Original Article
Patterns of Response and Progression in Patients With BRAF-Mutant Melanoma Metastatic to the Brain Who Were Treated With Dabrafenib Mary W. F . Azer, MB ChB1,2; Alexander M. Menzies, MBBS2,3; Lauren E. Haydu, BSCHE2,3; Richard F. Kefford, MBBS, PhD1,2,3,4; and Georgina V. Long, MBBS, PhD2,3,4
BACKGROUND: Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib. METHODS: Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed. RESULTS: A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P 5.416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P 5.465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days. CONCLUSIONS: IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progresC 2013 American Cancer Society. sion, with ongoing dabrafenib treatment possible in a subset of patients. Cancer 2014;120:530–6. V KEYWORDS: melanoma, BRAF inhibitor, brain metastases, dabrafenib, response, progression.
INTRODUCTION Melanoma commonly metastasizes to the brain. Twenty percent of patients have brain metastases at diagnosis of stage IV disease,1 and approximately 50% ultimately develop them through the course of disease.2 They occur more frequently in those with BRAF -mutant than BRAF wild-type melanoma.1 Brain metastases carry a poor prognosis, with a median survival of 3 to 5 months from diagnosis, contributing to death in up to 50% of patients.2,3 Surgery and radiotherapy can provide local control and improvement in neurological symptoms in those with limited disease,4 but until the availability of selective BRAF inhibitors, systemic therapies had limited efficacy, with response rates of no more than 10%.2,4-8 BRAF inhibitors have significant activity in patients with melanoma brain metastases, as seen in the phase 1 and 2 clinical trials of dabrafenib9,10 and the pilot study of vemurafenib.11 The phase 2 trial of dabrafenib in 172 patients with progressing brain metastases with or without prior local treatment demonstrated an intracranial (IC) response rate of 30% to 40%, an IC disease control rate of > 80%, a median progression-free survival (PFS) of 16.1 and 16.6 weeks in 2 cohorts, and a median overall survival (OS) of 33.1 and 31.4 weeks in the same cohorts of BRAFV600E (Val600Glu substitution in BRAF) metastatic melanoma patients. Although this study demonstrated unprecedented efficacy in patients with
Corresponding author : Georgina Long, PhD, MBBS, Melanoma Institute Australia and The University of Sydney, 40 Rocklands Road, North Sydney, NSW 2060, Australia; Fax: (011) 161 2 9954 9290; [email protected] 1 Westmead Hospital, Westmead, Australia; 2Melanoma Institute Australia, Sydney, Australia; 3The University of Sydney, Sydney, Australia; 4Westmead Institute for Cancer Research, Westmead, Australia
This study was presented in part at the 2012 American Society of Clinical Oncology Annual General Meeting, Chicago, Illinois, and the 2012 Medical Oncology Group Australia Annual Scientific Meeting, Brisbane, Australia. We thank the Westmead melanoma and clinical trials team: Arthur Clements, Lydia Visintin, Rebecca Hinshelwood, Amie Cho, Vicky Wegener, Andrea Del Pilar Forero V., Jacob Cunningham, Natalie Byrne, Katherine Carson, Joanna Jackson, Medhia Survery, Meenal Rai, Larry Hernandez; and Angela Hong, Gerald Fogarty, Brindha Shivalingham, Peter Lebowitz, Jeffrey Legos (GlaxoSmithKline), Michael Streit (GlaxoSmithKline), and Vicki Goodman (GlaxoSmithKline) for their assistance with this work. The first 2 authors are equal contributors to this study. DOI: 10.1002/cncr.28445, Received: July 30, 2013; Revised: September 6, 2013; Accepted: September 13, 2013, Published online November 5, 2013 in Wiley Online Library (wileyonlinelibrary.com)
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both untreated and previously treated brain metastases, it did not report data regarding the extracranial (EC) response to therapy in patients on the trial, nor did it examine the degree of concordance of response to therapy within individual patients (IC versus EC). No studies to date have examined the nature of disease progression in patients with brain metastases treated with BRAF inhibitors, nor have they examined treatments received afterward. There are now several strategies for the management of brain metastases in patients with metastatic melanoma, including surgery, radiotherapy, immunotherapy, and BRAF inhibitors. In order to assist with the translation of clinical trial data into effective patient care, particularly for patients with IC and EC disease at the time of first diagnosis of metastatic disease, it is critical to understand the comparative IC and EC tumor response to BRAF inhibition, the nature of disease progression, and the effective management of patients after intracranial disease progression. In this study, we sought to analyze the nature of IC and EC response and progression in patients with melanoma brain metastases treated with dabrafenib, and hypothesized that IC and EC metastases respond and progress similarly to BRAF inhibitors.
MATERIALS AND METHODS Patient Selection
The study was undertaken at Westmead Hospital in association with the Melanoma Institute of Australia (NSW, Australia), with Human Research Ethics Committee approval and patient informed consent. All patients who were enrolled in the brain cohort of the phase 1 trial9 and the phase 2 brain metastasis trial (BREAK-MB)10 of dabrafenib at Westmead Hospital between September 2009 and June 2011 were assessed. Patients were eligible for enrollment if they had BRAFV600E or BRAFV600K metastatic melanoma as assessed by high-resolution melt analysis and sequencing (phase 1 trial), or trial-specific polymerase chain reaction–based test (phase 2 trial), and either: 1) untreated, or 2) progressive but previously locally treated asymptomatic brain metastases (progression in the brain was determined using RECIST [Response Evaluation Criteria In Solid Tumors] version 1.0 for the phase 1 trial or modified RECIST version 1.1 in the phase 2 trial).12,13 Previous local brain treatment included surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or a combination of local therapies. At least 1 measurable IC lesion ( 0.3 cm and 4 cm for the phase 1 trial, 0.5 cm and 4 cm for the Cancer
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phase 2 trial) as determined by gadolinium-enhanced magnetic resolution imaging (MRI) was required for trial entry. Concomitant corticosteroids were permitted if at a stable or reducing dose, and prophylactic or preventative antiepileptic therapy was allowed. Patients were allowed up to 2 lines of prior systemic treatment excluding mitogen-activated protein kinase inhibitors and were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. BRAF Inhibitor Treatment
All patients were treated with dabrafenib at the recommended phase 2 dose (RP2D) of 150 mg twice daily (bid), except for one patient on the phase 1 trial who commenced 70 mg bid and was escalated to the RP2D after 12 weeks. Patients with progressive disease (PD), defined as either IC, EC, or overall (as per RECIST criteria), were allowed to continue on dabrafenib if deemed to have ongoing clinical benefit from this treatment, including after local therapies (surgery, radiotherapy). Disease Assessments
Baseline demographics including patient age, sex, BRAF genotype, the date of diagnosis of stage IV disease, and diagnosis of first brain metastasis, as well as details of prior brain metastasis treatment were collected. Baseline clinicopathologic parameters examining the patient’s burden of disease including lactate dehydrogenase level and RECIST sum of diameters (SoD) of target lesions (IC, EC, and overall total [SoD of IC and EC]). In addition, computed tomography (CT) and MRI scans were reviewed, and the sites of EC metastases as well as the total number of IC and EC metastases were collected. The number and site of EC metastases were recorded, and patients with 20 IC metastases were classified into groups (20-30, 30-40, 40-50 metastases). Disease assessments performed during treatment included clinical assessment every 4 weeks and imaging studies (cerebral MRI and chest, abdomen, and pelvis CT scans) at week 4, week 8, and every 8 weeks thereafter. RECIST criteria (version 1.0 for the phase 1 trial, version 1.1 for the phase 2 trial)12,13 were used to determine disease response extracranially, and modified RECIST10 was used to assess intracranial response. Overall response was determined by combining the RECIST SoD of target lesions at both IC and EC sites.10 Concordance of IC and EC response was defined as either partial/complete response (PR/CR, IC, and EC), stable disease (SD, IC, and EC), or progressive disease (PD, IC, and EC). We determined disease progression at IC and EC sites 531
Original Article TABLE 1. Baseline Patient and Disease Characteristics Characteristic Sex Male Female Age at trial start (years) Median (range) BRAF genotype V600E V600K BM at stage IV diagnosis Yes No Previous local treatment to BM Nil Surgery SRS WBRT Combination Baseline ECOG ECOG 0 ECOG 1 Baseline LDH ULN >ULN Total number of IC metastases Median (range) RECIST SoD of IC targets (mm) Median (range) Total number of EC metastases Median (range) RECIST SoD of EC targets (mm) Median (range) Number of EC sites Median (range) Clinical trial Phase 1 Phase 2 Total
Total N (%)
15 (65%) 8 (35%) 58 (23-82) 19 (83%) 4 (17%) 10 (43%) 13 (57%) 12 (52%) 3 (13%) 1 (4%) 2 (9%) 5 (22%) 13 (57%) 10 (43%) 9 (39%) 14 (61%) 4 (1-50) 17 (4-91) 4 (0-50) 85 (0-226)
RESULTS Patient Characteristics
Twenty-three patients were included for analysis, and baseline characteristics are shown in Table 1. Twelve patients (52%) had no prior local treatment for brain metastases, and 11 patients (48%) had received prior local treatment with subsequent disease progression intracranially. These groups were not analyzed separately due to the small patient numbers and unbalanced baseline characteristics. Patients had a median of 4 IC and 10 EC metastases, with a median RECIST SoD of 17 mm (IC) and 85 mm (EC) at baseline. One patient had no EC disease at trial entry, and another had EC disease that was not RECIST-measurable, and neither were included for EC response assessment. The median number of EC sites was 4 with a range of 1 to 8 sites, reflecting variable burden of EC disease.
4 (1-8)
Response, PFS, and OS 6 17 23
Abbreviations: BM, brain metastases; EC, extracranial; ECOG, Eastern Cooperative Oncology Group performance status; IC, intracranial; LDH, lactate dehydrogenase; SoD, sum of diameter; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; ULN, upper limit of normal.
separately based on RECIST criteria. For PFS, we used the earliest progressing site (IC or EC) and not the overall RECIST SoD, which was used in determining progression in BREAK-MB.10 Statistical Methods
All statistical analyses were carried out with IBM SPSS Statistic, version 19.0. Univariate survival analyses were conducted with the Kaplan-Meier method together with the log-rank (Mantel-Cox) test for statistical significance of categorical variables. Cox regression was used to test survival for continuous variables. P values < .05 were considered statistically significant. PFS was defined as the time interval in days from commencement of dabrafenib to the first date of progression intracranially (IC PFS), 532
extracranially (EC PFS), or overall (overall PFS, defined as PFS of the first progressing site). In those with PD in either IC or EC sites alone who continued on dabrafenib treatment beyond progression for ongoing clinical benefit, PFS for the other site was calculated. OS was defined as the time interval in days from commencement of dabrafenib to the date of last follow-up or death. All patient deaths in this cohort were attributed to melanoma.
The overall, IC, and EC response rates, and PFS as well as OS, are shown in Table 2. The overall response rate was 87% (20 of 23 patients), with median time to best response of 7.7 weeks, median PFS of 16.3 weeks, and median OS of 36.6 weeks. IC and EC response rates were similar at 78% (18 of 23 patients) and 90% (19 of 21 patients), respectively (P 5 .416). There was a trend toward shorter time to best response in the IC compared with EC sites (median 7.4 versus 12.4 weeks, P 5 .107). The median PFS was similar in IC and EC sites (23.6 weeks each, P 5 .465). Intrapatient IC and EC Concordance of Response
For those with measurable IC and EC disease at baseline as per RECIST (N 5 21), IC and EC best RECIST response category was concordant (ie, PR/CR IC and EC; SD IC and EC; or PD IC and EC) in 15 (71%) patients. The degree of response was also similarly concordant (Fig. 1). Only one patient had tumor growth in EC disease (although still classified as stable disease) with shrinkage in IC disease. Cancer
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TABLE 2. Response, Progression-Free Survival, and Overall Survival Based on Site of Disease
RECIST response category Progressive disease Stable disease Partial response Complete response Total Time to best response Total N Median (weeks) (95% CI) Range (weeks) Progression-free survival N progressed Median (weeks) (95% CI) Range (weeks) Overall Survival N died Median (weeks) (95% CI) Range
Overall
Intracranial
Extracraniala
Pb
1 2 20 0 23
1 4 16 2 23
0 2 19 0 21
0.416c
23 7.7 (6.4-9.1) 3.4-31.3
23 7.4 (7.0-7.9) 3.4-31.3
21 12.4 (8.4-16.5) 3.4-24.3
0.107
20 16.3 (14.1-18.5) 4.0-44.9
18 23.6 (13.6-33.6) 4.0-58.9
16 23.6 (13.9-33.2) 4.0-56.9
0.465
17 36.6 (22.2-50.9) 14.4-103.1
-
-
-
Abbreviations: CI, confidence interval; PD/SD, progressive/stable disease; PR/CR, partial/complete response; RECIST, Response Evaluation Criteria In Solid Tumors. a One patient did not have measurable extracranial disease, one patient did not have extracranial disease. Neither included in extracranial response assessment. b Comparing intracranial versus extracranial disease. c Comparing PD/SD versus PR/CR, Fisher’s exact test.
existing lesions, IC versus EC site); however, no patients progressed due to the development of new lesions alone. Management After Disease Progression
Figure 1. Scatter plot demonstrates concordance of best response (percent change in sum of diameters of target lesions from baseline) in intracranial (IC) and extracranial (EC) sites within each patient (N 5 21).
Disease Progression
Twenty patients had PD at the time of analysis: 30% (N 5 6) of patients progressed in IC sites alone, 40% (N 5 8) progressed in both IC and EC sites simultaneously, whereas 30% (N 5 6) progressed in EC sites alone with ongoing IC response (Table 3). There was no dominant pattern to the nature of progression (new versus Cancer
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In those with isolated IC progression (N 5 6) (Table 3), 5 underwent local therapy to the brain. Two patients underwent SRS, 2 patients underwent surgery, and one patient received WBRT. The patient who did not receive subsequent treatment to the brain had received prior local brain treatment prior to trial entry (surgery and WBRT) and the lesions were not amenable to further therapy. Five of the 6 patients continued on dabrafenib for > 30 days after progression, with one patient continuing on treatment for 39 weeks after surgery to an isolated progressing IC lesion. In those who progressed at both IC and EC sites (N 5 8) (Table 3), 4 received salvage local therapy to IC metastases and 3 patients continued on dabrafenib (> 30 days) after progression. In patients with isolated EC progression (N 5 6), 4 continued on dabrafenib (> 30 days) after progression. In total, 14 patients had IC progression (isolated or in combination with EC progression). Five patients underwent SRS/surgery, another 5 patients underwent WBRT, and further treatment of the progressing lesion(s) was not possible in the remaining 4 patients. In the SRS/ surgery group, the median duration of dabrafenib continuation beyond progression was 11 weeks (range, 5-39 weeks) (Table 3). 533
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16> 17 18 19 20 21 22 23
42 61 10 42 6 30 13 91 8 91 44 6 36 31 4 10 28 9 11 6 17 8 20
IC SoD at Baseline (mm) 257 25 0 264 267 253 246 241 0 243 211 250 239 242 2100 270 225 267 255 2100
Best % Response in IC Lesions IC IC IC IC IC IC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC EC EC EC EC EC EC No PD No PD Ceased Rx prior to PD
Site of First PD
X X X
X X X X
New IC met
X X X X X
X X X X X X X X
Existing IC met
X
X X X
New EC met
X X X X X X X X X X
X X X
Existing EC met 110 95 108 127 209 314 28 84 100 220 52 165 114 112 155 220 112 113 109 294 294c 211c 80d
TTFP WBRT Nil Sx WBRT Sx SRS WBRT Nil WBRT SRS Nil nil WBRT Nil # # # # # #
Local Rx to IC Lesions Post-IC PD 66 0 89a 147 273 8a 16 1 3 70 32 55 3 28 0 71 204 53 22 86 N/A N/A N/A
Dabrafenib Rx Post-PD (days)
88 10 89a 184 513a 8a 85 17 156 70 55 83a 42 42 151 88 208 102 73 148 N/A N/A N/A
Survival After First PD (days)
198 105 197b 311 722b 323b 113 101 256 290 107 248b 156 154 306 308 320 215 182 230 294b 211b 224
OS From Start of Study (days)
b
Ongoing at data cut; patient alive at last follow-up; c duration of follow-up; d duration on treatment. Abbreviations: BM, brain metastasis; EC, extracranial; IC, intracranial; met, metastasis; N/A, not applicable; OS, overall survival; PD, progressive disease; Pt., patient; Rx, treatment; SoD, sum of diameter; SRS, stereotactic radiosurgery; Sx, surgery; TTFP, time to first progression; WBRT, whole-brain radiotherapy; X, site of progression; #, no IC progression.
nil Sx, WBRT SRS nil nil Sx nil Sx, WBRT nil WBRT WBRT nil nil Sx, SRS nil nil Sx, WBRT, SRS Sx Sx, WBRT nil nil Sx nil
Pt.
a
Rx to BM Prior to Trial Entry
Progression
TABLE 3. Site and Time to First Progression for Each Patient From Commencement of Treatment, Arranged According to Site of Progression
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Dabrafenib and Melanoma Brain Metastases/Azer et al
DISCUSSION Several trials have demonstrated BRAF inhibitors are active in patients with melanoma brain metastases.9-11 To the authors’ knowledge, this is the first study to assess the nature of IC and EC response and progression in patients with melanoma brain metastases treated with a BRAF inhibitor. Results from this study of dabrafenib treatment suggest that IC and EC melanoma metastases respond in a concordant manner, with high response rates and similar PFS. Disease progression in those with brain metastases treated with dabrafenib is heterogeneous, and the brain is not necessarily the site of treatment failure in patients with active brain metastases at start of treatment. The results of this study are strengthened by the inclusion of patients with a broad spectrum of IC and EC disease burden, the detailed assessment of both IC and EC disease during treatment, and the inclusion of multiple clinicopathologic parameters for analysis. The median PFS and OS seen in this study (16 and 36 weeks, respectively) are similar to those reported in the BREAK-MB trial10 (16 and 32 weeks, respectively), suggesting that the patients included in this study are a representative subgroup of the phase 2 trial. The response rates in both IC and EC sites observed in this study are higher than those previously reported in trials,9,10,14,15 potentially due to the bias introduced by the single radiologist reporting every scan. This bias affected assessment of both IC and EC sites in equal measure, however, and therefore should not have significantly influenced comparative response assessments. Our data show that disease control in the brain is similar to that in EC sites, and the IC and EC “site-specific” PFS was the same (median, 23 weeks). “Whole body” PFS, however, was shorter (median, 16 weeks). The explanation for this is that site-specific PFS only measures a subset of the total disease. Almost a third of patients progressed in EC sites with ongoing IC disease control. Overall, this is an important illustration of the fact that formal “whole body” RECIST reporting of studies of patients with brain metastases may underrepresent the rate of disease control in the brain. This could also explain the shorter PFS in BREAKMB (median, 16 weeks) compared to that reported for studies of dabrafenib in patients with exclusively EC disease (5-6 months).9,14,15 After IC disease progression, local treatment to progressing lesions with concurrent ongoing dabrafenib treatment was used in several patients. This “salvage” local treatment enabled many patients to remain on dabrafenib treatment for control of the remainder of their disease, particularly in those with isolated progression amenable to SRS. Cancer
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The heterogeneous nature of disease progression observed in this study, and the availability and success of local therapies to treat isolated areas of progression, demonstrate that RECIST-defined progression does not always mean treatment failure. Unlike chemotherapy, this phenomenon is particularly true for targeted therapies in general, regardless of the type of malignancy they are used to treat, and ceasing treatment at RECIST progression may lead to early cessation of treatment that may still be beneficial to the patient.16 In metastatic melanoma, the approach of switching to immunotherapy (eg, ipilimumab) after BRAF inhibitor disease progression has been shown to have little efficacy in retrospective studies,17,18 particularly if patients have brain metastases, whereas ongoing treatment with BRAF inhibitors beyond progression may have a survival advantage.19,20 No prospective studies have assessed this issue, however, and novel treatments such as PD-1 antibodies may have superior efficacy in this setting. The management approach to patients with melanoma brain metastases is complicated and changing rapidly. Results of this study suggest that brain metastases respond and progress similarly to EC metastases in patients treated with dabrafenib, and this should assist with choices regarding the nature and timing of local and systemic treatments. Although a prospective clinical trial sequencing local and targeted therapies for patients with brain metastases is required to clarify the general treatment algorithm, a multidisciplinary approach remains critical to ensure optimal outcomes for patients with melanoma brain metastases. FUNDING SUPPORT This work was supported by capital grant funding from the Australian Cancer Research Foundation (recipient: Westmead Institute for Cancer Research). Dr. Long is recipient of a Cancer Institute NSW Research Fellowship. GlaxoSmithKline sponsored the clinical trials from which these data were derived, but had no involvement in the design or conduct of this study.
CONFLICT OF INTEREST DISCLOSURE Dr. Menzies has received travel support for conference attendance from GlaxoSmithKline (GSK) and Roche, and honoraria from Roche. Dr. Kefford has received institutional compensation as a consultant advisory board member for GSK, Roche, and Novartis. Dr. Long has received compensation as a consultant advisory board member for GSK, Roche, and Novartis, and has received honoraria from Roche. All other authors made no disclosure.
REFERENCES 1. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014–4023.
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Original Article 2. Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117: 1687–1696. 3. Skibber JM, Soong SJ, Austin L, Balch CM, Sawaya RE. Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol. 1996;3:118–123. 4. Carlino MS, Fogarty GB, Long GV. Treatment of melanoma brain metastases: a new paradigm. Cancer J. 2012;18:208–212. 5. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol. 2004;22:2101–2107. 6. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004;22:1118–1125. 7. Eigentler TK, Figl A, Krex D, et al. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer. 2011;117:1697–1703. 8. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–465. 9. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–1901. 10. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–1095. 11. Dummer R, Goldinger SM, Turtschi CP, et al. Open-label pilot study of vemurafenib in previously treated metastatic melanoma (mM) patients (pts) with symptomatic brain metastases (BM) [abstract]. Ann Oncol. 2012;23(suppl 9):ix366. Abstract 1125P.
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12. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors.European Organization for Research and Treatment of Cancer,National Cancer Institute of the United States,National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. 13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. 14. Ascierto PA, Minor D, Ribas A, et al. A phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31:3205–3211. 15. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAFmutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–365. 16. Oxnard GR, Morris MJ, Hodi FS, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst. 2012;104:1534–1541. 17. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after BRAF targeted inhibitors [abstract]. J Immunother. 2012;35:721–791. 18. Ascierto PA, Simeone E, Giannarelli D, Grimaldi AM, Romano A, Mozzillo N. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med. 2012;10:107. 19. Chan M, Haydu L, Menzies AM, et al. Clinical characteristics and survival of BRAF-mutant metastatic melanoma patients treated with BRAF inhibitor dabrafenib or vemurafenib beyond disease progression [abstract]. J Clin Oncol. 2013;31: Abstract 9062. 20. Carlino MS, Gowrishankar K, Saunders CA, et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013;12:1332–1342.
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Patterns of Response and Progression in Patients With BRAF-Mutant Melanoma Metastatic to the Brain Who Were Treated With Dabrafenib Mary W. F . Azer, MB ChB1,2; Alexander M. Menzies, MBBS2,3; Lauren E. Haydu, BSCHE2,3; Richard F. Kefford, MBBS, PhD1,2,3,4; and Georgina V. Long, MBBS, PhD2,3,4
BACKGROUND: Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib. METHODS: Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed. RESULTS: A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P 5.416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P 5.465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days. CONCLUSIONS: IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progresC 2013 American Cancer Society. sion, with ongoing dabrafenib treatment possible in a subset of patients. Cancer 2014;120:530–6. V KEYWORDS: melanoma, BRAF inhibitor, brain metastases, dabrafenib, response, progression.
INTRODUCTION Melanoma commonly metastasizes to the brain. Twenty percent of patients have brain metastases at diagnosis of stage IV disease,1 and approximately 50% ultimately develop them through the course of disease.2 They occur more frequently in those with BRAF -mutant than BRAF wild-type melanoma.1 Brain metastases carry a poor prognosis, with a median survival of 3 to 5 months from diagnosis, contributing to death in up to 50% of patients.2,3 Surgery and radiotherapy can provide local control and improvement in neurological symptoms in those with limited disease,4 but until the availability of selective BRAF inhibitors, systemic therapies had limited efficacy, with response rates of no more than 10%.2,4-8 BRAF inhibitors have significant activity in patients with melanoma brain metastases, as seen in the phase 1 and 2 clinical trials of dabrafenib9,10 and the pilot study of vemurafenib.11 The phase 2 trial of dabrafenib in 172 patients with progressing brain metastases with or without prior local treatment demonstrated an intracranial (IC) response rate of 30% to 40%, an IC disease control rate of > 80%, a median progression-free survival (PFS) of 16.1 and 16.6 weeks in 2 cohorts, and a median overall survival (OS) of 33.1 and 31.4 weeks in the same cohorts of BRAFV600E (Val600Glu substitution in BRAF) metastatic melanoma patients. Although this study demonstrated unprecedented efficacy in patients with
Corresponding author : Georgina Long, PhD, MBBS, Melanoma Institute Australia and The University of Sydney, 40 Rocklands Road, North Sydney, NSW 2060, Australia; Fax: (011) 161 2 9954 9290; [email protected] 1 Westmead Hospital, Westmead, Australia; 2Melanoma Institute Australia, Sydney, Australia; 3The University of Sydney, Sydney, Australia; 4Westmead Institute for Cancer Research, Westmead, Australia
This study was presented in part at the 2012 American Society of Clinical Oncology Annual General Meeting, Chicago, Illinois, and the 2012 Medical Oncology Group Australia Annual Scientific Meeting, Brisbane, Australia. We thank the Westmead melanoma and clinical trials team: Arthur Clements, Lydia Visintin, Rebecca Hinshelwood, Amie Cho, Vicky Wegener, Andrea Del Pilar Forero V., Jacob Cunningham, Natalie Byrne, Katherine Carson, Joanna Jackson, Medhia Survery, Meenal Rai, Larry Hernandez; and Angela Hong, Gerald Fogarty, Brindha Shivalingham, Peter Lebowitz, Jeffrey Legos (GlaxoSmithKline), Michael Streit (GlaxoSmithKline), and Vicki Goodman (GlaxoSmithKline) for their assistance with this work. The first 2 authors are equal contributors to this study. DOI: 10.1002/cncr.28445, Received: July 30, 2013; Revised: September 6, 2013; Accepted: September 13, 2013, Published online November 5, 2013 in Wiley Online Library (wileyonlinelibrary.com)
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Dabrafenib and Melanoma Brain Metastases/Azer et al
both untreated and previously treated brain metastases, it did not report data regarding the extracranial (EC) response to therapy in patients on the trial, nor did it examine the degree of concordance of response to therapy within individual patients (IC versus EC). No studies to date have examined the nature of disease progression in patients with brain metastases treated with BRAF inhibitors, nor have they examined treatments received afterward. There are now several strategies for the management of brain metastases in patients with metastatic melanoma, including surgery, radiotherapy, immunotherapy, and BRAF inhibitors. In order to assist with the translation of clinical trial data into effective patient care, particularly for patients with IC and EC disease at the time of first diagnosis of metastatic disease, it is critical to understand the comparative IC and EC tumor response to BRAF inhibition, the nature of disease progression, and the effective management of patients after intracranial disease progression. In this study, we sought to analyze the nature of IC and EC response and progression in patients with melanoma brain metastases treated with dabrafenib, and hypothesized that IC and EC metastases respond and progress similarly to BRAF inhibitors.
MATERIALS AND METHODS Patient Selection
The study was undertaken at Westmead Hospital in association with the Melanoma Institute of Australia (NSW, Australia), with Human Research Ethics Committee approval and patient informed consent. All patients who were enrolled in the brain cohort of the phase 1 trial9 and the phase 2 brain metastasis trial (BREAK-MB)10 of dabrafenib at Westmead Hospital between September 2009 and June 2011 were assessed. Patients were eligible for enrollment if they had BRAFV600E or BRAFV600K metastatic melanoma as assessed by high-resolution melt analysis and sequencing (phase 1 trial), or trial-specific polymerase chain reaction–based test (phase 2 trial), and either: 1) untreated, or 2) progressive but previously locally treated asymptomatic brain metastases (progression in the brain was determined using RECIST [Response Evaluation Criteria In Solid Tumors] version 1.0 for the phase 1 trial or modified RECIST version 1.1 in the phase 2 trial).12,13 Previous local brain treatment included surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or a combination of local therapies. At least 1 measurable IC lesion ( 0.3 cm and 4 cm for the phase 1 trial, 0.5 cm and 4 cm for the Cancer
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phase 2 trial) as determined by gadolinium-enhanced magnetic resolution imaging (MRI) was required for trial entry. Concomitant corticosteroids were permitted if at a stable or reducing dose, and prophylactic or preventative antiepileptic therapy was allowed. Patients were allowed up to 2 lines of prior systemic treatment excluding mitogen-activated protein kinase inhibitors and were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. BRAF Inhibitor Treatment
All patients were treated with dabrafenib at the recommended phase 2 dose (RP2D) of 150 mg twice daily (bid), except for one patient on the phase 1 trial who commenced 70 mg bid and was escalated to the RP2D after 12 weeks. Patients with progressive disease (PD), defined as either IC, EC, or overall (as per RECIST criteria), were allowed to continue on dabrafenib if deemed to have ongoing clinical benefit from this treatment, including after local therapies (surgery, radiotherapy). Disease Assessments
Baseline demographics including patient age, sex, BRAF genotype, the date of diagnosis of stage IV disease, and diagnosis of first brain metastasis, as well as details of prior brain metastasis treatment were collected. Baseline clinicopathologic parameters examining the patient’s burden of disease including lactate dehydrogenase level and RECIST sum of diameters (SoD) of target lesions (IC, EC, and overall total [SoD of IC and EC]). In addition, computed tomography (CT) and MRI scans were reviewed, and the sites of EC metastases as well as the total number of IC and EC metastases were collected. The number and site of EC metastases were recorded, and patients with 20 IC metastases were classified into groups (20-30, 30-40, 40-50 metastases). Disease assessments performed during treatment included clinical assessment every 4 weeks and imaging studies (cerebral MRI and chest, abdomen, and pelvis CT scans) at week 4, week 8, and every 8 weeks thereafter. RECIST criteria (version 1.0 for the phase 1 trial, version 1.1 for the phase 2 trial)12,13 were used to determine disease response extracranially, and modified RECIST10 was used to assess intracranial response. Overall response was determined by combining the RECIST SoD of target lesions at both IC and EC sites.10 Concordance of IC and EC response was defined as either partial/complete response (PR/CR, IC, and EC), stable disease (SD, IC, and EC), or progressive disease (PD, IC, and EC). We determined disease progression at IC and EC sites 531
Original Article TABLE 1. Baseline Patient and Disease Characteristics Characteristic Sex Male Female Age at trial start (years) Median (range) BRAF genotype V600E V600K BM at stage IV diagnosis Yes No Previous local treatment to BM Nil Surgery SRS WBRT Combination Baseline ECOG ECOG 0 ECOG 1 Baseline LDH ULN >ULN Total number of IC metastases Median (range) RECIST SoD of IC targets (mm) Median (range) Total number of EC metastases Median (range) RECIST SoD of EC targets (mm) Median (range) Number of EC sites Median (range) Clinical trial Phase 1 Phase 2 Total
Total N (%)
15 (65%) 8 (35%) 58 (23-82) 19 (83%) 4 (17%) 10 (43%) 13 (57%) 12 (52%) 3 (13%) 1 (4%) 2 (9%) 5 (22%) 13 (57%) 10 (43%) 9 (39%) 14 (61%) 4 (1-50) 17 (4-91) 4 (0-50) 85 (0-226)
RESULTS Patient Characteristics
Twenty-three patients were included for analysis, and baseline characteristics are shown in Table 1. Twelve patients (52%) had no prior local treatment for brain metastases, and 11 patients (48%) had received prior local treatment with subsequent disease progression intracranially. These groups were not analyzed separately due to the small patient numbers and unbalanced baseline characteristics. Patients had a median of 4 IC and 10 EC metastases, with a median RECIST SoD of 17 mm (IC) and 85 mm (EC) at baseline. One patient had no EC disease at trial entry, and another had EC disease that was not RECIST-measurable, and neither were included for EC response assessment. The median number of EC sites was 4 with a range of 1 to 8 sites, reflecting variable burden of EC disease.
4 (1-8)
Response, PFS, and OS 6 17 23
Abbreviations: BM, brain metastases; EC, extracranial; ECOG, Eastern Cooperative Oncology Group performance status; IC, intracranial; LDH, lactate dehydrogenase; SoD, sum of diameter; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; ULN, upper limit of normal.
separately based on RECIST criteria. For PFS, we used the earliest progressing site (IC or EC) and not the overall RECIST SoD, which was used in determining progression in BREAK-MB.10 Statistical Methods
All statistical analyses were carried out with IBM SPSS Statistic, version 19.0. Univariate survival analyses were conducted with the Kaplan-Meier method together with the log-rank (Mantel-Cox) test for statistical significance of categorical variables. Cox regression was used to test survival for continuous variables. P values < .05 were considered statistically significant. PFS was defined as the time interval in days from commencement of dabrafenib to the first date of progression intracranially (IC PFS), 532
extracranially (EC PFS), or overall (overall PFS, defined as PFS of the first progressing site). In those with PD in either IC or EC sites alone who continued on dabrafenib treatment beyond progression for ongoing clinical benefit, PFS for the other site was calculated. OS was defined as the time interval in days from commencement of dabrafenib to the date of last follow-up or death. All patient deaths in this cohort were attributed to melanoma.
The overall, IC, and EC response rates, and PFS as well as OS, are shown in Table 2. The overall response rate was 87% (20 of 23 patients), with median time to best response of 7.7 weeks, median PFS of 16.3 weeks, and median OS of 36.6 weeks. IC and EC response rates were similar at 78% (18 of 23 patients) and 90% (19 of 21 patients), respectively (P 5 .416). There was a trend toward shorter time to best response in the IC compared with EC sites (median 7.4 versus 12.4 weeks, P 5 .107). The median PFS was similar in IC and EC sites (23.6 weeks each, P 5 .465). Intrapatient IC and EC Concordance of Response
For those with measurable IC and EC disease at baseline as per RECIST (N 5 21), IC and EC best RECIST response category was concordant (ie, PR/CR IC and EC; SD IC and EC; or PD IC and EC) in 15 (71%) patients. The degree of response was also similarly concordant (Fig. 1). Only one patient had tumor growth in EC disease (although still classified as stable disease) with shrinkage in IC disease. Cancer
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TABLE 2. Response, Progression-Free Survival, and Overall Survival Based on Site of Disease
RECIST response category Progressive disease Stable disease Partial response Complete response Total Time to best response Total N Median (weeks) (95% CI) Range (weeks) Progression-free survival N progressed Median (weeks) (95% CI) Range (weeks) Overall Survival N died Median (weeks) (95% CI) Range
Overall
Intracranial
Extracraniala
Pb
1 2 20 0 23
1 4 16 2 23
0 2 19 0 21
0.416c
23 7.7 (6.4-9.1) 3.4-31.3
23 7.4 (7.0-7.9) 3.4-31.3
21 12.4 (8.4-16.5) 3.4-24.3
0.107
20 16.3 (14.1-18.5) 4.0-44.9
18 23.6 (13.6-33.6) 4.0-58.9
16 23.6 (13.9-33.2) 4.0-56.9
0.465
17 36.6 (22.2-50.9) 14.4-103.1
-
-
-
Abbreviations: CI, confidence interval; PD/SD, progressive/stable disease; PR/CR, partial/complete response; RECIST, Response Evaluation Criteria In Solid Tumors. a One patient did not have measurable extracranial disease, one patient did not have extracranial disease. Neither included in extracranial response assessment. b Comparing intracranial versus extracranial disease. c Comparing PD/SD versus PR/CR, Fisher’s exact test.
existing lesions, IC versus EC site); however, no patients progressed due to the development of new lesions alone. Management After Disease Progression
Figure 1. Scatter plot demonstrates concordance of best response (percent change in sum of diameters of target lesions from baseline) in intracranial (IC) and extracranial (EC) sites within each patient (N 5 21).
Disease Progression
Twenty patients had PD at the time of analysis: 30% (N 5 6) of patients progressed in IC sites alone, 40% (N 5 8) progressed in both IC and EC sites simultaneously, whereas 30% (N 5 6) progressed in EC sites alone with ongoing IC response (Table 3). There was no dominant pattern to the nature of progression (new versus Cancer
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In those with isolated IC progression (N 5 6) (Table 3), 5 underwent local therapy to the brain. Two patients underwent SRS, 2 patients underwent surgery, and one patient received WBRT. The patient who did not receive subsequent treatment to the brain had received prior local brain treatment prior to trial entry (surgery and WBRT) and the lesions were not amenable to further therapy. Five of the 6 patients continued on dabrafenib for > 30 days after progression, with one patient continuing on treatment for 39 weeks after surgery to an isolated progressing IC lesion. In those who progressed at both IC and EC sites (N 5 8) (Table 3), 4 received salvage local therapy to IC metastases and 3 patients continued on dabrafenib (> 30 days) after progression. In patients with isolated EC progression (N 5 6), 4 continued on dabrafenib (> 30 days) after progression. In total, 14 patients had IC progression (isolated or in combination with EC progression). Five patients underwent SRS/surgery, another 5 patients underwent WBRT, and further treatment of the progressing lesion(s) was not possible in the remaining 4 patients. In the SRS/ surgery group, the median duration of dabrafenib continuation beyond progression was 11 weeks (range, 5-39 weeks) (Table 3). 533
534
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16> 17 18 19 20 21 22 23
42 61 10 42 6 30 13 91 8 91 44 6 36 31 4 10 28 9 11 6 17 8 20
IC SoD at Baseline (mm) 257 25 0 264 267 253 246 241 0 243 211 250 239 242 2100 270 225 267 255 2100
Best % Response in IC Lesions IC IC IC IC IC IC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC IC & EC EC EC EC EC EC EC No PD No PD Ceased Rx prior to PD
Site of First PD
X X X
X X X X
New IC met
X X X X X
X X X X X X X X
Existing IC met
X
X X X
New EC met
X X X X X X X X X X
X X X
Existing EC met 110 95 108 127 209 314 28 84 100 220 52 165 114 112 155 220 112 113 109 294 294c 211c 80d
TTFP WBRT Nil Sx WBRT Sx SRS WBRT Nil WBRT SRS Nil nil WBRT Nil # # # # # #
Local Rx to IC Lesions Post-IC PD 66 0 89a 147 273 8a 16 1 3 70 32 55 3 28 0 71 204 53 22 86 N/A N/A N/A
Dabrafenib Rx Post-PD (days)
88 10 89a 184 513a 8a 85 17 156 70 55 83a 42 42 151 88 208 102 73 148 N/A N/A N/A
Survival After First PD (days)
198 105 197b 311 722b 323b 113 101 256 290 107 248b 156 154 306 308 320 215 182 230 294b 211b 224
OS From Start of Study (days)
b
Ongoing at data cut; patient alive at last follow-up; c duration of follow-up; d duration on treatment. Abbreviations: BM, brain metastasis; EC, extracranial; IC, intracranial; met, metastasis; N/A, not applicable; OS, overall survival; PD, progressive disease; Pt., patient; Rx, treatment; SoD, sum of diameter; SRS, stereotactic radiosurgery; Sx, surgery; TTFP, time to first progression; WBRT, whole-brain radiotherapy; X, site of progression; #, no IC progression.
nil Sx, WBRT SRS nil nil Sx nil Sx, WBRT nil WBRT WBRT nil nil Sx, SRS nil nil Sx, WBRT, SRS Sx Sx, WBRT nil nil Sx nil
Pt.
a
Rx to BM Prior to Trial Entry
Progression
TABLE 3. Site and Time to First Progression for Each Patient From Commencement of Treatment, Arranged According to Site of Progression
Original Article
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Dabrafenib and Melanoma Brain Metastases/Azer et al
DISCUSSION Several trials have demonstrated BRAF inhibitors are active in patients with melanoma brain metastases.9-11 To the authors’ knowledge, this is the first study to assess the nature of IC and EC response and progression in patients with melanoma brain metastases treated with a BRAF inhibitor. Results from this study of dabrafenib treatment suggest that IC and EC melanoma metastases respond in a concordant manner, with high response rates and similar PFS. Disease progression in those with brain metastases treated with dabrafenib is heterogeneous, and the brain is not necessarily the site of treatment failure in patients with active brain metastases at start of treatment. The results of this study are strengthened by the inclusion of patients with a broad spectrum of IC and EC disease burden, the detailed assessment of both IC and EC disease during treatment, and the inclusion of multiple clinicopathologic parameters for analysis. The median PFS and OS seen in this study (16 and 36 weeks, respectively) are similar to those reported in the BREAK-MB trial10 (16 and 32 weeks, respectively), suggesting that the patients included in this study are a representative subgroup of the phase 2 trial. The response rates in both IC and EC sites observed in this study are higher than those previously reported in trials,9,10,14,15 potentially due to the bias introduced by the single radiologist reporting every scan. This bias affected assessment of both IC and EC sites in equal measure, however, and therefore should not have significantly influenced comparative response assessments. Our data show that disease control in the brain is similar to that in EC sites, and the IC and EC “site-specific” PFS was the same (median, 23 weeks). “Whole body” PFS, however, was shorter (median, 16 weeks). The explanation for this is that site-specific PFS only measures a subset of the total disease. Almost a third of patients progressed in EC sites with ongoing IC disease control. Overall, this is an important illustration of the fact that formal “whole body” RECIST reporting of studies of patients with brain metastases may underrepresent the rate of disease control in the brain. This could also explain the shorter PFS in BREAKMB (median, 16 weeks) compared to that reported for studies of dabrafenib in patients with exclusively EC disease (5-6 months).9,14,15 After IC disease progression, local treatment to progressing lesions with concurrent ongoing dabrafenib treatment was used in several patients. This “salvage” local treatment enabled many patients to remain on dabrafenib treatment for control of the remainder of their disease, particularly in those with isolated progression amenable to SRS. Cancer
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The heterogeneous nature of disease progression observed in this study, and the availability and success of local therapies to treat isolated areas of progression, demonstrate that RECIST-defined progression does not always mean treatment failure. Unlike chemotherapy, this phenomenon is particularly true for targeted therapies in general, regardless of the type of malignancy they are used to treat, and ceasing treatment at RECIST progression may lead to early cessation of treatment that may still be beneficial to the patient.16 In metastatic melanoma, the approach of switching to immunotherapy (eg, ipilimumab) after BRAF inhibitor disease progression has been shown to have little efficacy in retrospective studies,17,18 particularly if patients have brain metastases, whereas ongoing treatment with BRAF inhibitors beyond progression may have a survival advantage.19,20 No prospective studies have assessed this issue, however, and novel treatments such as PD-1 antibodies may have superior efficacy in this setting. The management approach to patients with melanoma brain metastases is complicated and changing rapidly. Results of this study suggest that brain metastases respond and progress similarly to EC metastases in patients treated with dabrafenib, and this should assist with choices regarding the nature and timing of local and systemic treatments. Although a prospective clinical trial sequencing local and targeted therapies for patients with brain metastases is required to clarify the general treatment algorithm, a multidisciplinary approach remains critical to ensure optimal outcomes for patients with melanoma brain metastases. FUNDING SUPPORT This work was supported by capital grant funding from the Australian Cancer Research Foundation (recipient: Westmead Institute for Cancer Research). Dr. Long is recipient of a Cancer Institute NSW Research Fellowship. GlaxoSmithKline sponsored the clinical trials from which these data were derived, but had no involvement in the design or conduct of this study.
CONFLICT OF INTEREST DISCLOSURE Dr. Menzies has received travel support for conference attendance from GlaxoSmithKline (GSK) and Roche, and honoraria from Roche. Dr. Kefford has received institutional compensation as a consultant advisory board member for GSK, Roche, and Novartis. Dr. Long has received compensation as a consultant advisory board member for GSK, Roche, and Novartis, and has received honoraria from Roche. All other authors made no disclosure.
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