-PD-1 based therapy may still have greater overall and median survival in patients.13
LIMITATIONS AND COMBINATION THERAPY
In the current approaches to MM treatment, combination therapy between PD-1 and CTLA-4 inhibitors as well as BRAF and MEK inhibitors has proven to increase overall efficacy of drug response. 2,9,12 However, in targeted therapy, 15% of patients with BRAFv600-mutated MM exhibit an innate resistance to BRAF/MEK inhibitors and most gain an acquired resistance in around a year.8,11 Similarly, 50% of patients with MM treated with immune checkpoint inhibitors will possess or develop resistance.13 A proposed solution to the treatment resistance was to combine targeted therapy and immunotherapy into a combination therapy for MM.13,14
In support, scientists believed that durable responses from immunotherapy and high response rates from targeted MAPK signalling inhibitors may be synthesized into a more robust combination therapy.11,14 Further research suggests that the BRAF/MEK inhibitors may exhibit a synergistic effect on anti-PD-1 treatments through complex interactions. 14,15 One theory proposes that BRAF inhibitors and MEK inhibitors can sensitize tumor to immune response via up-regulation melanocyte differentiation antigens (MDAs) in BRAF mutant melanoma (MEK inhibitors also upregulate MDAs in wild-type melanoma).15,16 As a result, T cells will have improved antigen-specific recognition in tandem with inhibited PD-1 receptors to better identify tumors.14,15 Alternatively, immune evasion of tumors cells due to PD-L1 overexpression contribute to the primary and acquired resistance to MAPK inhibitors; as a result, one theory suggests immune checkpoint blockades could promote melanoma termination by reducing resistance.16 An in vivo study demonstrated that the addition of trametinib (a MEK inhibitor) increased T cell recognition of malignant tumors and attenuated other immunosuppressive cells.15 Another preclinical trial demonstrates vemurafenib plus atezolizumab (an anti-PD-L1 drug) as well as atezolizumab plus vemurafenib and cobimetinib (a MEK inhibitor) both resulted in manageable toxicity and a high response rate of 85.3%.11
Based on promising preclinical data, several clinical trials on combination therapy between MAPK target therapy and immunotherapy are in progress.14,16 Despite the potential for a high-response, durable treatment, not every combination of BRAF/MEK inhibitors and immune checkpoint inhibitors are safe as certain interaction my reveal unexpected toxicity.17 Notably, early phase clinical trials found ipilimumab with either vemurafenib or dabrafenib plus trametinib would cause hepatotoxicity or colitis respectively.11,17 In general, immunotherapy exhibit unique safety profiles which are difficult to predict and likely more so in combination with target therapy. 6,17 For example, excessive immune activation may overwhelm organ tolerance to manifest autoimmune-like adverse events.8,18
Application of highly specific combination therapies to optimize melanoma treatments will rely heavily on identification of biomarkers.2,8,18 This may involve repeated invasive biopsies in the tumour microenvironment which poses many risks to the patient.18 In addition, MM possess multiple tumor microenvironment at different stages which have been shown to be able to demonstrate varying PD-L1 expression.18 Increased specificity of biomarkers as predictors of treatment response and adverse events will enable personalized treatments with high OS and RR at a reduced cost.4,19 Future developments should investigate methods of improving biomarker identification to better inform clinical management of MM and support the implementation of combination therapy.4,18,19
Currently, approved treatments of MM involve either immune checkpoint inhibitors or targeted MAPK therapy, depending on the variant, are improvements from systemic chemotherapy with negligible impact of medianoveral survival.4,8 Although the best method to increase melanoma mortality remains early detection,3 new advancements in the synergistic effects of combination therapy suggest potential for better response rates and durability of MM treatment.13,14 Moreover, insights into the therapeutic treatment of MM can provide many insights into the management of similar malignant cancers. In the progression of clinical testing, researchers will face more challenges in biomarker detection and testing combinations with optimal prognosis to redefine the current standard of MM treatment.
- Liu Y, Sheikh MS. Melanoma: Molecular pathogenesis and therapeutic management. Mol Cell Pharmacol. 2014;6(3):228. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346328/ [cited 2020 Dec 20].
- Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, et al. Melanoma. Lancet. 2018;392(10151):971-84. Available from: doi:10.1016/S0140-6736(18)31559-9.
- Weyers W. Screening for malignant melanoma-a critical assessment in historical perspective. Dermatol Pract Concept. 2018;8(2):89-103. Available from: doi:10.5826/dpc.0802a06.
- Davis LE, Shalin SC, Tackett AJ. Current state of melanoma diagnosis and treatment. Cancer Biol Ther. 2019;20(11):1366-79. Available from: doi:10.1080/15384047.2019.1640032.
- Paton EL, Turner JA, Schlaepfer IR. Overcoming resistance to therapies targeting the MAPK pathway in BRAF-mutated tumours. J Oncol. 2020;2020:1079827. Available from: doi:10.1155/2020/1079827.
- Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: A move toward precision medicine. Mod Pathol. 2018;31(1):24-38. Available from: doi:10.1038/modpathol.2017.104.
- Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell. 2015;162(6):1242-56. Available from: doi:10.1016/j.cell.2015.08.052.
- Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination immunotherapy: A road map. J Immunother Cancer. 2017;5:16. Available from: doi:10.1186/s40425-017-0218-5.
- Kee D, McArthur G. Immunotherapy of melanoma. Eur J Surg Oncol. 2017;43(3):594-603. Available from: doi:10.1016/j.ejso.2016.07.014.
- Li X, Wang J, Yao Y, Yang L, Li Z, Yu C, Zhao P, Yu Y, Wang L. Comparative efficacy and safety of immune checkpoint inhibitor-related therapies for advanced melanoma: a Bayesian network analysis. Oncotarget. 2017;8(48):83637-49. Available from: doi:10.18632/oncotarget.18906.
- Vanella V, Festino L, Trojaniello C, Vitale MG, Sorrentino A, Paone M, et al. The role of BRAF-targeted therapy for advanced melanoma in the immunotherapy era. Curr Oncol Rep. 2019;21(9):76. Available from: doi:10.1007/s11912-019-0827-x.
- da Silveira Nogueira Lima JP, Georgieva M, Haaland B, de Lima Lopes G. A systematic review and network meta-analysis of immunotherapy and targeted therapy for advanced melanoma. Cancer Med. 2017;6(6):1143-53. Available from: doi:10.1002/cam4.1001.
- Weiss SA, Wolchok JD, Sznol M. Immunotherapy of melanoma: Facts and hopes. Clin Cancer Res. 2019;25(17):5191-01. Available from: doi:10.1158/1078-0432.CCR-18-1550.
- Reddy SM, Reuben A, Wargo JA. Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr Oncol Rep. 2016;18(7):42. Available from: doi:10.1007/s11912-016-0531-z.
- Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015;7(279):279ra41. Available from: doi:10.1126/scitranslmed.aaa4691.
- Rozeman EA, Blank CU. Combining checkpoint inhibition and targeted therapy in melanoma. Nat Med. 2019;25(6):879-82. Available from: doi:10.1038/s41591-019-0482-7.
- Mackiewicz J, Mackiewicz A. BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients. Contemp Oncol (Pozn). 2018 Mar;22(1A):68-72. Available from: doi:10.5114/wo.2018.73890.
- Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-72. Available from: doi:10.1038/nrc3973.
- Yu C, Liu X, Yang J, Zhang M, Jin H, Ma X, et al. Combination of immunotherapy with targeted therapy: Theory and practice in metastatic melanoma. Front Immunol. 2019;10:990. Available from: doi:10.3389/fimmu.2019.00990.