513009
research-article2013
AOPXXX10.1177/1060028013513009Annals of PharmacotherapyTrinh et al
Review Article
Dabrafenib Therapy for Advanced Melanoma
Annals of Pharmacotherapy 2014, Vol. 48(4) 519–529 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013513009 aop.sagepub.com
Van Anh Trinh, PharmD1, Jennifer E. Davis, PharmD1, Jaime E. Anderson, PharmD1, and Kevin B. Kim, MD1
Abstract Objective: To summarize the clinical development of dabrafenib and to highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib. Data Source: An English-language literature search of MEDLINE/ PubMed (1966-June 2013), using the keywords GSK2118436, dabrafenib, vemurafenib, selective BRAF inhibitor, and advanced melanoma, was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection and Data Extraction: All relevant published articles on dabrafenib and vemurafenib were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing studies. Data Synthesis: BRAFV600E mutation confers constitutive BRAK kinase activation in melanoma cells, promoting tumor growth. This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. Dabrafenib has been approved to treat patients with BRAFV600E-positive unresectable or metastatic melanoma based on its clinical benefit demonstrated in a randomized phase III study. It has also been shown to be safe and effective in patients with BRAF mutant advanced melanoma involving the brain. Dabrafenib is well tolerated, with the most common adverse effects being hyperkeratosis, headache, pyrexia, and arthralgia. Currently, there is no evidence to suggest that one BRAF inhibitor is superior to the other. With similar efficacy, therapy selection will likely be influenced by differential tolerability and cost. Conclusions: Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAFV600E-positive advanced melanoma. Active research is ongoing to expand its utility into the adjuvant setting and to circumvent rapid emergence of drug resistance. Keywords advanced melanoma, BRAF mutation, selective BRAF inhibitor, GSK2118436, dabrafenib, vemurafenib
Introduction In 2013, 76690 new cases of melanoma will be diagnosed in the United States, with projected deaths of 9480.1 Melanoma accounts for only 4% of all skin cancers; however, it is responsible for approximately 80% of all skin cancer deaths.2 The diagnosis of unresectable stage III or stage IV melanoma signals poor outcome, with a 1-year survival rate of 25% and median overall survival (OS) of 6.2 months.3 Until recently, treatment options for advanced melanoma have been extremely limited. Prior to 2011, dacarbazine and interleukin-2 (IL-2) were the only 2 agents approved by the US Food and Drug Administration (FDA) for the treatment of advanced or metastatic melanoma for more than 2 decades. Recent molecular insight into melanomagenesis has propelled drug development for advanced melanoma into the realm of genomic medicine. Vemurafenib, the first selective BRAF inhibitor approved in 2011, pioneers the effort of
personalizing cancer therapy for patients with advanced melanoma. At present, the class of selective BRAF inhibitors consists of 2 compounds: vemurafenib (Zelboraf, Genentech, South San Francisco, CA) and dabrafenib (Tafinlar, GlaxoSmithKline, London, UK). Both agents are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. This review will discuss the pharmacology, pharmacokinetics, and clinical experience of dabrafenib in patients with advanced melanoma. It will also highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib. 1
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Corresponding Author: Van Anh Trinh, PharmD, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0377, Houston, TX 77030, USA. Email: [email protected]
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Figure 1. Mitogen-activated protein kinase (MAPK) pathway and mechanism of dabrafenib: A. When extracellular growth factor binds to membrane-bound receptor tyrosine kinase, the MAPK signaling pathway is activated to promote proliferation and survival. B. V600E kinase is constitutively active, sustaining MAPK signaling and perpetuating growth. C. Dabrafenib inhibits V600E kinase, inducing apoptosis.
MAPK Pathway and Mechanism of Action of Dabrafenib (Figure 1) The mitogen-activated protein kinase (MAPK) pathway is an important signaling cascade regulating cell growth, differentiation, and survival. Normally, MAPK pathway activation begins with the binding of extracellular growth factors, such as epidermal growth factor, to membrane-bound receptor tyrosine kinases, such as epidermal growth factor receptor.4 Sequential phosphorylation of RAS, RAF, MEK, and ERK within the MAPK pathway communicates the growth signal downstream to the nucleus, inducing gene expressions to promote cell proliferation, differentiation, and survival. A decade ago, melanoma tumors were found to harbor genetic mutations in various components of the MAPK signaling pathway. BRAF mutation is the most common event, occurring in about 50% of melanomas.5 The 2 most prevalent mutant BRAF genotypes are BRAFV600E and BRAFV600K, representing 80% to 90% and 10% to 20% of all BRAF mutations, respectively.6,7 BRAFV600E and BRAFV600K are point mutations corresponding to the valineto-glutamic acid and valine-to-lysine substitutions at amino acid 600, respectively. BRAFV600E and BRAFV600K kinases are constitutively active, sustaining MAPK signaling and perpetuating cell growth. Phenotypically, BRAFV600E and
BRAFV600K confer aggressive behavior to melanoma cells8,9 and have been correlated with unfavorable survival outcome in patients with metastatic disease.7 There is also evidence to indicate an association between BRAF mutations and the frequency of central nervous system metastases at the time of stage IV diagnosis.6 Identification of activating BRAF mutations in melanoma tumors has fostered the development of selective BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of advanced melanoma. Blocking the mutation-driven constitutive activation of the MAPK pathway, these agents have been shown to improve the response rate and survival for patients with BRAFV600E-positive advanced melanoma in randomized phase III studies, leading to the FDA approval of vemurafenib in 2011 and dabrafenib in 2013.10-13 Besides mutant BRAF kinases, BRAF inhibitors also inhibit wildtype (nonmutated) BRAF and CRAF (another RAF isoform) enzymes. The in vitro half-maximal inhibitory concentration (IC50) values of dabrafenib for BRAFV600E, wild-type BRAF, and CRAF are 0.65, 3.2, and 5.0 nM,14 respectively, whereas the corresponding IC50 values of vemurafenib are 31, 100, and 48 nM.15 Because the IC50 value reflects the inhibitory potency of antagonistic compounds, the considerable difference among the IC50 values of dabrafenib suggests that dabrafenib may be more selective for BRAFV600E than wild-type
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Trinh et al BRAF and CRAF. Interestingly, BRAF inhibitors can paradoxically activate the MAPK pathway via heterodimerization of BRAF and CRAF kinases to promote growth in tumors harboring wild-type BRAF or activating RAS mutations.16-18 Therefore, BRAF inhibitor monotherapy should not be used in patients with advanced melanoma with wildtype BRAF or RAS mutation.
Pharmacokinetics After oral administration at fasting condition, dabrafenib achieves a mean absolute bioavailability of 95%, with a median time to peak plasma concentration (Tmax) of 2 hours and a mean terminal half-life of 8 hours. When taken with a high-fat meal, the maximum concentration of dabrafenib was reduced by 51%, and Tmax was prolonged by 3.6 hours. Thus, dabrafenib should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. Medications affecting gastric pH may decrease the solubility and, thus, the bioavailability of dabrafenib. Concurrent administration of dabrafenib with proton pump inhibitors, H2-receptor antagonists, or antacids is not recommended.14 Dabrafenib is highly bound to plasma proteins (99.7%) and has a large volume of distribution (70.3 L). The metabolism of dabrafenib is complex, occurring mainly through cytochrome P450 (CYP) 2C8 and CYP3A4. Two of the metabolites, hydroxy- and desmethyl-dabrafenib, are active and likely to contribute to the clinical activity of dabrafenib. Dabrafenib is primarily eliminated fecally. Mild to moderate renal dysfunction (creatinine clearance > 29 mL/min)14 or mild hepatic impairment (bilirubin ≤ 1.5 times upper limit of normal and aspartate aminotransferase of any value)19 do not appear to affect the systemic exposure of dabrafenib and its metabolites. Therefore, dosage adjustment is not needed in patients with mild to moderate kidney dysfunction or mild hepatic impairment. However, dabrafenib should be used with caution in the presence of severe kidney (creatinine clearance < 30 mL/min) or moderate to severe liver impairment because an appropriate dose of dabrafenib has not been established in these clinical scenarios. In vitro studies with human hepatic microsomes demonstrated that dabrafenib is a substrate of CYP3A4 and CYP2C8, whereas its active metabolites are substrates of CYP3A4. Dabrafenib is a moderate inducer of CYA3A4 and may also induce other enzymes. Concurrent administration of dabrafenib with strong CYP3A4 or CYP2C8 inhibitors or inducers and other CYP substrates with narrow therapeutic index should be avoided.14 From the pharmacokinetic standpoint, one clinically relevant dissimilarity exists between the 2 BRAF inhibitors, which relates to the influence of food on their absorption. The absorption of dabrafenib is affected by food; therefore, dabrafenib should be taken on an empty stomach. In contrast, vemurafenib can be administered with or without food.20
Clinical Trial Experience (Table 1) BREAK-121 The BREAK-1 trial was a 2-stage phase I dose-finding study of GSK2118436, later known as dabrafenib. The trial began with a dose escalation phase in patients with metastatic cancer of various tumor types to define the safety profile and to establish the recommended phase 2 dose (RP2D) of dabrafenib. Dose titration was done in conjunction with correlative pharmacokinetic and pharmacodynamic evaluations. Mutant BRAF status was initially not required for enrollment but became mandatory in the latter part of the study because of absence of drug activity in patients with wildtype BRAF. The maximum tolerated dose (MTD) of dabrafenib was not achieved in the dose range between 12 mg daily to 300 mg orally twice a day. Dose-limiting toxicities, manifesting as grade 3 cutaneous squamous cell carcinoma (cSCC), grade 3 syncope, and grade 2 pyrexia, were noted in 3 out of 20 patients treated at 200 mg twice daily. Because of the marginal increase in drug exposure, pharmacodynamic effects, and tumor response at 200 mg twice daily, the RP2D was set at 1 dose level lower, which was 150 mg twice daily. On determination of the RP2D, the expansion phase followed to evaluate the efficacy of dabrafenib in 3 different cohorts of patients with tumors positive for mutant BRAF: (1) individuals with metastatic melanoma without brain involvement; (2) individuals with stage IV melanoma with asymptomatic, untreated brain metastases; and (3) individuals with nonmelanoma solid tumors. Out of 36 patients enrolled in cohort 1, 25 (69%, 95% CI = 51.9-83.7) achieved an objective response, with median duration of response of 6.2 months (95% CI = 4.2-7.7). The response rate appeared to be higher in individuals with V600E-positive melanomas than those with V600K-positive tumors; however, median progression-free survival (PFS) duration was similar between the 2 groups. The median PFS duration was 5.5 months (95% CI = 3.5-9.5) in patients with V600E-positive melanoma and 5.6 months (95% CI = 3.9-10.8) in those with V600K-positive tumors. Intracranial tumor responses were observed in 9 out of 10 patients in cohort 2. Remarkably, 4 of them achieved complete resolution of all brain lesions. Modified Response Evaluation Criteria in Solid Tumors (RECIST) were used to assess intracranial response, which was determined by the percentage change from baseline in the sum of brain lesions of 3 mm or more. The median PFS for this cohort was 4.2 months (95% CI = 3.3-5.3), with 2 patients surviving more than a year.
BREAK-222 The BREAK-2 trial was a single-arm, phase II study conducted to verify the clinical activity of dabrafenib at 150 mg orally twice daily in 92 patients with BRAF mutant
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Table 1. Clinical Trial Summary.12,13,20-22 Study Population (n)
Treatment Regimen
Results
21
BREAK-1 (phase I, Falchook et al ): advanced solid tumors Escalation cohort (n = 110) 12 mg daily to 300 mg bid Expansion cohort 150 mg bid Melanoma, no brain metastasis (n = 36) Melanoma, brain metastasis (n = 10) BREAK-2 (phase II, Ascierto et al22): V600-mutant advanced melanoma V600E (n = 76) 150 mg bid
MTD: Not reached; RP2D: 150 mg bid ORR: 69% (95% CI = 51.9-83.7) • Median DOR: 6.2 months (95% CI = 4.2-7.7) • Median PFS: 5.5 months (95% CI = 4.1-8.3) • 9/10 Patients had reduction in size of brain metastasis • 4 Patients achieved CR intracranially
• ORR: 59% (95% CI = 48.2-70.3) • Median PFS: 6.3 months • Median OS: 13.1 months V600K (n = 16) • ORR: 13% (95% CI = 0.0-28.7) • Median PFS: 4.5 months • Median OS: 12.9 months BREAK-MB (phase II, Long et al7): V600-mutant metastatic melanoma involving the brain No prior local therapy to 150 mg bid brain lesions (n = 89) V600E (n = 74) • OIR: 39.2% (95% CI = 28.0-51.2) • Median PFS: 16.1 weeks (95% CI: 15.7-21.9) • Median OS: 33.1 weeks (95% CI: 25.6-NR) V600K (n = 15) • OIR: 6.7% (95% CI = 0.2-31.9) • Median PFS: 8.1 weeks (95% CI: 3.1-16.1) • Median OS: 16.3 weeks (95% CI: 6.9-22.4) Progression despite local therapy (n = 83) V600E (n = 65) • OIR: 30.8% (95% CI = 19.9-43.4) • Median PFS: 16.6 weeks (95% CI = 15.9-23.7) • Median OS: 31.4 weeks (95% CI = 25.7-NR) V600K (n = 18) • OIR: 22.2% (95% CI = 6.4-47.6) • Median PFS: 15.9 weeks (95% CI = 7.9-22.4) • Median OS: 21.9 weeks (95% CI = 15.3-NR) BREAK-3 (phase III, Hauschild et al12): V600E-positive advanced melanoma, previously untreateda Investigators’ assessment Arm A (n = 187) Dabrafenib 150 mg bid Median PFS: 5.1 months • Median PFS: 2.7 months Arm B (n = 63) Dacarbazine 1 g/m2 q3w • HR progression: 0.3 (95% CI = 0.18-0.51) Independent review panel’s assessment Arm A (n = 187) Dabrafenib 150 mg bid Median PFS: 6.7 months • Median PFS: 2.9 months Arm B (n = 63) Dacarbazine 1 g/m2 q3w • HR progression: 0.35 (95% CI = 0.2-0.61) Updated data at ASCO 2013 Arm A (n = 187) Dabrafenib 150 mg bid • Median PFS: 6.9 months • Median OS: 18.2 months • Median PFS: 2.7 mo Arm B (n = 63) Dacarbazine 1 g/m2 q3w • Median OS: 15.6 mo • HR progression: 0.37 (95% CI = 0.23-0.57) • HR death: 0.76 (95% CI = 0.48-1.21) Abbreviations: MTD, maximal tolerated dose; RP2D, recommended phase II dose; ORR, overall response rate; DOR, duration of response; PFS, progression-free survival; CR, complete response; HR, hazard ratio; OS, overall survival; OIR, overall intracranial response; NR, not reached; ASCO, American Society of Clinical Oncology. a Except high-dose interleukin-2.
stage IV melanoma; 76 patients carried V600E-positive tumors, whereas the remaining 16 individuals harbored V600K-positive melanomas. The majority of patients had
stage M1c disease and had been previously treated. Nearly all patients had undergone surgical interventions, and 84% of patients had received prior systemic therapies, which
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Trinh et al mostly involved dacarbazine or temozolomide. Per investigators’ assessment, the overall response rates were 59% and 13% in V600E and V600K subsets, respectively. The median PFS duration was 6.3 months in patients with V600E-positive melanomas and 4.5 months in those with V600K-positive tumors. Per independent reviewers’ assessment, the overall response rates were 41% and 25% in V600E and V600K subsets, respectively. The median PFS duration was 6.2 months in patients with V600Epositive melanomas and 4.5 months in those with V600Kpositive tumors.
BREAK-312 The BREAK-3 study was the pivotal randomized phase III trial conducted to confirm the clinical benefit of dabrafenib. In this trial, 250 patients with BRAFV600E-positive unresectable stage III or stage IV melanomas were randomly assigned 3:1 to receive either dabrafenib 150 mg orally twice a day continuously (n = 187) or dacarbazine 1 g/m2 intravenously every 3 weeks (n = 63). Previous therapy, except for IL-2, was not allowed. Patients initially assigned to receive dacarbazine were able to cross over to receive dabrafenib on disease progression. The primary end point of the study was investigator-assessed PFS. Secondary end points included PFS as assessed by an independent review committee, OS, objective response rate, duration of response and safety. At a median follow-up of 5.1 months and 3.5 months for those treated with dabrafenib or dacarbazine, respectively, 44% of the dacarbazine-treated patients had crossed over to the dabrafenib arm. Per investigators’ assessment, the median PFS was 5.1 months in the dabrafenib group and 2.7 months in the dacarbazine group, with the hazard ratio (HR) for progression of 0.30 (95% CI = 0.18-0.51; P < .001) favoring dabrafenib. The evaluation by the independent review panel revealed similar results, with a median PFS of 6.7 months for the dabrafenib group and 2.9 months for the dacarbazine group (HR = 0.35; 95% CI = 0.20-0.61). Median OS was not reached at this analysis. Objective response rate with dabrafenib was 53%, superior to 19% with dacarbazine. Updated survival data have recently been presented at the 2013 American Society of Clinical Oncology (ASCO) meeting, confirming the PFS advantage of dabrafenib.13 The updated median PFS was 6.9 months in the dabrafenib arm and 2.7 months in the dacarbazine arm, with the HR for progression of 0.37 (95 % CI = 0.23-0.57) favoring dabrafenib. The OS results were difficult to interpret because of the crossover effect. Median OS was 18.2 months and 15.6 months in the patients treated with dabrafenib and dacarbazine, respectively (HR = 0.76; 95% CI = 0.48-1.21). Of note, independent review was not continued beyond the primary analysis.
BREAK-MB23 The results of the BREAK-1 trial provided the rationale for BREAK-MB, a large phase II study evaluating the safety and efficacy of dabrafenib 150 mg orally twice daily in melanoma patients with brain metastases. A total of 172 patients with V600E- or V600K-positive advanced melanoma with at least 1 asymptomatic brain metastasis measuring 5 to 40 mm in diameter were assigned to 1 of 2 cohorts: patients who had not received local therapy for brain metastases were assigned to cohort A, whereas those with progressive intracranial disease despite local therapy went to cohort B. Half of the patients had 2 to 4 brain lesions, and 81% of them harbored V600E-positive melanomas. The primary end point of the study was investigatorassessed intracranial response in patients with V600Epositive melanomas. Secondary efficacy end points included intracranial response in patients with V600K-positive melanomas, overall response, duration of intracranial and overall response, PFS, and OS grouped by mutation subtype. Intracranial response to dabrafenib was 39.2% and 30.8% in patients with V600E-positive tumors in cohort A and cohort B, respectively. The response rate in the brain was lower in patients with V600K-positive tumors: 6.7% in cohort A and 22.2% in cohort B. Median durations of intracranial tumor regression lasted 20.1 and 28.1 weeks in cohort A and B for individuals with V600E-positive melanomas, respectively. Median durations of response in the brain were shorter for patients with V600K-positive tumors: 12.4 weeks in cohort A and 16.6 weeks in cohort B. Overall response rates, based on tumor response when both intracranial and extracranial disease was assessed, were 37.8% (95% CI = 26.8-49.9) and 30.8% (95%CI = 19.9-43.5) in patients with V600E-positive tumors in cohort A and cohort B, respectively. Overall response rates were less robust in those with V600K-positive melanoma: 0% (95% CI = 0-21.8) in cohort A and 27.8% (95% CI = 9.7-53.5) in cohort B. Median OS was 31.4 to 33.1 weeks for those with V600E-positive tumors, which appeared favorable when compared with historical controls, whose median OS was approximately 4 months in published data.24-27 Median OS was shorter for those with V600K-positive melanomas, ranging from 16.3 to 21.9 weeks. The safety profile of dabrafenib in this study was similar to previous experience from the other BREAK trials. Intracranial hemorrhages occurred in 10 patients, and 1 was deemed treatment related. In general, the efficacy of dabrafenib in the treatment of patients with BRAF-mutant advanced melanoma appears to be similar to that of vemurafenib.10-13 Like vemurafenib, the duration of tumor response to dabrafenib is relatively short, implicating a similar problem with rapid emergence of drug resistance. However, there are subtle differences between the 2 agents. It should be pointed out that vemurafenib is dosed at its MTD, whereas the MTD for dabrafenib was not
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reached with up to 300 mg twice daily in the BREAK-1 trial. The approved dabrafenib dosage of 150 mg twice daily was established based on the near-maximum effect in tumor responses, pharmacokinetic parameters, and pharmacodynamic correlates. In addition, dabrafenib has clinically meaningful intracranial activity, with phase I and II trial data supporting its safety and efficacy in patients with V600E- and V600K-positive metastatic melanomas and active brain metastases.21,23 Currently, data regarding the intracranial activity of vemurafenib are limited to a few anecdotal reports and a single case series.28,29 A multicenter, phase II study is under way to assess the efficacy of vemurafenib in the treatment of patients with BRAF-mutant metastatic melanoma involving the brain (NCT01378975). Results from this trial will help determine whether intracranial activity is a unique feature of dabrafenib or a class effect of the selective BRAF inhibitors.
vemurafenib-treated patients in the pivotal BRIM-3 trial that led to the FDA approval of vemurafenib.10,20 The most frequently reported adverse effects of dabrafenib include hyperkeratosis, headache, pyrexia, and arthralgia (Table 2). However, the most common reasons for dose reduction of dabrafenib in the BREAK-3 trial were pyrexia (9%), palmar-plantar erythrodysesthesia syndrome (PPES, 3%), chills (3%), fatigue (2%), and headache (2%).14 It is recommended that dabrafenib be interrupted for fever of 101.3°F or above; fever accompanied with rigors, hypotension, dehydration, or renal insufficiency; or other intolerable grade 2 or higher toxicities.14 Once symptoms resolve, risk-benefit assessment should be conducted to decide whether to permanently discontinue dabrafenib or rechallenge at a reduced dose level. Please refer to Table 3 for dabrafenib dose modification recommendation.
Cutaneous Toxicities
Dosing and Administration Because dabrafenib is indicated for the treatment of patients with BRAFV600E-positive unresectable or metastatic melanomas, the patient selection process should begin with BRAF mutational analysis of the patient’s tumor tissues. Once BRAFV600E positivity is confirmed, the standard screening procedure must include a thorough dermatology exam and a detailed assessment of comorbidities. A complete review of concurrent medications to identify potential drug interactions with dabrafenib should also be conducted.14 Dabrafenib, available as 50- and 75-mg capsules, is dosed at 150 mg orally twice a day on an empty stomach. Patients should be instructed to swallow the tablets whole with a glass of water. If a dose is missed, it can be made up to maintain the twice-daily regimen as long as there is a minimum of 6 hours from the next scheduled dose. Currently, dabrafenib therapy is continued without a break until disease progression or unacceptable toxicity. However, intermittent dosing schedules of BRAF inhibitors are being considered to delay drug resistance.30 Indeed, tumor sensitivity to dabrafenib was restored after a drug-free period in 2 patients with BRAFV600E-positive advanced melanomas who had developed disease progression during previous therapy with selective BRAF inhibitors.31
Safety Profile and Management of Side Effects Dabrafenib is well tolerated. In the BREAK-3 study, 28% of patients required dose modification or interruption as a result of adverse events; however, permanent treatment discontinuation occurred in only 3% of the study population.12 In contrast, adverse events caused dose modification and therapy termination in 38% and 7%, respectively, of
Hyperkeratosis, alopecia, PPES, and skin rash are common cutaneous manifestations of dabrafenib (Table 2).14 Skin rash typically presents as maculopapular or follicular hyperkeratotic eruptions affecting the face, neck, trunk, and extremities and variably associated with itching.32,33 The rash tends to occur early in therapy, often within weeks from treatment initiation. The main management approach for maculopapular rash begins with topical steroids and oral antihistamines.34 Refractory cases may require systemic steroids, dabrafenib interruption, and referral to dermatologists. For follicular hyperkeratotic eruptions, keratolytic agents such as salicylic acid or urea cream should accompany topical steroids and oral antihistamines.33,34 PPES usually manifests as painful, yellow, hyperkeratotic calluses at points of friction or pressure surrounded by erythema on palms and soles.35 Patients should be instructed to practice preventive measures, including heavy use of topical emollients and avoidance of friction on hands and feet. Besides suspending dabrafenib, PPES should be managed with symptom support with rest, cool compresses, topical emollients, and topical steroids. Oral analgesics should be added for pain and discomfort. A distinct feature of the selective BRAF inhibitors is their ability to induce secondary cutaneous malignancies, such as keratoacanthomas (benign squamous cell proliferations), cSCCs, and melanomas. The median onset of dabrafenib-related cSCCs occurs around 9 weeks after initiation of therapy.14 Patients may have multiple cSCC lesions; the median time between diagnosis of the first cSCC and the second one is about 6 weeks.14 The proposed mechanism underlying the development of cSCCs is that BRAF inhibitors paradoxically activate the MAPK pathway in cutaneous squamous cells harboring HRAS mutations, which are present in 20% of squamous skin tissues.36 If detected, these skin cancers should be completely excised without
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Trinh et al Table 2. Toxicity Profiles of Dabrafenib and Vemurafenib: Selecta Adverse Events. Incidence in Percentage,b (Grade 3-4c ) Adverse Event Cutaneous manifestations Squamous cell carcinoma/Keratoacanthoma Hyperkeratosis Rash Alopecia Photosensitivity Palmar-plantar erythrodysesthesia syndrome General and musculoskeletal disorders Arthralgias Pyrexia Headache Fatigue Laboratory investigations Elevated liver enzymes Alkaline phosphatase Alanine aminotransferase Gamma glutamyltransferase Hyperglycemia Hypophosphatemia
Dabrafenib12,14,22
Vemurafenib10,19,36
6-7 (4-7) 37 (1) 17 (0) 22 3 (0) 20 (2-3)
24-26 (22-24) 24-28 (1) 37-52 (7-8) 36-45 33-49 (3) 10 (2)
27 (5 (
research-article2013
AOPXXX10.1177/1060028013513009Annals of PharmacotherapyTrinh et al
Review Article
Dabrafenib Therapy for Advanced Melanoma
Annals of Pharmacotherapy 2014, Vol. 48(4) 519–529 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013513009 aop.sagepub.com
Van Anh Trinh, PharmD1, Jennifer E. Davis, PharmD1, Jaime E. Anderson, PharmD1, and Kevin B. Kim, MD1
Abstract Objective: To summarize the clinical development of dabrafenib and to highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib. Data Source: An English-language literature search of MEDLINE/ PubMed (1966-June 2013), using the keywords GSK2118436, dabrafenib, vemurafenib, selective BRAF inhibitor, and advanced melanoma, was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection and Data Extraction: All relevant published articles on dabrafenib and vemurafenib were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing studies. Data Synthesis: BRAFV600E mutation confers constitutive BRAK kinase activation in melanoma cells, promoting tumor growth. This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. Dabrafenib has been approved to treat patients with BRAFV600E-positive unresectable or metastatic melanoma based on its clinical benefit demonstrated in a randomized phase III study. It has also been shown to be safe and effective in patients with BRAF mutant advanced melanoma involving the brain. Dabrafenib is well tolerated, with the most common adverse effects being hyperkeratosis, headache, pyrexia, and arthralgia. Currently, there is no evidence to suggest that one BRAF inhibitor is superior to the other. With similar efficacy, therapy selection will likely be influenced by differential tolerability and cost. Conclusions: Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAFV600E-positive advanced melanoma. Active research is ongoing to expand its utility into the adjuvant setting and to circumvent rapid emergence of drug resistance. Keywords advanced melanoma, BRAF mutation, selective BRAF inhibitor, GSK2118436, dabrafenib, vemurafenib
Introduction In 2013, 76690 new cases of melanoma will be diagnosed in the United States, with projected deaths of 9480.1 Melanoma accounts for only 4% of all skin cancers; however, it is responsible for approximately 80% of all skin cancer deaths.2 The diagnosis of unresectable stage III or stage IV melanoma signals poor outcome, with a 1-year survival rate of 25% and median overall survival (OS) of 6.2 months.3 Until recently, treatment options for advanced melanoma have been extremely limited. Prior to 2011, dacarbazine and interleukin-2 (IL-2) were the only 2 agents approved by the US Food and Drug Administration (FDA) for the treatment of advanced or metastatic melanoma for more than 2 decades. Recent molecular insight into melanomagenesis has propelled drug development for advanced melanoma into the realm of genomic medicine. Vemurafenib, the first selective BRAF inhibitor approved in 2011, pioneers the effort of
personalizing cancer therapy for patients with advanced melanoma. At present, the class of selective BRAF inhibitors consists of 2 compounds: vemurafenib (Zelboraf, Genentech, South San Francisco, CA) and dabrafenib (Tafinlar, GlaxoSmithKline, London, UK). Both agents are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. This review will discuss the pharmacology, pharmacokinetics, and clinical experience of dabrafenib in patients with advanced melanoma. It will also highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib. 1
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Corresponding Author: Van Anh Trinh, PharmD, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0377, Houston, TX 77030, USA. Email: [email protected]
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Figure 1. Mitogen-activated protein kinase (MAPK) pathway and mechanism of dabrafenib: A. When extracellular growth factor binds to membrane-bound receptor tyrosine kinase, the MAPK signaling pathway is activated to promote proliferation and survival. B. V600E kinase is constitutively active, sustaining MAPK signaling and perpetuating growth. C. Dabrafenib inhibits V600E kinase, inducing apoptosis.
MAPK Pathway and Mechanism of Action of Dabrafenib (Figure 1) The mitogen-activated protein kinase (MAPK) pathway is an important signaling cascade regulating cell growth, differentiation, and survival. Normally, MAPK pathway activation begins with the binding of extracellular growth factors, such as epidermal growth factor, to membrane-bound receptor tyrosine kinases, such as epidermal growth factor receptor.4 Sequential phosphorylation of RAS, RAF, MEK, and ERK within the MAPK pathway communicates the growth signal downstream to the nucleus, inducing gene expressions to promote cell proliferation, differentiation, and survival. A decade ago, melanoma tumors were found to harbor genetic mutations in various components of the MAPK signaling pathway. BRAF mutation is the most common event, occurring in about 50% of melanomas.5 The 2 most prevalent mutant BRAF genotypes are BRAFV600E and BRAFV600K, representing 80% to 90% and 10% to 20% of all BRAF mutations, respectively.6,7 BRAFV600E and BRAFV600K are point mutations corresponding to the valineto-glutamic acid and valine-to-lysine substitutions at amino acid 600, respectively. BRAFV600E and BRAFV600K kinases are constitutively active, sustaining MAPK signaling and perpetuating cell growth. Phenotypically, BRAFV600E and
BRAFV600K confer aggressive behavior to melanoma cells8,9 and have been correlated with unfavorable survival outcome in patients with metastatic disease.7 There is also evidence to indicate an association between BRAF mutations and the frequency of central nervous system metastases at the time of stage IV diagnosis.6 Identification of activating BRAF mutations in melanoma tumors has fostered the development of selective BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of advanced melanoma. Blocking the mutation-driven constitutive activation of the MAPK pathway, these agents have been shown to improve the response rate and survival for patients with BRAFV600E-positive advanced melanoma in randomized phase III studies, leading to the FDA approval of vemurafenib in 2011 and dabrafenib in 2013.10-13 Besides mutant BRAF kinases, BRAF inhibitors also inhibit wildtype (nonmutated) BRAF and CRAF (another RAF isoform) enzymes. The in vitro half-maximal inhibitory concentration (IC50) values of dabrafenib for BRAFV600E, wild-type BRAF, and CRAF are 0.65, 3.2, and 5.0 nM,14 respectively, whereas the corresponding IC50 values of vemurafenib are 31, 100, and 48 nM.15 Because the IC50 value reflects the inhibitory potency of antagonistic compounds, the considerable difference among the IC50 values of dabrafenib suggests that dabrafenib may be more selective for BRAFV600E than wild-type
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Trinh et al BRAF and CRAF. Interestingly, BRAF inhibitors can paradoxically activate the MAPK pathway via heterodimerization of BRAF and CRAF kinases to promote growth in tumors harboring wild-type BRAF or activating RAS mutations.16-18 Therefore, BRAF inhibitor monotherapy should not be used in patients with advanced melanoma with wildtype BRAF or RAS mutation.
Pharmacokinetics After oral administration at fasting condition, dabrafenib achieves a mean absolute bioavailability of 95%, with a median time to peak plasma concentration (Tmax) of 2 hours and a mean terminal half-life of 8 hours. When taken with a high-fat meal, the maximum concentration of dabrafenib was reduced by 51%, and Tmax was prolonged by 3.6 hours. Thus, dabrafenib should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. Medications affecting gastric pH may decrease the solubility and, thus, the bioavailability of dabrafenib. Concurrent administration of dabrafenib with proton pump inhibitors, H2-receptor antagonists, or antacids is not recommended.14 Dabrafenib is highly bound to plasma proteins (99.7%) and has a large volume of distribution (70.3 L). The metabolism of dabrafenib is complex, occurring mainly through cytochrome P450 (CYP) 2C8 and CYP3A4. Two of the metabolites, hydroxy- and desmethyl-dabrafenib, are active and likely to contribute to the clinical activity of dabrafenib. Dabrafenib is primarily eliminated fecally. Mild to moderate renal dysfunction (creatinine clearance > 29 mL/min)14 or mild hepatic impairment (bilirubin ≤ 1.5 times upper limit of normal and aspartate aminotransferase of any value)19 do not appear to affect the systemic exposure of dabrafenib and its metabolites. Therefore, dosage adjustment is not needed in patients with mild to moderate kidney dysfunction or mild hepatic impairment. However, dabrafenib should be used with caution in the presence of severe kidney (creatinine clearance < 30 mL/min) or moderate to severe liver impairment because an appropriate dose of dabrafenib has not been established in these clinical scenarios. In vitro studies with human hepatic microsomes demonstrated that dabrafenib is a substrate of CYP3A4 and CYP2C8, whereas its active metabolites are substrates of CYP3A4. Dabrafenib is a moderate inducer of CYA3A4 and may also induce other enzymes. Concurrent administration of dabrafenib with strong CYP3A4 or CYP2C8 inhibitors or inducers and other CYP substrates with narrow therapeutic index should be avoided.14 From the pharmacokinetic standpoint, one clinically relevant dissimilarity exists between the 2 BRAF inhibitors, which relates to the influence of food on their absorption. The absorption of dabrafenib is affected by food; therefore, dabrafenib should be taken on an empty stomach. In contrast, vemurafenib can be administered with or without food.20
Clinical Trial Experience (Table 1) BREAK-121 The BREAK-1 trial was a 2-stage phase I dose-finding study of GSK2118436, later known as dabrafenib. The trial began with a dose escalation phase in patients with metastatic cancer of various tumor types to define the safety profile and to establish the recommended phase 2 dose (RP2D) of dabrafenib. Dose titration was done in conjunction with correlative pharmacokinetic and pharmacodynamic evaluations. Mutant BRAF status was initially not required for enrollment but became mandatory in the latter part of the study because of absence of drug activity in patients with wildtype BRAF. The maximum tolerated dose (MTD) of dabrafenib was not achieved in the dose range between 12 mg daily to 300 mg orally twice a day. Dose-limiting toxicities, manifesting as grade 3 cutaneous squamous cell carcinoma (cSCC), grade 3 syncope, and grade 2 pyrexia, were noted in 3 out of 20 patients treated at 200 mg twice daily. Because of the marginal increase in drug exposure, pharmacodynamic effects, and tumor response at 200 mg twice daily, the RP2D was set at 1 dose level lower, which was 150 mg twice daily. On determination of the RP2D, the expansion phase followed to evaluate the efficacy of dabrafenib in 3 different cohorts of patients with tumors positive for mutant BRAF: (1) individuals with metastatic melanoma without brain involvement; (2) individuals with stage IV melanoma with asymptomatic, untreated brain metastases; and (3) individuals with nonmelanoma solid tumors. Out of 36 patients enrolled in cohort 1, 25 (69%, 95% CI = 51.9-83.7) achieved an objective response, with median duration of response of 6.2 months (95% CI = 4.2-7.7). The response rate appeared to be higher in individuals with V600E-positive melanomas than those with V600K-positive tumors; however, median progression-free survival (PFS) duration was similar between the 2 groups. The median PFS duration was 5.5 months (95% CI = 3.5-9.5) in patients with V600E-positive melanoma and 5.6 months (95% CI = 3.9-10.8) in those with V600K-positive tumors. Intracranial tumor responses were observed in 9 out of 10 patients in cohort 2. Remarkably, 4 of them achieved complete resolution of all brain lesions. Modified Response Evaluation Criteria in Solid Tumors (RECIST) were used to assess intracranial response, which was determined by the percentage change from baseline in the sum of brain lesions of 3 mm or more. The median PFS for this cohort was 4.2 months (95% CI = 3.3-5.3), with 2 patients surviving more than a year.
BREAK-222 The BREAK-2 trial was a single-arm, phase II study conducted to verify the clinical activity of dabrafenib at 150 mg orally twice daily in 92 patients with BRAF mutant
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Table 1. Clinical Trial Summary.12,13,20-22 Study Population (n)
Treatment Regimen
Results
21
BREAK-1 (phase I, Falchook et al ): advanced solid tumors Escalation cohort (n = 110) 12 mg daily to 300 mg bid Expansion cohort 150 mg bid Melanoma, no brain metastasis (n = 36) Melanoma, brain metastasis (n = 10) BREAK-2 (phase II, Ascierto et al22): V600-mutant advanced melanoma V600E (n = 76) 150 mg bid
MTD: Not reached; RP2D: 150 mg bid ORR: 69% (95% CI = 51.9-83.7) • Median DOR: 6.2 months (95% CI = 4.2-7.7) • Median PFS: 5.5 months (95% CI = 4.1-8.3) • 9/10 Patients had reduction in size of brain metastasis • 4 Patients achieved CR intracranially
• ORR: 59% (95% CI = 48.2-70.3) • Median PFS: 6.3 months • Median OS: 13.1 months V600K (n = 16) • ORR: 13% (95% CI = 0.0-28.7) • Median PFS: 4.5 months • Median OS: 12.9 months BREAK-MB (phase II, Long et al7): V600-mutant metastatic melanoma involving the brain No prior local therapy to 150 mg bid brain lesions (n = 89) V600E (n = 74) • OIR: 39.2% (95% CI = 28.0-51.2) • Median PFS: 16.1 weeks (95% CI: 15.7-21.9) • Median OS: 33.1 weeks (95% CI: 25.6-NR) V600K (n = 15) • OIR: 6.7% (95% CI = 0.2-31.9) • Median PFS: 8.1 weeks (95% CI: 3.1-16.1) • Median OS: 16.3 weeks (95% CI: 6.9-22.4) Progression despite local therapy (n = 83) V600E (n = 65) • OIR: 30.8% (95% CI = 19.9-43.4) • Median PFS: 16.6 weeks (95% CI = 15.9-23.7) • Median OS: 31.4 weeks (95% CI = 25.7-NR) V600K (n = 18) • OIR: 22.2% (95% CI = 6.4-47.6) • Median PFS: 15.9 weeks (95% CI = 7.9-22.4) • Median OS: 21.9 weeks (95% CI = 15.3-NR) BREAK-3 (phase III, Hauschild et al12): V600E-positive advanced melanoma, previously untreateda Investigators’ assessment Arm A (n = 187) Dabrafenib 150 mg bid Median PFS: 5.1 months • Median PFS: 2.7 months Arm B (n = 63) Dacarbazine 1 g/m2 q3w • HR progression: 0.3 (95% CI = 0.18-0.51) Independent review panel’s assessment Arm A (n = 187) Dabrafenib 150 mg bid Median PFS: 6.7 months • Median PFS: 2.9 months Arm B (n = 63) Dacarbazine 1 g/m2 q3w • HR progression: 0.35 (95% CI = 0.2-0.61) Updated data at ASCO 2013 Arm A (n = 187) Dabrafenib 150 mg bid • Median PFS: 6.9 months • Median OS: 18.2 months • Median PFS: 2.7 mo Arm B (n = 63) Dacarbazine 1 g/m2 q3w • Median OS: 15.6 mo • HR progression: 0.37 (95% CI = 0.23-0.57) • HR death: 0.76 (95% CI = 0.48-1.21) Abbreviations: MTD, maximal tolerated dose; RP2D, recommended phase II dose; ORR, overall response rate; DOR, duration of response; PFS, progression-free survival; CR, complete response; HR, hazard ratio; OS, overall survival; OIR, overall intracranial response; NR, not reached; ASCO, American Society of Clinical Oncology. a Except high-dose interleukin-2.
stage IV melanoma; 76 patients carried V600E-positive tumors, whereas the remaining 16 individuals harbored V600K-positive melanomas. The majority of patients had
stage M1c disease and had been previously treated. Nearly all patients had undergone surgical interventions, and 84% of patients had received prior systemic therapies, which
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Trinh et al mostly involved dacarbazine or temozolomide. Per investigators’ assessment, the overall response rates were 59% and 13% in V600E and V600K subsets, respectively. The median PFS duration was 6.3 months in patients with V600E-positive melanomas and 4.5 months in those with V600K-positive tumors. Per independent reviewers’ assessment, the overall response rates were 41% and 25% in V600E and V600K subsets, respectively. The median PFS duration was 6.2 months in patients with V600Epositive melanomas and 4.5 months in those with V600Kpositive tumors.
BREAK-312 The BREAK-3 study was the pivotal randomized phase III trial conducted to confirm the clinical benefit of dabrafenib. In this trial, 250 patients with BRAFV600E-positive unresectable stage III or stage IV melanomas were randomly assigned 3:1 to receive either dabrafenib 150 mg orally twice a day continuously (n = 187) or dacarbazine 1 g/m2 intravenously every 3 weeks (n = 63). Previous therapy, except for IL-2, was not allowed. Patients initially assigned to receive dacarbazine were able to cross over to receive dabrafenib on disease progression. The primary end point of the study was investigator-assessed PFS. Secondary end points included PFS as assessed by an independent review committee, OS, objective response rate, duration of response and safety. At a median follow-up of 5.1 months and 3.5 months for those treated with dabrafenib or dacarbazine, respectively, 44% of the dacarbazine-treated patients had crossed over to the dabrafenib arm. Per investigators’ assessment, the median PFS was 5.1 months in the dabrafenib group and 2.7 months in the dacarbazine group, with the hazard ratio (HR) for progression of 0.30 (95% CI = 0.18-0.51; P < .001) favoring dabrafenib. The evaluation by the independent review panel revealed similar results, with a median PFS of 6.7 months for the dabrafenib group and 2.9 months for the dacarbazine group (HR = 0.35; 95% CI = 0.20-0.61). Median OS was not reached at this analysis. Objective response rate with dabrafenib was 53%, superior to 19% with dacarbazine. Updated survival data have recently been presented at the 2013 American Society of Clinical Oncology (ASCO) meeting, confirming the PFS advantage of dabrafenib.13 The updated median PFS was 6.9 months in the dabrafenib arm and 2.7 months in the dacarbazine arm, with the HR for progression of 0.37 (95 % CI = 0.23-0.57) favoring dabrafenib. The OS results were difficult to interpret because of the crossover effect. Median OS was 18.2 months and 15.6 months in the patients treated with dabrafenib and dacarbazine, respectively (HR = 0.76; 95% CI = 0.48-1.21). Of note, independent review was not continued beyond the primary analysis.
BREAK-MB23 The results of the BREAK-1 trial provided the rationale for BREAK-MB, a large phase II study evaluating the safety and efficacy of dabrafenib 150 mg orally twice daily in melanoma patients with brain metastases. A total of 172 patients with V600E- or V600K-positive advanced melanoma with at least 1 asymptomatic brain metastasis measuring 5 to 40 mm in diameter were assigned to 1 of 2 cohorts: patients who had not received local therapy for brain metastases were assigned to cohort A, whereas those with progressive intracranial disease despite local therapy went to cohort B. Half of the patients had 2 to 4 brain lesions, and 81% of them harbored V600E-positive melanomas. The primary end point of the study was investigatorassessed intracranial response in patients with V600Epositive melanomas. Secondary efficacy end points included intracranial response in patients with V600K-positive melanomas, overall response, duration of intracranial and overall response, PFS, and OS grouped by mutation subtype. Intracranial response to dabrafenib was 39.2% and 30.8% in patients with V600E-positive tumors in cohort A and cohort B, respectively. The response rate in the brain was lower in patients with V600K-positive tumors: 6.7% in cohort A and 22.2% in cohort B. Median durations of intracranial tumor regression lasted 20.1 and 28.1 weeks in cohort A and B for individuals with V600E-positive melanomas, respectively. Median durations of response in the brain were shorter for patients with V600K-positive tumors: 12.4 weeks in cohort A and 16.6 weeks in cohort B. Overall response rates, based on tumor response when both intracranial and extracranial disease was assessed, were 37.8% (95% CI = 26.8-49.9) and 30.8% (95%CI = 19.9-43.5) in patients with V600E-positive tumors in cohort A and cohort B, respectively. Overall response rates were less robust in those with V600K-positive melanoma: 0% (95% CI = 0-21.8) in cohort A and 27.8% (95% CI = 9.7-53.5) in cohort B. Median OS was 31.4 to 33.1 weeks for those with V600E-positive tumors, which appeared favorable when compared with historical controls, whose median OS was approximately 4 months in published data.24-27 Median OS was shorter for those with V600K-positive melanomas, ranging from 16.3 to 21.9 weeks. The safety profile of dabrafenib in this study was similar to previous experience from the other BREAK trials. Intracranial hemorrhages occurred in 10 patients, and 1 was deemed treatment related. In general, the efficacy of dabrafenib in the treatment of patients with BRAF-mutant advanced melanoma appears to be similar to that of vemurafenib.10-13 Like vemurafenib, the duration of tumor response to dabrafenib is relatively short, implicating a similar problem with rapid emergence of drug resistance. However, there are subtle differences between the 2 agents. It should be pointed out that vemurafenib is dosed at its MTD, whereas the MTD for dabrafenib was not
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reached with up to 300 mg twice daily in the BREAK-1 trial. The approved dabrafenib dosage of 150 mg twice daily was established based on the near-maximum effect in tumor responses, pharmacokinetic parameters, and pharmacodynamic correlates. In addition, dabrafenib has clinically meaningful intracranial activity, with phase I and II trial data supporting its safety and efficacy in patients with V600E- and V600K-positive metastatic melanomas and active brain metastases.21,23 Currently, data regarding the intracranial activity of vemurafenib are limited to a few anecdotal reports and a single case series.28,29 A multicenter, phase II study is under way to assess the efficacy of vemurafenib in the treatment of patients with BRAF-mutant metastatic melanoma involving the brain (NCT01378975). Results from this trial will help determine whether intracranial activity is a unique feature of dabrafenib or a class effect of the selective BRAF inhibitors.
vemurafenib-treated patients in the pivotal BRIM-3 trial that led to the FDA approval of vemurafenib.10,20 The most frequently reported adverse effects of dabrafenib include hyperkeratosis, headache, pyrexia, and arthralgia (Table 2). However, the most common reasons for dose reduction of dabrafenib in the BREAK-3 trial were pyrexia (9%), palmar-plantar erythrodysesthesia syndrome (PPES, 3%), chills (3%), fatigue (2%), and headache (2%).14 It is recommended that dabrafenib be interrupted for fever of 101.3°F or above; fever accompanied with rigors, hypotension, dehydration, or renal insufficiency; or other intolerable grade 2 or higher toxicities.14 Once symptoms resolve, risk-benefit assessment should be conducted to decide whether to permanently discontinue dabrafenib or rechallenge at a reduced dose level. Please refer to Table 3 for dabrafenib dose modification recommendation.
Cutaneous Toxicities
Dosing and Administration Because dabrafenib is indicated for the treatment of patients with BRAFV600E-positive unresectable or metastatic melanomas, the patient selection process should begin with BRAF mutational analysis of the patient’s tumor tissues. Once BRAFV600E positivity is confirmed, the standard screening procedure must include a thorough dermatology exam and a detailed assessment of comorbidities. A complete review of concurrent medications to identify potential drug interactions with dabrafenib should also be conducted.14 Dabrafenib, available as 50- and 75-mg capsules, is dosed at 150 mg orally twice a day on an empty stomach. Patients should be instructed to swallow the tablets whole with a glass of water. If a dose is missed, it can be made up to maintain the twice-daily regimen as long as there is a minimum of 6 hours from the next scheduled dose. Currently, dabrafenib therapy is continued without a break until disease progression or unacceptable toxicity. However, intermittent dosing schedules of BRAF inhibitors are being considered to delay drug resistance.30 Indeed, tumor sensitivity to dabrafenib was restored after a drug-free period in 2 patients with BRAFV600E-positive advanced melanomas who had developed disease progression during previous therapy with selective BRAF inhibitors.31
Safety Profile and Management of Side Effects Dabrafenib is well tolerated. In the BREAK-3 study, 28% of patients required dose modification or interruption as a result of adverse events; however, permanent treatment discontinuation occurred in only 3% of the study population.12 In contrast, adverse events caused dose modification and therapy termination in 38% and 7%, respectively, of
Hyperkeratosis, alopecia, PPES, and skin rash are common cutaneous manifestations of dabrafenib (Table 2).14 Skin rash typically presents as maculopapular or follicular hyperkeratotic eruptions affecting the face, neck, trunk, and extremities and variably associated with itching.32,33 The rash tends to occur early in therapy, often within weeks from treatment initiation. The main management approach for maculopapular rash begins with topical steroids and oral antihistamines.34 Refractory cases may require systemic steroids, dabrafenib interruption, and referral to dermatologists. For follicular hyperkeratotic eruptions, keratolytic agents such as salicylic acid or urea cream should accompany topical steroids and oral antihistamines.33,34 PPES usually manifests as painful, yellow, hyperkeratotic calluses at points of friction or pressure surrounded by erythema on palms and soles.35 Patients should be instructed to practice preventive measures, including heavy use of topical emollients and avoidance of friction on hands and feet. Besides suspending dabrafenib, PPES should be managed with symptom support with rest, cool compresses, topical emollients, and topical steroids. Oral analgesics should be added for pain and discomfort. A distinct feature of the selective BRAF inhibitors is their ability to induce secondary cutaneous malignancies, such as keratoacanthomas (benign squamous cell proliferations), cSCCs, and melanomas. The median onset of dabrafenib-related cSCCs occurs around 9 weeks after initiation of therapy.14 Patients may have multiple cSCC lesions; the median time between diagnosis of the first cSCC and the second one is about 6 weeks.14 The proposed mechanism underlying the development of cSCCs is that BRAF inhibitors paradoxically activate the MAPK pathway in cutaneous squamous cells harboring HRAS mutations, which are present in 20% of squamous skin tissues.36 If detected, these skin cancers should be completely excised without
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Trinh et al Table 2. Toxicity Profiles of Dabrafenib and Vemurafenib: Selecta Adverse Events. Incidence in Percentage,b (Grade 3-4c ) Adverse Event Cutaneous manifestations Squamous cell carcinoma/Keratoacanthoma Hyperkeratosis Rash Alopecia Photosensitivity Palmar-plantar erythrodysesthesia syndrome General and musculoskeletal disorders Arthralgias Pyrexia Headache Fatigue Laboratory investigations Elevated liver enzymes Alkaline phosphatase Alanine aminotransferase Gamma glutamyltransferase Hyperglycemia Hypophosphatemia
Dabrafenib12,14,22
Vemurafenib10,19,36
6-7 (4-7) 37 (1) 17 (0) 22 3 (0) 20 (2-3)
24-26 (22-24) 24-28 (1) 37-52 (7-8) 36-45 33-49 (3) 10 (2)
27 (5 (
