Parisa Momtaz, MD
Memorial Sloan-Kettering Cancer Center
Mario E. Lacouture, MD
Memorial Sloan-Kettering Cancer Center
Paul B. Chapman, MD
Attending Physician, Melanoma/Sarcoma Service
Memorial Sloan-Kettering Cancer Center
Professor of Medicine
Weill Cornell University Medical College
New York City
Unresectable or metastatic melanoma remains an aggressive disease with a high mortality rate. In the US, the incidence of advanced melanoma continues to rise, and an estimated 9,710 patients will die from the disease in 2014.1 Prior to 2011, systemic therapy for cutaneous melanoma was limited to cytotoxic chemotherapy, high-dose interleukin 2, or combination biochemotherapy. A minority of patients did respond, and some responses were quite durable. However, we could not predict who would respond, and no evidence existed that these treatments improved median progression-free survival (PFS) or overall survival (OS).
A greater understanding of the biology of melanoma, both in molecular biology with the identification of the mitogen-activated protein kinase (MAPK) pathway, and in immunology with a better characterization of immune checkpoint inhibition, has changed the landscape of systemic therapeutic options.
Since 2011, four new agents, after demonstrating an advantage in both response and survival compared to dacarbazine [DTIC, traditional chemotherapy for advanced melanoma], have been FDA-approved for treatment. Three of these agents target the MAPK pathway: the RAF inhibitors vemurafenib (Zelboraf™) and dabrafenib (Tafinlar™), and the MEK inhibitor trametinib (Mekinist™). The fourth agent approved was ipilimumab (Yervoy™), an anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody.
A New Direction in Immunotherapy
A greater understanding of immune activation has identified immune checkpoints that negatively regulate T-lymphocyte activation. Two such checkpoints, B7/CTLA-4 and PD-1/PD-L1, have been the target for monoclonal antibody therapy (Figure 1).
CTLA-4 is a T-lymphocyte surface protein that recognizes B7 on antigenpresenting cells and leads to downregulation of T-lymphocyte activation. Ipilimumab is a humanized monoclonal antibody that blocks CTLA-4, thereby releasing T-cells from suppression, although recent data raise the possibility that ipilimumab may function by depleting regulatory T-cells from within tumors.2 The objective response rate to ipilimumab, using traditional RECIST criteria (Response Evaluation Criteria in Solid Tumors), is about 15 percent. Although these responses are sometimes delayed and may not be evident until several months after initiation of therapy,3 most responses are quite durable. An additional 25 percent of patients will experience stabilization of disease, which also can be extremely durable. Overall, this led to a near doubling of OS at 2 years (23.5 vs. 13.7 percent) in the first randomized trial, which compared ipilimumab to a peptide vaccine.4 A second randomized trial of ipilimumab + dacarbazine vs. dacarbazine alone also showed an OS advantage for ipilimumab — a 3-year OS of 20.8 percent in the ipilimumab plus dacarbazine group compared to 12.2 percent for dacarbazine alone.5
This improvement in long-term OS is likely due to the durability of ipilimumab's anti-melanoma effects. In compiling all survival data from 1,861 patients treated with ipilimumab, Schadendorf, Hodi, and Robert recently reported an estimated 3-year OS rate of 22 percent (95 percent CI 20-24 percent). Remarkably, approximately 84 percent of patients alive at 3 years were estimated to be alive at 5 and 10 years, confirming that clinical benefit from ipilimumab is generally durable.6 Indeed, complete responses are essentially cures. Among the 15 complete responders reported by the NCI, only one had disease recurrence with follow-up of 4.5-8 years.7
The T-cell activating effects of ipilimumab are relatively nonspecific, and autoimmune reactions are the most common adverse events, especially colitis, rash, pruritus, and skin depigmentation. Endocrinopathies (especially hypophysitis), hepatitis, and pancreatitis are also seen and require management.8 9 The incidence and complexity of these toxicities have discouraged some community oncologists from using ipilimumab.
A second immune checkpoint, the protein programmed death 1 (PD-1) and one of its ligands, PD-L1, is another target for immunotherapy. PD-1 is an inhibitory receptor on T-lymphocytes, and after chronic T-lymphocyte activation, expression of its ligand PD-L1 on tumor cells and other cells in the tumor microenvironment can protect the tumor cells from immune destruction. Monoclonal antibodies that block PD-1 or PD-L1 are currently in late-stage clinical trials, although not yet FDA-approved. Initial results indicate that PD-1/PD-L1 blockade results in higher response rates and a more favorable side effect profile than seen with ipilimumab.10 11 12 13 We await the results of several randomized trials comparing ipilimumab with anti-PD-1 therapy.
Targeting the MAPK Pathway
Along with the advancements in immunotherapy, parallel advancements have been made in understanding the molecular biology of melanoma cells. It appears that these cells are absolutely reliant on the MAPK pathway (Figure 2), and almost all melanomas have mutually exclusive driver mutations that activate the MAPK pathway, most commonly mutations in BRAF (40-60 percent of cases), NRAS (about 20 percent of cases), or loss of NF1 function (about 4 percent of cases).14 In BRAF-activated cells, the MAPK pathway is hyperactivated, leading to feedback inhibition of upstream RAS. This maintains the RAF kinases in the monomeric state which, under normal circumstances, would fail to signal downstream MEK. But mutated BRAF can signal as a monomer. However, as a monomer, it is very susceptible to pan-RAF inhibitors such as vemurafenib and dabrafenib. These drugs immediately shut down the MAPK pathway in BRAFmutated cells. Interestingly, in cells without a BRAF mutation, the RAF kinases are free to dimerize, and in these cells, RAF inhibitors inhibit one member of the dimer pair but trans-activate the other member. The result is that RAF inhibitors actually stimulate the MAPK pathway in cells with wild-type BRAF.15 This is the basis for the specificity of the anti-melanoma effect. The RAF inhibitors shut down the MAPK pathway in the BRAF-mutated melanoma cells but do not inhibit the pathway (in fact, slightly stimulate the pathway) in the patient's normal tissues.
Vemurafenib was the first RAF inhibitor to receive FDA approval for advanced melanoma with a BRAFV600E mutation. Phase I and II data showed striking and rapid antitumor activity in patients with BRAFV600E-mutated melanoma.16 17 The randomized phase III trial (BRIM-3) comparing vemurafenib to dacarbazine showed both a PFS and OS advantage in favor of vemurafenib, with a median PFS of 5.3 months vs. 1.9 months, an RR of 48 percent vs. 5 percent, and an estimated median OS of 13.6 months vs. 9.7 months.18 19 This trial and subsequent studies showed that less common BRAF mutations — V600K and V600R — also are sensitive to vemurafenib treatment. 19 20 Common toxicities associated with vemurafenib therapy include arthralgias, fatigue, rash, painful callus formation of the soles and/or palms, photosensitivity, hair thinning, and cutaneous squamous proliferations, most commonly keratoacanthomas but occasionally squamous cell carcinoma (SCC). These toxicities are reversible with discontinuation of the drug (although we do not know if SCCs regress), but can often be managed with drug holidays, antiinflammatory drugs (either NSAIDs or low-dose prednisone), and topical keratolytics and steroids. Some investigators have detected new primary BRAF wild-type melanomas while patients are on the drug. These have been very superficial, and it is still unclear if the frequency is truly increased. Keratoacanthomas generally are seen within the first 8 weeks of therapy and often stop appearing afterwards.
Dabrafenib, the second RAF inhibitor to gain FDA approval, has performed on par with vemurafenib. The randomized phase III trial (BREAK-3) of dabrafenib vs. dacarbazine showed an RR of 50 percent vs. 6 percent and a PFS of 5.3 months vs. 2.7 months.21 A subsequent phase II trial in patients with V600E or V600K BRAF-mutated melanoma and at least one asymptomatic brain metastasis showed that 49/139 (35 percent) had an intracranial response with dabrafenib therapy.22 The adverse event profile of dabrafenib is similar to that of vemurafenib, except that dabrafenib does not induce photosensitivity. It is thought to induce cutaneous squamous proliferations less frequently than vemurafenib, although the two drugs have not been compared side to side. In our experience, dabrafenib is definitely associated with cutaneous toxicities. It is also occasionally associated with fever.
Despite the favorable response to RAF inhibitors, resistance develops at a median time of 6-7 months,16 17 18 21 although it is important to stress that resistance is not inevitable. Long-term follow-up shows that approximately 14 percent of patients remain on RAF inhibitors and free from relapse at 18 months of treatment.19 Several mechanisms of RAF inhibitor resistance have been described, but virtually all lead to reactivation of the MAPK pathway. The most common mechanisms are: a post-transcriptional splice variant of the mutated BRAF mRNA that enhances dimerization in the absence of RAS activation; overexpression of the mutated BRAF protein; and acquisition of an NRAS mutation (reviewed in Cancer Cell23). Based on preclinical models,24 there is interest in exploring intermittent dosing schedules as a way to prevent or delay the development of resistance. [See "Oncogene Addiction and Overdose: Intermittent Treatment in Models of Drug- Resistant BRAF-Mutated Melanoma," in this issue.]
MEK, being downstream of RAF, is also a target of therapeutic interest. In a phase III trial of previously untreated BRAF-mutated melanoma, patients were randomized to receive either the MEK inhibitor trametinib or chemotherapy. Trametinib showed a response rate of 22 percent (compared with 8 percent in the chemotherapy arm), an improvement in median PFS (4.8 months for trametinib vs 1.5 months for chemotherapy), and a benefit in estimated OS at 6 months (81 percent versus 67 percent).25 Based on this study, trametinib was FDA-approved for use in BRAF-mutated melanoma that had not been previously treated with a RAF inhibitor. In reality, trametinib is rarely used for this indication, as the RAF inhibitors are more effective single agents.
Common adverse events from trametinib include rash (Figure 3), diarrhea, and fatigue. MEK inhibitors also commonly cause CPK (creatine phosphokinase) elevations, and while it is usually not symptomatic, significant muscle weakness is occasionally seen. In rare cases, MEK inhibitors have also been associated with central serous retinopathy.
Given the frequent cutaneous toxicities, namely acneiform rash, xerosis, alopecia, and paronychia for MEK inhibitors, and hand-foot skin reaction, xerosis, alopecia, skin neoplasms (keratoacanthomas and squamous cell carcinomas), and photosensitivity for RAF inhibitors, close collaboration with dermatologic colleagues is important.26 For the acneiform rash caused by MEK inhibitor, topical steroids and oral antibiotics are commonly used as a preventative or treatment method. For hyperkeratosis or thickening of the palms and soles associated with the use of RAF inhibitors, otherwise referred to as hand-foot skin reaction, keratolytics (creams containing ammonium lactate 12 percent, topical urea 20-40 percent, or salicylic acid 6 percent) are helpful for the callus formation on the palms and soles (Table 1).27 Vemurafenib is a highly photosensitive agent, so the use of a broad-spectrum sunscreen with an SPF of at least 30 when exposed to the sun, along with protective wear, is critical to prevent painful sunburns. In addition, for similar reasons, vemurafenib should be discontinued approximately one week prior to planned radiation therapy.
There is great interest in exploring combination therapies. Combining RAF and MEK inhibitors is a rational strategy to inhibit the MAPK pathway more completely and to delay or prevent emergence of resistance. In a randomized phase II trial, 162 patients with BRAF-mutated metastatic melanoma (Stage IIIC or IV) were randomized to dabrafenib treatment alone (150 mg twice daily), or dabrafenib plus trametinib at 1mg/d or 2 mg/d.28 The combination of dabrafenib + trametinib at 2 mg/d was associated with a median PFS benefit of 9.4 months compared to 5.3 months with dabrafenib monotherapy. The response rate with this combination was 76 percent compared to 54 percent for dabrafenib monotherapy, and had a longer median PFS (10.5 months vs 5.6 months). Although the combination is associated with less cutaneous toxicity than monotherapy (less hyperkeratosis and fewer keratoacanthomas/SCCs), it is also associated with more frequent systemic toxicities, including fever, chills, and fatigue in more than half of patients. Based on the improved response rate and PFS data, however, the FDA recently granted this combination accelerated approval. A formal phase III trial has been completed, and we await the results.
Efforts are now under way to combine targeted therapy and immunotherapy. The rationale is based on the observation that RAF inhibition releases MITF microphthalmia-associated transcription factor) inhibition, which leads to increased expression of melanoma-specific proteins, hopefully including relevant tumor rejection antigens.29 30 The initial effort, a phase I trial combining vemurafenib and ipilimumab, was closed early due to a high rate of significant hepatoxicity.31 Currently, combinations of RAF inhibitors and immunotherapy agents should be used only in the context of a clinical trial.
A phase I immune checkpoint inhibitor trial combining ipilimumab with the anti-PD-1 therapy nivolumab was shown to be safe and to have intriguing clinical activity.11 The objective response rate was 60 percent, far higher than what has been seen with ipilimumab alone. Multiple questions remain: is the combination better than nivolumab alone? Is sequential therapy equivalent to (or better than) combination therapy? What is the durability of these responses? Many of these questions will likely be answered by the phase III trial that just recently completed accrual, in which patients were randomized to ipilimumab, nivolumab, or combination therapy.
Choosing First-Line Therapy for BRAF-mutated Melanoma
In patients with BRAF-mutated melanoma, uncertainty remains as to first-line therapy — single agent RAF inhibitors, combination dabrafenib/trametinib, or immunotherapy. (Currently ipilimumab is the only FDA-approved option, but anti-PD-1 antibodies are expected to be FDA-approved in the near future.) (Table 2). Because of the high response rates and rapid onset of action, RAF inhibitors may be preferred first-line treatments in patients with BRAF-mutated melanomas with bulky disease or who are symptomatic. Also, in patients with brain metastases, RAF inhibitors appear to have a higher response rate than ipilimumab or even whole-brain radiotherapy and may again be the preferable first-line therapy. Alternatively, in patients with low burden of disease and no brain metastases, immunotherapy might be considered as a first-line treatment even in the setting of a BRAF mutation.
Given the high incidence of developing resistance to RAF inhibitors, some physicians switch patients to ipilimumab once a maximal tumor response has been achieved. This strategy has the potential advantage of providing immunotherapy in a setting of decreased tumor burden, and maintains the option of returning to RAF inhibitor therapy at a later date should immunotherapy not be effective. However, this strategy has not yet been tested in a prospective randomized trial.
Over the past 5 years, new treatment options for unresectable or metastatic melanoma have changed the field completely, resulting in improved OS for the first time. We are seeing longterm survivors in our clinics, which is a welcome sight. Still, many challenges lie ahead to improve outcomes further. In targeted therapy, resistance and lack of durable complete responses remain a problem. We also have to develop therapeutic options for patients whose tumors do not harbor a BRAF mutation. On the immunotherapy side, we need to understand the mechanisms of resistance and identify which checkpoint mechanisms are operative in which patients. Combination therapies hold promise but are likely to be associated with more toxicity. Continued innovative clinical trials will remain critical.
- Cancer Facts & Figures 2014. American Cancer Society, Inc., 500814:4. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-041770.pdf. Last checked February 13,2014. ↑
- Selby MJ, Engelhardt JJ, Quigley M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Canc Immunol Res 2013; 1(1):1–11. ©2013 AACR. Published online 04/2013; DOI:10.1158/2326-6066.CIR-13-0013 ↑
- Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Canc Immun 2008; 8:1. ↑
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711-23. ↑
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364(26):2517-26. ↑
- Schadendorf D, Hodi FS, Robert C. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma (abstract 24), Melanoma and Skin Cancer, European Cancer Congress 2013. http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Abstract-search.aspx#. Last checked February 13, 2014. ↑
- Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Canc Res 2012; 18(7):2039-47. ↑
- O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010; 21(8):1712-7. ↑
- Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30(21):2691-7. ↑
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26):2443-54. ↑
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369(2):122-33. ↑
- Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Canc Res 2013; 19(19):5300-9. ↑
- Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369(2):134-44. ↑
- Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150(2):251-63. ↑
- Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464(7287):427-30. ↑
- Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363(9):809-19. ↑
- Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366(8):707-14. ↑
- Chapman PB, Hauschild A, Robert C. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26):2507-2516. ↑
- McArthur GA, Chapman PB, Robert C, et al. Improved survival with vemurafenib in BRAFV600E and BRAFV600K mutation–positive melanoma. Lancet Oncol 2014. (in press). ↑
- Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R metastatic melanoma. Eur J Canc 2013; 49(5):1073-1079. ↑
- Hauschild A, Grob JJ, Demidov LV. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet 2012; 380(9839):358-65. doi:10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. Last checked February 14, 2014. ↑
- Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(11):1087-95. doi: 10.1016/S1470-2045(12)70431-X. Epub 2012 Oct 8. Last checked February 14, 2014. ↑
- Lito P, Pratilas CA, Joseph EW, et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 2012; 22(5):668-682. ↑
- Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013; 494(7436):251-5. ↑
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367(2):107-14. ↑
- Belum VR, Fischer A, Choi JN, Lacouture ME. Dermatological adverse events from BRAF inhibitors: a growing problem. Curr Oncol Rep 2013; 15(3):249-259. ↑
- Rosen A, Amitay-Laish I, Lacouture ME. Management algorithms for dermatologic adverse events, in Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients. M.E. Lacouture, Ed. 2013. chapter 33:367-383. Published Online: 30 NOV 2013. DOI: 10.1002/9781118590638. 2014 by John Wiley & Sons, Inc, Hoboken, NJ. ↑
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367(18):1694-703. ↑
- Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Canc Res 2010; 70(13). ↑
- Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Canc Res 2012; 18(5):1386-94. ↑
- Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013; 368(14):1365-6. ↑