Brought to you by the publisher of PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM Recent Advances and Emerging Therapies In the Systemic Treatment of Metastatic Melanoma ll A s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig JEFFREY T. YORIO, MD Fellow, Hematology and Oncology KEVIN B. KIM, MD Associate Professor Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas M elanoma, the malignant transformation of melanocytes, most commonly occurs in the skin but also may arise from the mucosal surfaces or in the choroid of the eyes. Melanoma is the fifth and sixth most common cancer in men and women, respectively, in the United States.1 In 2012, more than 76,000 people will be diagnosed with malignant melanoma, and more than 9,000 people will die from the disease nationally.1 I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G agent’s ability to induce a durable response. Unfortunately, this response is observed in only a small subset of patients, and IL-2 is associated with significant toxicities, such as capillary leak syndrome, that frequently require intensive monitoring in a dedicated unit or intensive care facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine, paclitaxel, carmustine, and lomustine (CeeNu, BristolMyers Squibb)—are commonly used off-label to treat melanoma, but none of these agents or their various combinations have been found to offer a survival advantage over dacarbazine alone.9 Clearly, more active and d. Although surgery offers a great cure rate for patients with early-stage melanoma, those who have either metastatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4 Dacarbazine remains the only cytotoxic chemotherapy that is FDA-approved for the treatment of metastatic melanoma. However, dacarbazine has modest clinical efficacy, with a response rate of only about 10%.2,4-6 The FDA also has approved high-dose interleukin-2 (IL-2) for the treatment of advanced melanoma because of the C L I N I C A L O N C O L O G Y N E W S • J U LY 2 0 1 2 1 less toxic drugs are needed for patients with advanced melanoma. In this article, we review recent advances and emerging therapeutic approaches in the systemic treatment of metastatic melanoma. Newly Approved Drugs For Late-Stage Melanoma IPILIMUMAB ll A Immunotherapy has been used to treat melanoma for decades. Cancer cells, such as those that make up melanoma, have tumor-associated antigens that can be recognized by T cells. This recognition leads to a host response that targets the tumor cells.10 The standard immunotherapy, high-dose IL-2, enhances this response but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively sought to identify and develop more effective immunologic agents with better safety profiles. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells. T-cell activation begins when the T-cell receptor binds to an antigen presented by a major histocompatibility complex on antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7 (CD80/CD86) found on antigen-presenting cells, leading to T-cell proliferation and IL-2 production. As T cells become activated, CTLA-4 is upregulated to the cell surface, where it competes successfully with CD28 for B7 to halt further cell proliferation in a self-regulatory mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7 molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and IL-2 production.13,14 Ultimately, this can help increase the immune response to cancer cells. Initial clinical studies revealed that ipilimumab could be a promising new therapy for metastatic melanoma.15,16 A Phase I/II trial of ipilimumab (≤10 mg/kg every 3 weeks) in 23 patients with metastatic melanoma demonstrated a disease control rate of 39%, with at least 2 patients experiencing a durable response of longer than 21 months.15 These encouraging results led to several Phase III trials of ipilimumab in patients with metastatic melanoma (Table 1).17,18 In the first Phase III study of ipilimumab, 676 previously treated patients with unresectable stage III or IV melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab with a glycoprotein 100 (gp100) peptide vaccine (n=403), ipilimumab alone (n=137), or the gp100 peptide vaccine alone (n=136).17 Ipilimumab was given at a dose of 3 mg/kg every 3 weeks for 4 doses. The median OS of patients who received ipilimumab alone (10.1 months) was significantly longer than that of patients who received the gp100 vaccine alone (6.4 months; hazard ratio [HR], 0.66; P=0.003). s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the FDA’s approval of the drug for the treatment of metastatic melanoma in March 2011. In the second Phase III study of ipilimumab, 502 treatment-naive patients with metastatic melanoma were randomized to receive dacarbazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses. During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS duration of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacarbazine alone (P=0.006). As with other immune-stimulating agents, ipilimumab induces immune-related adverse events (AEs). In the first Phase III trial, the most common immune-related AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diarrhea and colitis was seen in 5% of the patients. The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen in 21% and 17%, respectively. Endocrine immune-related AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon. Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive highdose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-α antibody, has been used with some success to treat patients who are unresponsive to high-dose steroids. The use of highdose IV corticosteroids also has been suggested for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies. I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G d. 2 Table 1. Clinical Data From Positive Phase III Studies of Melanoma N Treatment Setting Primary End Point Results Hazard Ratio (95% CI) gp100 vaccine 136 Second-line OS, 6.4 mo Reference Ipilimumab 137 OS, 10.1 mo 0.66 (0.51-0.87) 0.003 Ipilimumab + gp100 vaccine 403 OS, 10.0 mo 0.68 (0.55-0.85) <0.001 OS, 9.1 mo Reference OS, 11.2 mo 0.72 (0.59-0.87) OSa Reference Trial and Regimen P Value NCT00094653 ll A NCT00324155 Co rig Dacarbazine + placebo First-line 250 ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Dacarbazine + ipilimumab 252 <0.001 s NCT01006980 Dacarbazine 338 Vemurafenib 337 Dacarbazine Vemurafenib First-line; V600E BRAF mutation a OS 0.37 (0.26-0.55) 338 PFS, 1.6 mo Reference 337 PFS, 5.3 mo 0.26 (0.20-0.33) PFS, 2.7 mo Reference PFS, 5.1 mo 0.30 (0.18-0.51) PFS, 1.5 mo Reference PFS, 4.8 mo 0.45 (0.33-0.63) <0.001 <0.001 NCT01227889 (BREAK-3) Dacarbazine 63 Dabrafenib 187 First-line; V600E BRAF mutation <0.0001 NCT01245062 (METRIC) Chemotherapyb 108 Trametinib 214 ≤1 prior systemic therapy; V600E BRAF mutation <0.001 CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival a b Inadequate number of patients in follow-up to provide reliable estimates of the survival curve Dacarbazine or paclitaxel VEMURAFENIB d. The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, which codes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most BRAF mutations are the result of a single nucleotide substitution in which valine is replaced by glutamic acid at codon 600 (V600E) of exon 15, leading to the constitutive activation of the MEK protein and ERKs, which are essential to melanoma cell proliferation. Melanoma cells with the BRAF mutation do not require Ras activation to proliferate, indicating that the BRAF mutation is a driving force behind melanoma cell growth. To inhibit the Raf/MEK/ERK pathway, researchers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth factor receptor (VEGFR). However, 2 Phase II trials of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additionally, the presence of the BRAF mutation was not correlated with response.21,22 Similarly, 2 large randomized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional clinical benefit in patients with metastatic melanoma.23,24 Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the mutated Raf kinase. One of these new drugs, PLX4032 (later named vemurafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A first-in-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melanoma harboring a BRAF mutation were then enrolled in the dose-extension cohort and received vemurafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, a large Phase II study of vemurafenib was conducted in 132 previously treated patients who had metastatic melanoma harboring a V600E BRAF I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G 3 Cell membrane receptor PI3K Ras PTEN A AKT ll Raf mTOR ERK 1/2 IF4E s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig MEK 1/2 Cyclin D1 Transcription factors p70 MMP-2 Tumor cell survival, proliferation, invasion Nucleus Figure. Commonly activated signal transduction pathways in melanoma. ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin 4 I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G of patients experienced grade 2 or 3 photosensitivity reactions, but the use of sunblock helped prevent the blistering typically observed in grade 3 reactions. Eighteen percent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoacanthomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs. These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrated that the binding of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actually leads to transactivation of adenosine triphosphate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated when vemurafenib binds to wild-type BRAF.28,29 Based on the statistically significant improvement in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic melanoma harboring a V600E d. mutation.27 The ORR, which was validated by an independent review committee, was 53%, with a median PFS duration of 6.8 months, thus confirming the promising results of the Phase I study. A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacarbazine in treatment-naive patients with metastatic melanoma harboring a V600E BRAF mutation (Table 1).5 Six hundred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of the interim analysis so that patients in the dacarbazine arm could receive vemurafenib. Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma Trial and Regimen Primary End Point N V600E BRAF mutation PFS 340 First-line V600E/K BRAF mutation OS 694 First-line C-Kit (juxtamembrane) OS 200 First-line Any OS 700 Treatment Setting Mutation Criteria First-line NCT01584648 Dabrafenib (GSK2118436) plus trametinib (GSK1120212) versus dacarbazine NCT01597908 ll A Dabrafenib plus trametinib versus vemurafenib (Zelboraf, Roche) Co rig NCT01280565 s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Masitinib versus dacarbazine NCT01515189 Ipilimumab (3 mg/kg) versus ipilimumab (10 mg/kg) OS, overall survival; PFS, progression-free survival BRAF mutation. However, despite the high response rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed. Emerging Targeted Therapies SELECTIVE RAF INHIBITORS MEK INHIBITORS Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstream of BRAF kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but also by kinase-activating NRAS mutations or other upstream aberrations, such as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway. The results of clinical trials of first-generation MEK inhibitors were disappointing. For example, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein occlusion, which resulted in the discontinuation of their d. The successful development of vemurafenib has generated great interest in the clinical evaluation of selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent, dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, investigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic melanoma harboring a V600 BRAF mutation and received at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33 Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melanoma harboring a V600E/K BRAF mutation.34 Of these 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks. The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin. Recently, a Phase III study (NCT01227889) was conducted to compare the PFS associated with dabrafenib to that associated with dacarbazine in treatment-naive patients with V600E BRAF-mutated melanoma. The results demonstrated that patients who received dabrafenib had a significantly longer median PFS over dacarbazine (6.7 vs. 2.9 months, respectively; HR, 0.35, 95% confidence interval [CI], 0.20-0.61).35 The ORR also was superior in the dabrafenib arm (50% vs. 6%). The OS data are not available because the study was not designed to compare the OS, and the follow-up thus far is too short for OS evaluation. Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly. I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G 5 ll A development. 36,37 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibitor of MEK1/2. Although in vitro studies revealed that melanoma cell lines containing a BRAF mutation were particularly sensitive to selumetinib,38,39 a randomized Phase II study showed that the drug had no clinical benefit over temozolomide in chemotherapy-naive patients with metastatic melanoma.40 The differences in the median PFS duration (78 vs 80 days) and ORR (5.8% vs 9.4%) between the patients who received selumetinib and those who received temozolomide, respectively, were not statistically significant, and the response rates among patients with melanoma containing a BRAF mutation in each group were both the same, at 11%. Clinical outcomes with the next-generation, hydrogen sulfate (Hyd-sulfate) formulation of selumetinib, which has better oral bioavailability than does the original crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hydsulfate selumetinib to be 75 mg twice daily.41 In a separate Phase I study of combination regimens containing Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF mutation had a higher clinical response rate and longer median time to progression than did those without a BRAF mutation, suggesting that BRAF mutation is a positive predictive factor for Hyd-sulfate selumetinib.42 A randomized Phase II study comparing dacarbazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatment-naive patients with BRAF-mutated melanoma (NCT00936221) recently completed patient accrual, and the results of this study are highly anticipated. Another potent, highly selective, non–ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212, GlaxoSmithKline). Although a Phase I study revealed the MTD of trametinib to be 3 mg per day, 2 mg per day was chosen as the recommended dose for future studies on the basis of pharmacokinetic, clinical activity, and safety data.43 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with metastatic melanoma harboring a V600 BRAF mutation are encouraging.44 In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a V600E BRAF mutation and 75% had M1c disease), 14 (25%) had a confirmed response, and the median PFS duration was 4 months (CI, 3.5-5.6 months). However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mechanisms s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig of resistance to BRAF inhibitors also might confer resistance to MEK inhibitors. The results of an open-label randomized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacarbazine or paclitaxel in patients with metastatic melanoma harboring a V600 BRAF mutation was recently announced (Table 1). The trametinib arm had a statistically significant improvement in all 3 clinical parameters (RR, PFS and OS).45 The median PFS was 4.8 months for the trametinib arm compared with 1.4 months for the chemotherapy arm (HR, 0.44; CI, 0.310.64; P<0.0001). In addition, a HR for OS was 0.54 (CI, 0.32-0.92) with a P value of 0.0136, favoring the trametinib arm. Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech). The common AEs of MEK inhibitors include skin rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.36,37,40,41,43,44 Visual disturbances, such as blurry vision or flashing lights, are common but generally mild. Serious ocular toxicity, including central serous retinopathy and retinal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomatic and is reversible upon discontinuation of the drugs. I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced melanoma harboring a BRAF mutation, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisition of activating NRAS mutations,46 acquisition of activating MEK mutations,47 upregulation of upstream receptor kinases,48 upregulation of CRAF kinase,49 induction of splicing variants of BRAF kinase,50 increased Cot expression,51 and activation of PI3K/AKT signaling pathways.52,53 Loss of BRAF mutations and the development of secondary mutations to the drug-binding domain of BRAF kinase have not been observed at the time of drug resistance, however.46,48 A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was re-upregulated at the time of d. 6 COMBINATION STRATEGIES USING TARGETED THERAPIES ll A disease progression in a subset of patients.54 This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associated with resistance to the Raf inhibitors and can, at least partially, bypass the inhibition of the BRAF mutations. In vitro studies have shown that the addition of a MEK inhibitor can delay the development of drug resistance to a selective Raf inhibitor.47 On the basis of these encouraging findings, a Phase I study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma. The clinical data generated from the study’s interim analysis are promising.55,56 Given at the recommended doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diarrhea, and fatigue.55 Skin toxicity, including the development of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxically activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who had metastatic melanoma containing a V600E/K/D BRAF mutation and who had never received a BRAF inhibitor, 43 (66%) had objective responses, including 5 (8%) CRs.55 Of the 26 patients who previously had been treated with a selective Raf inhibitor, 5 (19%) had partial responses.56 The updated results of the Phase II study showed that median PFS was 10.8 months among 24 BRAF inhibitor-naive patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily.57 s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 12 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig melanoma harboring KIT mutations.65-68 Additionally, the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma harboring a KIT mutation had a clinical response to the drug.69 However, none of 10 patients with KIT amplification without a mutation had a response. In another Phase II study of imatinib in 43 patients with metastatic melanoma harboring a KIT mutation or amplification, 10 (23%) patients had an overall clinical response, and 9 of the 10 responders had a KIT mutation in exon 11 or 13.70 In a separate Phase II study of imatinib in a similar population, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.71 The response rate among patients who had mutations affecting recurrent hotspots of the KIT gene or a higher KIT mutant-to-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these features was 0% (P=0.05), suggesting that the presence of a functionally relevant KIT mutation is required for imatinib or other KIT inhibitors to have clinical benefit. KIT INHIBITORS ANTI-PD1 ANTIBODY Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and is involved in T-cell regulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the antigen-presenting cells found in tumors), PD1 suppresses T-cell effector function. Tumoral PD-L1 expression has been associated with negative prognosis in cancer patients.72,73 MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, thereby reactivating T-cell function.74 In a Phase I dose-escalating study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well tolerated with only one serious AE (colitis).75 Of the 39 patients in the study, 3 patients, including one with metastatic melanoma, had a clinical response to MDX-1106. Another Phase I study evaluated the safety profile of a biweekly dosing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.76 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nausea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the preliminary response evaluation, 6 (38%) of 16 patients had objective responses; among these patients, 3 patients with metastatic melanoma had a partial response. The clinical investigation of MDX-1106 is ongoing. d. Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precursors,58,59 and KIT’s frequent expression in melanoma specimens59,60 led investigators to conduct 3 studies evaluating the use of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.61-63 Imatinib had minimal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug. Interest in KIT-targeted therapy in melanoma was renewed when Curtin et al showed that KIT mutation and/or amplification is more common in certain subtypes of melanoma than in others.64 In their analysis of 102 primary melanomas, they used a comparative genomic hybridization assay and found KIT mutations and/or increased copy numbers of KIT in 36% of acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chronically sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have Emerging Immunotherapies I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G 7 ADOPTIVE T-CELL THERAPY ll A In the mid-1980s, Rosenberg et al found that tumorinfiltrating lymphocytes (TILs) isolated from murine sarcomas and colon adenocarcinomas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of metastatic tumors.77 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a single dose of cyclophosphamide.78 Other researchers found that when the adoptive transfer of TILs and IL-2 infusion were preceded by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endogenous regulatory cells and lymphocytes competing with the transferred TILs for growth-promoting homeostatic cytokines, 6 of 13 patients had a clinical response.79 Notably, this approach resulted in the persistent clonal repopulation of T cells, which proliferated in vivo and traveled to tumor sites in these patients. In an expanded Phase II study conducted by the same group of investigators, lympho-depleting chemotherapy followed by TIL transfer and high-dose IL-2 infusion elicited a response rate of 51% among 35 patients with metastatic melanoma.80 When TIL transfer and IL-2 infusion were preceded by myeloablative chemoradiation (lympho-depleting chemotherapy plus 2 or 12 Gy of total-body irradiation), clinical activity of the regimen was even better, with response rates of 52% and 72%, respectively.81 Of 20 patients who had CRs in these trials of adoptive TIL transfer, only 1 patient’s disease has relapsed. 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