Dabrafenib and Trametinib, Alone and in Combination for BRAF-Mutant Metastatic Melanoma

Published OnlineFirst February 28, 2014; DOI: 10.1158/1078-0432.CCR-13-2054

Clinical Cancer CCR Drug Updates Research

Alexander M. Menzies and Georgina V. Long

Abstract Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAFV600E metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor–na€ve patients with BRAFV600E or BRAFV600K also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma. Clin Cancer Res; 20(8); 2035–43. 2014 AACR.

Introduction BRAFV600E melanoma. In 2013, the approval of dabrafenib and trametinib for BRAF-mutant metastatic melanoma in The mitogen-activated protein kinase (MAPK) pathway is V600E V600E/K constitutively activated in the majority of melanomas as a the United States (BRAF for dabrafenib, BRAF result of molecular alterations in genes encoding key com- for trametinib) increased the number of available effective BRAF ponents of the pathway (e.g., BRAF and NRAS mutations) systemic treatments for -mutant metastatic melanoma KIT to four. In early 2014, the combination of dabrafenib and or upstream cell-surface receptors (e.g., ), resulting in V600E/K uncontrolled tumor proliferation and survival (1). Approx- trametinib was approved for BRAF melanoma. This imately 40% to 50% of cutaneous melanomas harbor review outlines the development of dabrafenib and trame- mutations in BRAF (2). Mutations most commonly occur tinib as monotherapies and in combination, and places in exon 15, at codon 600 (BRAFV600), with more than 75% these new drugs in context with approved treatments. characterized by substitution of valine by glutamic acid at residue 600 (BRAFV600E). Less-frequent mutations include Dabrafenib BRAFV600K (valine by lysine, 10% to 30%), BRAFV600R Drug design and preclinical activity (valine by arginine, 1% to 7%), and BRAFK601E (lysine by Dabrafenib (GSK2118436) is a reversible and potent glutamic acid at residue 601, 1% to 4%; ref. 3). ATP-competitive inhibitor that selectively inhibits the In 2011, two drugs were approved by the U.S. Food and BRAFV600E kinase. The drug concentration required for V600E Drug Administration (FDA) for American Joint Committee 50% inhibition of BRAF kinase activity (IC50)is5- on Cancer (AJCC) stage IIIC unresectable and IV melano- times lower than that for BRAFwt or CRAF (4). Preclinical ma—ipilimumab, for all melanoma, regardless of BRAF data demonstrated that dabrafenib inhibited the MAPK mutation status of the tumor, and vemurafenib, for pathway in BRAFV600E melanoma cells, leading to decreased proliferation and regression in xenograft mouse models (4).

Authors' Affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, Australia Clinical trials Phase I trial (BREAK-1). Clinical trials of dabrafenib Corresponding Author: Georgina V. Long, Melanoma Institute Australia, University of Sydney, 40 Rocklands Road, North Sydney, NSW 2060, began in 2009. Initial results were presented in 2010, with Australia. Phone: 61-299-117-200; Fax: 61-299-549-435; E-mail: final results published in 2012 (5). The trial began with dose [email protected] titration from 12 mg daily until the recommended phase II doi: 10.1158/1078-0432.CCR-13-2054 dose (RP2D) of 150 mg twice a day was defined. After 2014 American Association for Cancer Research. establishment of the dosage, expanded cohorts were added,

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including a metastatic melanoma cohort and a cohort of Phase II brain metastases trial (BREAK-MB). Following patients with asymptomatic untreated melanoma brain the efficacy seen in 10 patients in the phase I trial with metastases (3 mm size). Of 156 patients with melanoma previously untreated brain metastases, a dedicated phase II enrolled in the study, 131 were BRAFV600E, 18 BRAFV600K,2 study was conducted to further examine the effect of dab- K601E V600_K601E wt BRAF , 1 BRAF , 3 BRAF , and 1 had an rafenib in those with untreated, or previously treated but uncharacterized BRAF mutation (Table 1). progressed, brain metastases, i.e., active brain metastases The most common toxicities were fatigue, cutaneous (7). This trial enrolled patients with BRAFV600E or effects (including palmar-plantar hyperkeratosis, actinic BRAFV600K melanoma with asymptomatic brain metastases. keratosis, and rash), and arthralgia. Rarely were these severe At least one brain metastasis needed to be 0.5 cm and 4.0 (Table 1). Notable toxicities included cutaneous squamous cm to be a measurable target lesion, and leptomeningeal cell carcinoma (cuSCC) or keratoacanthoma (11%) and disease was excluded. pyrexia (20%, 4% grade 3). Dose reductions occurred in 7% One hundred and seventy-two patients were enrolled in of patients. The maximum tolerated dose (MTD) was not two cohorts: (i) those without prior local treatment for reached at doses of up to 300 mg twice a day; however, a brain metastases (N ¼ 89) and (ii) those with brain metas- minority of patients developed dose-limiting effects at 300 tases previously treated with local therapy (surgery, stereo- mg twice a day (2 of 10 patients) and 200 mg twice a day (3 tactic radiosurgery, and/or whole brain radiotherapy) but of 20 patients). A RP2D of 150 mg twice a day was selected, with subsequent intracranial progression (N ¼ 83). as patients on 200 mg twice a day showed minimum Dabrafenib toxicity was similar to that seen in the earlier increase in drug exposure (AUC) with no increase in the trials, with the exception of intracranial hemorrhage, which proportion of patients with RECIST response, PET meta- occurred in 6% of patients, in both cohorts, in both bolic response, or MAPK inhibition (measured by pERK responding and progressive lesions, and did not seem expression on biopsy), and the development of some dose- higher than the background rate; thus, it was attributed to limiting events. the patient population rather than to the drug. V600 Of the 36 patients with BRAF melanoma treated at the Treatment responses were seen in both cohorts, and in RP2D, 25 (69%) had a RECIST response, and in 18 (50%) both BRAFV600E and BRAFV600K genotypes (Table 1). In this was confirmed on a subsequent scan. The response rate patients with BRAFV600E melanoma, the intracranial was higher in BRAFV600E patients (78%), than BRAFV600K response rates in untreated patients and in previously patients (22%), but the median PFS was similar (approx- treated patients were 39% and 31%, respectively, higher imately 5.5 months; Table 1). Nine of 10 patients with than in BRAFV600K patients (7% and 22%, respectively). V600 BRAF melanoma and previously untreated brain metas- The intracranial disease control rate (i.e., including tases showed a decrease in the size of their brain tumors, and RECIST-defined stable disease, partial response, and com- 4 patients achieved a complete response in the brain. This plete response) was 80% to 90% in BRAFV600E and 50% in was the first evidence that BRAF inhibitors were active BRAFV600K patients. In untreated BRAFV600E patients, the in melanoma brain metastases. No responses were seen in median PFS and OS was 3.7 and 7.6 months, respectively, K601E V600_K601E patients with BRAF or BRAF mutations or and in untreated BRAFV600K patients, 1.8 months and 3.7 those with wild-type BRAF. months, respectively (Table 1). Activity was also seen in Phase II trial (BREAK-2). The single arm, open label, patients with previously treated and progressed brain phase II trial recruited MAPK inhibitor–na€ve patients with metastases.Nodatawereavailableaboutthenatureof BRAFV600E or BRAFV600K metastatic melanoma (6). Patients disease progression, but a single institution substudy of with current or previous brain metastases were excluded. 23 patients reported that progression occurred in extra- Ninety-two patients were enrolled (76 BRAFV600E,16 cranial sites with ongoing intracranial disease control in BRAFV600K). Adverse events were similar to those seen in 30% (8). the phase I study, with arthralgia, cutaneous effects, pyrexia, The results of this trial were impressive when compared and fatigue being the most prevalent (Table 1). Most were with studies of other systemic agents, which reported mild, but led to dose reduction due in 22% of patients. response rates of less than 10%, PFS of less than 2 months Response rates were impressive in BRAFV600E patients and OS of 3 to 5 months (9). The findings suggest that (52%), but less so in BRAFV600K patients (13%), and only dabrafenib may be an effective adjunct for treatment of a minority of patients (16% BRAFV600E, 31% BRAFV600K) brain metastases (alongside surgery and radiotherapy), and had progressive disease at first assessment. Median PFS (6.3 that it warrants consideration as first-line therapy in patients months in BRAFV600E and 4.5 months in BRAFV600K with brain metastases, particularly if they are multiple or patients) and median OS (13.1 months in BRAFV600E and concurrent with rapidly progressing extracranial disease. 12.9 months in BRAFV600K patients) was longer than Phase III trial (BREAK-3). The phase III trial recruited reported for standard chemotherapies. Patients with patients with stage IV or unresectable stage IIIC BRAFV600E M1a/b disease appeared to have a greater degree of tumor melanoma (excluding BRAFV600K), with no prior therapy shrinkage and longer PFS than M1c disease, and the base- for advanced disease [apart from interleukin (IL)-2 in 1 line circulating free DNA (cfDNA) BRAFV600E mutation patient], and Eastern Cooperative Oncology Group fraction, which correlated with baseline tumor burden, (ECOG) performance score of 0 or 1 (10). Patients with inversely correlated with the response rate and PFS. a history of brain metastases required demonstration of

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Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2014 American Association for Cancer Research. www.aacrjournals.org Downloaded from Table 1. Summary of dabrafenib and trametinib clinical trial results

Dabrafenib þ Drug Dabrafenib Dabrafenib Dabrafenib Dabrafenib Trametinib Trametinib Trametinib trametinib (150/2) Phase 1 2 2 activea 312b 32 Published OnlineFirstFebruary28,2014;DOI:10.1158/1078-0432.CCR-13-2054

clincancerres.aacrjournals.org brain mets No. of melanoma patients 156 92 172 187c 97 57 214c 54 V600E 130 76 139 187 19 46 NR 47 V600K 18 16 33 0 6 8 NR 7 Other BRAF mutations 2 K601E 0 0 0 1 L597V 1 V600R 0 0 1 V600_K601E 1 K601E Efﬁcacy Untreated Previously treated and progressed Response rate (%) 78 V600E 59 V600E 39 V600Ed 31 V600Ed 59 40 25 22 76 22 V600K 13 V600K 7 V600Kd 22 V600Kd PFS (mo) 5.5 V600E 6.3 V600E 3.7 V600E 3.8 V600E 6.9 5.7 4.0 4.8 9.4 5.6 V600K 4.5 V600K 1.8 V600K 3.7 V600K on September 24, 2021. © 2014American Association for Cancer OS (mo) NR 13.1 V600E 7.6 V600E 7.2 V600E 18.2 NR 14.2 15.6 23.8 Research. 12.9 V600K 3.7 V600K 5.0 V600K Toxicity% (all grades; G3) cuSCC/KA 11 10 6 10 0007 Pyrexia 20 (4) 24 (3) 26 (6) 16 (3) NR NR NR 71 (5) Arthralgia 20 (0) 33 (1) (1) 19 (1) NR NR NR 27 (0) Fatigue 33 (2) 22 (1) (<1) 18 (1) 31 (4) 26 (2) 26 (4) 53 (4) Rashe 30 (0) 27 (1) (3) 30 (0) 88 (8) 75 (9) 57 (8) 27 (0) Diarrhoea 21 (0) 11 (1) (1) NR 45 (0) 52 (4) 43 (0) 36 (2) Serous retinopathyf NR NR NR NR 10 (0) 2 (0) 9 (<1) 2 (2) Cardiac NR NR NR NR 7 (0) (3) 7 (1) 0 Peripheral oedema NR NR NR NR 35 (0) 29 (3) 26 (1) 29 (0)

lnCne e;2()Arl1,2014 15, April 20(8) Res; Cancer Clin Dose reduction 7 22 32 28 12 15 27 58 Permanent discontinuation 0 NR 2 3 NR NR NR 9%

NOTE: For phase I trials, toxicity data are from all doing cohorts. Abbreviations: G3, grade 3 or greater; KA, cutaneous keratoacanthoma; mets, metastases; NR, not reported. Trametinib and Dabrafenib aActive indicates untreated, or previously treated but progressed brain metastases. bData from the BRAF inhibitor–naïve cohort. cNumber receiving drug. dInvestigator-assessed intracranial response rate. eNonspeciﬁc term for any skin rash, and includes hyperkeratosis (dabrafenib) and acneiform dermatitis (trametinib). fNo cases of retinal vein occlusion were reported in any patients with melanoma on the phase I to III trials of trametinib. 2037 Published OnlineFirst February 28, 2014; DOI: 10.1158/1078-0432.CCR-13-2054

Menzies and Long

stability for 3 months after local treatment (surgery or then be compared. Retrospective analysis of the vemurafe- stereotactic radiotherapy only). nib phase III trial demonstrated that 57 (8.6%) BRAFV600K Initial results were reported in mid 2012 (10), and patients had been enrolled, with response rates and survival updated in 2013 (11). Of note, 250 BRAFV600E patients similar to those reported in the phase II trial of dabrafenib were enrolled and randomized 3:1 to dabrafenib (n ¼ 187) (17). Neither drug has, therefore, been prospectively stud- or dacarbazine (n ¼ 63). Cross-over to dabrafenib upon ied in patients with BRAFV600K melanoma in a randomized progression was permitted in the dacarbazine arm. Most trial, but sufficient data exist to suggest that both drugs are patients receiving dabrafenib had ECOG performance sta- active, and likely equally active, in BRAFV600K melanoma. tus of 0 (66%), AJCC M1c disease (66%), and a normal Both drugs are also active in patients with BRAFV600R serum lactate dehydrogenase (LDH; 64%), which was sim- melanoma and there is a case report of response to vemur- ilar to the baseline characteristics of patients in the phase III afenib in BRAFL597R melanoma (18, 19). It, therefore, seems trial of vemurafenib (12). that patients with all forms of BRAFV600 mutations are likely The investigator-assessed response rate to dabrafenib was to benefit from BRAF inhibition. 59%, and median PFS in the dabrafenib arm was 6.9 Toxicity is the main difference between dabrafenib and months, compared with 2.7 months in the dacarbazine vemurafenib, although the drugs have not been compared arm. The median OS was 18.2 months in the dabrafenib head-to-head in a clinical trial. Cutaneous toxicities, includ- arm, and 15.6 months in the dacarbazine arm (Table 1). The ing rash, hyperkeratosis, cuSCC, and cutaneous keratoa- improved survival in the dacarbazine arm compared with canthoma, occur with both drugs, but have been reported to historic studies was attributed to the benefit of cross-over to occur less frequently in the dabrafenib trials. Of note, dabrafenib (59%) or treatment with vemurafenib (10%). cuSCCs were reported to occur in 19% of patients treated Twenty-five percent of patients on the dabrafenib arm with vemurafenib (12), and only in 5% with dabrafenib received ongoing BRAF inhibitor treatment after RECIST (10). Whether this difference was due to the drugs them- progression, potentially improving OS compared with the selves, or differences in trial design and clinical assessment phase III vemurafenib trial (13). is unknown (20). Other toxicities such as arthralgia and Toxicities were similar to those seen in the early-phase fatigue also seem to occur at a higher rate and grade with trials, the most common being cutaneous manifestations, vemurafenib. Photosensitivity (related to the chemical pyrexia, fatigue, and arthralgia. Dose reductions occurred in structure of the molecule and UVA exposure rather than 28% of patients, and 3% permanently discontinued dab- RAF inhibition) and hepatitis occur with vemurafenib but rafenib due to toxicity (Table 1). seldomly with dabrafenib, whereas pyrexia occurs more frequently and severely with dabrafenib than vemurafenib Comparisons with vemurafenib (10, 12, 21). The need for dose reduction or interruption Dabrafenib and vemurafenib are both selective type I due to toxicity is approximately 30% to 40% for both drugs, V600 BRAF inhibitors, with proven efficacy in BRAF meta- but only a minimal number of patients treated with either static melanoma. Unlike dabrafenib, which is more selec- drug permanently discontinue therapy due to toxicity. tive for BRAFV600E than wild-type RAF kinases, vemurafenib Another BRAF inhibitor, LGX818, is also in development has similar potency for CRAF, wild-type BRAF, and (22). Initial data from a phase I trial (n ¼ 54) suggest that it BRAFV600E (14). Furthermore, unlike dabrafenib, vemura- is active, and may have a more favourable toxicity profile fenib reached the MTD in the phase I trial. Despite these than vemurafenib or dabrafenib, with photosensitivity and differences, the reported efficacy is similar in BRAFV600E pyrexia reported in less than 10% of patients, and cuSCC in patients, with response rates of approximately 55% to 60%, less than 5% thus far. and median PFS of 6 to 7 months. The differences in median OS reported between vemurafenib (13.6 months) and Trametinib dabrafenib (18.2 months) are likely influenced by the Drug design and preclinical activity availability and use of treatments received after disease Trametinib (GSK1120212) is a reversible allosteric progression, such as ongoing treatment with BRAF inhibi- inhibitor of MEK1 and MEK2 activation and kinase activ- tors "beyond progression," ipilimumab, and trials of highly ity, with preclinical evidence of MAPK inhibition and active PD-1 antibodies, rather than true differences in growth inhibition in BRAFV600E melanoma cell lines and efficacy. The two drugs also have similar intracranial activ- xenografts (23). ity, as vemurafenib has a response rate of 29% in untreated patients, disease control rate of 73%, median PFS of 3.7 Clinical trials months, and OS of 6.5 months (15, 16). Phase I trial. The phase I trial commenced in 2008, and Vemurafenib was codeveloped with the Cobas 4800 of 206 patients, 97 had metastatic melanoma with no V600 mutation test, designed to accurately detect the restriction of eligibility by somatic mutations, for example BRAFV600E mutation, but it can also detect a proportion of BRAF mutations. Thirty-six patients had BRAF-mutant mel- BRAFV600K mutations. Initially, it was thought that almost anoma and 39 had wild-type BRAF melanoma (7 of whom all patients on the phase III trial of vemurafenib were had an NRAS-mutant melanoma), 6 had unknown BRAF BRAFV600E (12). The phase III dabrafenib trial was thus status, and 16 patients had uveal melanoma (24, 25). Dose designed to only include BRAFV600E, such that results could titration commenced at 0.125 mg, with dose-limiting

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toxicities observed at total daily doses of 3 mg and 4 mg, and patients were enrolled and randomized 2:1 to trametinib the RP2D was 2 mg once daily. At this dose, analysis of 2 mg daily (n ¼ 214) or chemotherapy (dacarbazine or biopsies taken early during treatment and compared with paclitaxel, n ¼ 108). Cross-over to trametinib upon pro- baseline samples showed that there was effective inhibition gression was permitted in the chemotherapy arm. Most of MAPK signaling as measured by phosphorylated extra- patients receiving trametinib had ECOG performance status cellular signal–regulated kinase (ERK; 60% reduction), of 0 (64%), AJCC M1c disease (67%), and a normal serum effective inhibition of proliferation (Ki67 reduced by LDH (63%). Thirty-three percent had received one prior 80%), and an increase in cell-cycle inhibition (p27 line of chemotherapy, and 4% had a history of treated and increased by 170%). stable brain metastases. The most frequent toxicities included MEK inhibitor The response rate to trametinib was 22%, and median PFS class-like toxicities such as an acneiform rash (88%), diar- in the trametinib arm was 4.8 months, compared with 1.4 rhoea, peripheral oedema, and fatigue (Table 1). In the trial months of PFS in the chemotherapy arm. The median OS of 206 patients with solid tumors, ocular toxicities occurred was 15.6 months in the trametinib arm, and 11.3 months in in 15% (n ¼ 31) of patients, including reversible central the chemotherapy arm (in which 65% crossed over to serous retinopathy (n ¼ 3) and rarely irreversible retinal trametinib upon progression). On both arms, most patients vein occlusion (n ¼ 1). Transient left ventricular dysfunc- received additional therapy after trametinib progression, tion was noted in 8% (n ¼ 16) of patients. Twelve percent of including a vemurafenib (20%–30%, for a median of 15–18 patients treated at 2 mg required dose reductions, most weeks) and ipilimumab (10%–20%, for a median of 9 commonly due to rash. weeks). The RECIST-defined response rate was 40% in the 30 Toxicities were similar to those in the earlier trials, patients with BRAF inhibitor–na€ve metastatic melanoma, including MEK inhibitor class-like effects such as rash, but only 17% in those with prior BRAF inhibitor treatment diarrhoea, peripheral oedema, hypertension, and transient (n ¼ 6) and 10% in wild-type BRAF patients (n ¼ 39). None mild cardiac dysfunction. Chorioretinopathy was rare (<1% of 7 NRAS-mutant patients or 16 patients with uveal mel- grade 3), and no cases of retinal vein occlusion were anoma had a response (25). One patient with BRAFL597V reported. Most toxicities were mild and did not require melanoma had a confirmed partial response and remained drug discontinuation; however, 27% of patients underwent on treatment for more than 2 years. dose reduction. Phase II trial. A phase II study in 97 patients with BRAFV600E/K metastatic melanoma with or without prior Other MEK inhibitors in development BRAF inhibitor treatment demonstrated a response rate of Several other MEK inhibitors are in clinical development 25% (n ¼ 57) in BRAF inhibitor–na€ve and 0% (n ¼ 36) in for metastatic melanoma, including selumetinib, MEK162, those treated after BRAF inhibitor failure (the 2 patients GDC-0973, and pimasertib. Trametinib is the only drug who responded had not progressed on prior BRAF inhib- that has undergone phase III trials as monotherapy in BRAF itor, but ceased due to toxicity; ref. 26). In BRAF inhibitor– patients with -mutant metastatic melanoma, but na€ve patients, the median PFS was 4.0 months, and median monotherapy phase II trials of selumetinib and MEK162 OS was 14.2 months. In contrast, in those with prior BRAF have been reported (29–31). As with trametinib, most drugs inhibitor treatment, the median PFS was only 1.8 months, are being investigated in combination with other targeted and median OS 5.8 was months, indicating that sequencing drugs (outlined below), and a randomized phase II trial of of treatment from BRAF inhibitor to trametinib was not selumetinib in combination with dacarbazine reported effective. One patient had BRAFK601E melanoma, and had a improved median PFS (5.6 months) than dacarbazine partial response to trametinib, and a PFS of 32 weeks. monotherapy (3.0 months; ref. 32). As in the phase I trial, adverse events were common and usually mild, with skin toxicity (acneiform rash, pruritis), The Current Treatment Approach for BRAF- diarrhoea, and peripheral edema being the most common. Mutant Metastatic Melanoma Ocular toxicity was rare, 2% of patients had reversible Two classes of treatments are currently available for central serous retinopathy, no patients developed retinal patients with BRAF-mutant melanoma, MAPK inhibitors vein occlusion, and 3% of patients had grade 3 reversible and ipilimumab. Ipilimumab can induce tumor regression reduction in left ventricular function. and provide durable benefit in only a subset of patients, Phase III trial (METRIC). The phase III trial recruited with data from the phase III trial suggesting greatest efficacy patients with stage IV or unresectable stage IIIC BRAFV600E/K in patients with lower disease burden (33). Conversely, melanoma, with up to one prior therapy for advanced BRAF inhibitors induce rapid tumor regression in the disease (excluding MAPK inhibitors and ipilimumab), and majority of patients, but subsequent resistance is near ECOG performance score of 0 or 1 (27). Patients with stable universal, and the majority of patients progress after 6 to brain metastases were eligible, but those with a history of 7 months. Retrospective studies suggest that there is little retinal vein occlusion or central serous retinopathy were benefit from ipilimumab treatment after BRAF inhibitor excluded. disease progression (34, 35). For patients with rapidly Initial results were presented in 2012 (27), with an update progressive symptomatic disease, there is little debate that in 2013 (28). Of note, 281 BRAFV600E and 40 BRAFV600K BRAF inhibitors are the current approved treatment of

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choice; however, it can be argued that in patients with low of BRAF inhibitors (and have not yet progressed on them), volume asymptomatic disease, ipilimumab therapy should or those with non-V600 exon 15 BRAF mutations such as be considered first-line, despite the fact that these patients BRAFK601E and BRAFL597V (25, 42), although the latter may may also derive the most benefit from BRAF inhibitors also be responsive to BRAF inhibitors (19). (6, 36). No studies to date have prospectively assessed the best sequence of therapy, and the first phase I trial of Combined Dabrafenib and Trametinib combined ipilimumab and vemurafenib was terminated because of excessive toxicity (37). Preclinical studies demonstrated that the combination of Among MAPK inhibitors, despite not being studied head- a BRAF and MEK inhibitor delayed the onset of resistance to-head, trametinib does not seem to be as effective as and increased apoptosis compared with BRAF inhibitor dabrafenib or vemurafenib in BRAFV600-mutant metastatic monotherapy (43). As both drugs target the MAPK pathway, melanoma. The phase II trametinib trial demonstrated that the aim of combined blockade was to (i) circumvent or treatment with trametinib after BRAF inhibitor progression delay acquired resistance that occurs due to reactivation of is not effective (38). In contrast, BRAF inhibitors may have the MAPK pathway and (ii) reduce the toxicities seen with benefit after trametinib, as observed in a subgroup of monotherapy, especially the cutaneous toxicity from BRAF patients on the phase III trametinib study who received inhibitors that occur due to paradoxical activation of the vemurafenib for several months after trametinib progres- MAPK pathway in BRAF wild-type keratinocytes (20). sion, as well as data from 23 patients at a single institution Dabrafenib and trametinib (CombiDT) was the first (39). Dabrafenib and vemurafenib resistance mechanisms combination of a BRAF and MEK inhibitor to be tested in are similar (40), therefore, treatment with one drug after clinical trials. Data were first published in 2012 (44) with progression on the other is unlikely to result in tumor updates presented in 2013 (45, 46). In the randomized regression, but there are data to suggest that ongoing BRAF phase II trial (part C), MAPK inhibitor–na€ve patients with inhibitor treatment beyond disease progression may be BRAF-mutant melanoma (n ¼ 54) on "full dose" CombiDT beneficial in certain scenarios (41). The best approach, 150/2 (dabrafenib at 150 mg twice daily and trametinib at however, may be combined BRAF and MEK inhibition 2 mg daily) had improved outcomes compared with those therapy up front (discussed below). Currently, the main with dabrafenib monotherapy. The response rate was sig- role for trametinib is limited to patients who are intolerant nificantly higher at 76% versus 54%, no patients had

CombiDT 9.4 (76%)

Dabrafenib 6.9 (59%)

Vemurafenib 6.9 (57%) Figure 1. Response rate and median PFS of MAPK inhibitors for BRAF-mutant melanoma. , These data are derived from a subgroup of Trametinib 4.0 patients who progressed on a (22%) BRAF inhibitor (BRAFi) and were still well enough to receive second-

Drug (response rate) line targeted therapy. The addition CombiDT after of the median PFS for this 3.6 dabrafenib (9%)* treatment to the dabrafenib median PFS is not accurate.

Trametinib after 1.8 BRAFi (0%)*

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Median PFS (mo)

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progressive disease as best response, the median PFS was cacy than BRAF inhibitor monotherapy, little efficacy in significantly longer at 9.4 months versus 5.8 months, and BRAF inhibitor–resistant patients, and different toxicity median OS was an impressive 23.8 months on the Com- profiles to CombiDT (48, 49). biDT arm (Table 1; ref. 46). The response rate to combination treatment in those who crossed over after progres- Conclusions and Future Directions sing on dabrafenib monotherapy was only 9%, suggesting Dabrafenib and vemurafenib are currently the standard that patients are best suited to combination treatment up BRAF inhibitors for BRAF-mutant metastatic melanoma, front (45). distinguished mainly through their toxicity profiles rather BRAF inhibitor class toxicities were less frequent, includ- than clinical efficacy. Trametinib is less effective, and is most ing hyperkeratosis, alopecia, arthralgia, and rash. Notably, suitable for patients intolerant to BRAF inhibitors or those the rate of cuSCC with CombiDT was one third that of with L597 or K601 BRAF mutations. Use of trametinib after dabrafenib monotherapy (7% vs. 19%, respectively). The BRAF inhibitor progression is not effective, and although most common toxicity was pyrexia, which occurred in 71% there is some efficacy of BRAF inhibitors after trametinib of patients (5% grade 3/4) treated with CombiDT 150/2 failure, and CombiDT after BRAF inhibitor failure, the best (44). Fifty-eight percent of patients underwent dose reduc- approach is up-front combination therapy (Fig. 1). The recent tions, many temporary with subsequent dose reescalation, FDA approval of CombiDT now means that this is the current and the majority were due to pyrexia. The pathogenesis of standard MAPK inhibitor treatment of choice. Several emerg- pyrexia is incompletely understood, but one study sug- ing treatments, including other BRAF and MEK inhibitor gested that it generally occurs early, is often repetitive, can combinations, inhibitors of the PD-1/PD-L1 immune axis, be managed with brief dose interruption and corticosteroid and other cell signaling pathway inhibitors, used alone and in prophylaxis (in recurrent cases), and may not necessitate combination with current drugs, will no doubt change the dose reduction (47). treatment paradigm further in the near future. Until then, Two phase III trials of CombiDT have completed recruit- there are now several standard treatment options for patients ment and results are expected shortly, comparing Com- with melanoma, with a vast array of clinical trials also biDT 150/2 with dabrafenib (NCT01584648) and vemur- available that hope to improve outcomes further. afenib (NCT01597908) monotherapy, and an adjuvant trial in high-risk stage III melanoma is underway (NCT01682083). In the interim, the FDA has approved Disclosure of Potential Conflicts of Interest CombiDT for patients with BRAFV600E/K melanoma based A.M. Menzies reports receiving speakers bureau honoraria from Roche and has provided expert testimony for GlaxoSmithKline. G.V. Long reports upon the impressive phase II data. Other BRAF and MEK receiving speakers bureau honoraria from GlaxoSmithKline and Roche and is inhibitor combinations are concurrently in phase III trials a consultant/advisory board member for GlaxoSmithKline, Roche, Bristol- [vemurafenib and cobimetinib (NCT01689519), and Myers Squibb, Novartis, and Amgen. LGX818 and MEK162 (NCT01909453)]. Preliminary Received December 10, 2013; revised February 17, 2014; accepted Feb- phase I results of these combinations suggest higher effi- ruary 22, 2014; published OnlineFirst February 28, 2014.

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www.aacrjournals.org Clin Cancer Res; 20(8) April 15, 2014 2043

Dabrafenib and Trametinib, Alone and in Combination for BRAF -Mutant Metastatic Melanoma

Alexander M. Menzies and Georgina V. Long

Clin Cancer Res 2014;20:2035-2043. Published OnlineFirst February 28, 2014.

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