BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer.

Thyroid BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer (doi: 10.1089/thy.2014.0123) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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1 BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer

Gerald S. Falchook, MD1, Michael Millward, MD2, David Hong, MD3, Aung Naing, MD3, Sarina Piha-Paul, MD3, Steven G. Waguespack, MD4, Maria E. Cabanillas, MD4, Steven I. Sherman, MD4, Bo Ma, PhD5, Martin Curtis, BA5, Vicki Goodman, MD5, Razelle Kurzrock, MD6

Sarah Cannon Research Institute – Denver, Denver, Colorado, United States of America†

1

2

Sir Charles Gairdner Hospital, University of Western Australia, Perth, Western Australia,

Australia 3

Dept. of Investigational Cancer Therapeutics, Division of Cancer Medicine, U.T. MD Anderson

Cancer Center, Houston, Texas, United States of America 4

Dept. of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, U.T. MD

Anderson Cancer Center, Houston, Texas, United States of America 5

GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania, United States of

America 6

Moores Cancer Center at the University of California, San Diego

†

Gerald Falchook was based at MD Anderson Cancer Center, Houston, Texas until 31st May

2014

Authors email addresses: Gerald S. Falchook: [email protected] Michael Millward: [email protected]

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2 David Hong: [email protected] Aung Naing: [email protected] Sarina Piha-Paul: [email protected] Steven G. Waguespack: [email protected] Maria E. Cabanillas: [email protected] Steven I. Sherman: [email protected] Bo Ma: [email protected] Martin Curtis: [email protected] Vicki Goodman: [email protected] Razelle Kurzrock: [email protected]

Running Title: Dabrafenib in BRAF-mutant thyroid cancer

Key terms: dabrafenib; BRAF; thyroid cancer; phase 1

Current status: Body text = 2705 words Abstract = 263 words References = 35 Tables = 2 Figures = 4

Name and reprint requests should be addressed to corresponding author.

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Thyroid BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer (doi: 10.1089/thy.2014.0123) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 3 of 53

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Clinical Trial Registration Number: NCT00880321

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4 ABSTRACT

Background: v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations are commonly identified in papillary and anaplastic thyroid carcinoma and are associated with worse prognosis compared with the wild type. BRAF inhibition in papillary thyroid carcinoma cell lines and xenografts inhibits proliferation and decreases downstream phosphorylation. Our objectives were to analyze safety and efficacy of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid carcinoma.

Methods: We present the subset of patients with BRAF-mutant thyroid carcinoma enrolled in a larger phase 1 study, the main results of which are reported elsewhere.

Results: 14 patients with V600E BRAF-mutant thyroid carcinoma were enrolled, of whom 13 (93%) had received prior radioactive iodine. The median duration on treatment was 8.4 months, and seven (50%) patients received treatment for ≥10 months. The most common treatmentrelated adverse events were skin papillomas (n=8, 57%), hyperkeratosis (n=5, 36%), and alopecia (n=4, 29%), all of which were grade 1. Treatment-related adverse events grade ≥3 included grade 4 elevated lipase and grade 3 elevated amylase, fatigue, febrile neutropenia, and cutaneous squamous cell carcinoma (n=1 for each). Four (29%) partial responses were observed, and nine (64%) patients achieved at least 10% decrease. Only one responder progressed while on the study drug after a response duration of 9.3 months. The other three responders had not progressed, with response duration of 4.6+, 10.4+ and 21.4+ months. With seven (50%) patients showing no progression at the time of study completion, the median progression-free survival was 11.3 months.

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Conclusions: Dabrafenib was well tolerated and resulted in durable responses in BRAF-mutant

differentiated thyroid carcinoma patients.

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6 INTRODUCTION

Effective standard therapies for patients with radioiodine-refractory thyroid carcinoma remain limited (1). Since the median progression free survival is approximately 1 year with sorafenib, new therapies are needed, especially as salvage therapy (2). In contrast to the 10-year survival rate of 92% in patients who achieve remission after treatment with radioactive iodine (131I), a 10year survival rate of 29% is observed in patients who do not achieve remission and a 10-year survival rate of only 10% is seen in patients without any initial 131I uptake (1). The median overall survival of patients who develop distant metastases ranges from 3 to 6 years (3). Traditional cytotoxic chemotherapy regimens, such as doxorubicin monotherapy or doxorubicin in combination with cisplatin, have yielded low response rates of short duration and have been associated with significant toxicity (3).

The mitogen-activated protein kinase (MAPK) signaling cascade, which includes the kinases RAS, RAF, MEK, and ERK, regulates cell proliferation, differentiation, apoptosis, and cell survival (4). In 80% of patients with papillary thyroid carcinoma, activating mutations are identified in genes encoding signaling molecules within the MAPK pathway (3).

Constitutive activation of BRAF by a somatic mutation results in oncogenic transformation of normal cells (5,6). Mutations in the RAF isoform BRAF typically entail substitution of valine with glutamic acid at amino acid residue 600 (V600E) and are seen in 36-86% of patients with papillary thyroid cancer and 20-25% of patients with anaplastic thyroid carcinoma (7-13). In these patients, the V600E BRAF mutation is associated with worse prognosis than wild type BRAF, including higher clinical stage, tumor size, extrathyroidal extension, lymph node metastasis, tumor recurrence, absence of tumor 131I avidity, and treatment failure of recurrent disease (8,14-17).

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In cell lines of BRAF-mutant papillary thyroid cancer, selective targeting of BRAF V600E inhibited proliferation, decreased phosphorylation of ERK and MEK, induced a G(1) block, and altered expression of genes involved in the control of G(1)-S cell-cycle transition (18). Similar promising results were observed in a xenograft model of BRAF-mutant papillary thyroid cancer, in which selective targeting of BRAF V600E achieved tumor inhibition, as well as reduction of phospho-ERK and phospho-MEK levels (18).

Dabrafenib (GSK2118436), a potent ATP-competitive inhibitor of BRAF kinase, is selective for mutant BRAF in kinase panel screening, cell lines, and xenografts (19). We performed a phase 1 study of dabrafenib in patients with advanced solid malignancies. The study design and pharmacokinetic, pharmacodynamic, and efficacy data for dabrafenib in tumors other than thyroid cancer are reported elsewhere (20). In this article, we report the safety and antitumor activity of dabrafenib in the subset of patients with advanced thyroid cancer.

MATERIALS AND METHODS

Study design

This report is a subanalysis of the BRAF-mutant thyroid cancer patients who enrolled on the firstin-human phase 1 trial of dabrafenib, in which safety, pharmacokinetic, pharmacodynamic, and antitumor activity endpoints were evaluated in patients with BRAF-mutant solid tumor malignancies (20). Dabrafenib doses administered orally to thyroid carcinoma patients included 150 mg twice daily or 100 mg three times daily. The protocol was approved by the Institutional

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8 Review Boards of the participating institutions, and all patients provided written informed consent.

Thyroid cancer patients were enrolled at the University of Texas MD Anderson Cancer Center and at the University of Western Australia Sir Gairdner Hospital. Eligibility criteria of the parent study included patients who had a histologically confirmed solid tumor for which no curative treatment was available, age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, and adequate organ function (Supplementary Methods).

Procedures

Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (21). Safety assessments are described in the appendix. Dermatological examination was performed at baseline and as clinically indicated. Disease assessments were completed using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.0 (22). Baseline radiological assessment was performed within 35 days before initiation of treatment. Initial restaging occurred at 9 weeks in the escalation cohorts and at 6 weeks in the expansion cohorts. Subsequent restaging occurred every 9 weeks. Patients who received at least one dose of study drug were included in both the safety and efficacy analyses. Accredited assays were used for tumor BRAF genotyping (appendix). Central genotyping was mandatory in the expansion cohorts and was done by Response Genetics (Los Angeles, CA, USA).

Statistical Analysis

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9 This report includes results based on the final study data on March 19, 2012. We calculated exact 95% confidence intervals (CIs) for the proportion of patients achieving a response. Progressionfree survival was defined as the interval between first dose and date of disease progression or death due to any cause. When no progression or death occurred, it was censored at the date of last adequate disease assessment. Kaplan-Meier method was used to estimate progression-free survival and Brookmeyer and Crowley’s method was used to estimate the 95% CI for median progression-free survival (23). Duration on treatment was defined as the time from first dose to the date of last dose. For patients with confirmed response, duration of response was defined as the interval between first documented response and the first date of disease progression or death due to any cause. Censoring rule for duration of response were the same as for progression-free survival. SAS version 9.1 was used for all analyses. This study is registered with ClinicalTrials.gov, number NCT00880321.

RESULTS

Between May 27, 2009 and March 2, 2011, 184 patients with various advanced malignancies were enrolled into the parent study. The pharmacokinetic and pharmacodynamic analysis of dabrafenib and adverse events in solid tumors are reported elsewhere (20). In this subanalysis, 14 patients with thyroid carcinoma were evaluated (Table 1). All 14 patients had V600E BRAF mutations and 13 (93%) patients had received prior radioactive iodine therapy. Nine of the 14 patients had not received systemic regimens in the metastatic setting, aside from 131I. Among the five patients who received systemic regimens in the metastatic setting, their best responses to their last lines of systemic therapy were partial response in one patient, stable disease in two patients, progressive disease in one patient and unknown in one patient. One patient had received prior treatment with a MEK inhibitor, and no patients had previously been treated with a selective

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10 BRAF inhibitor. Other prior systemic treatments included tamoxifen, sorafenib, tipifarnib, gemcitabine, docetaxel, interleukin-6, OPB31121 (STAT3 inhibitor), sunitinib, valproic acid, pazopanib, and axitinib.

Thirteen patients received the recommended phase 2 dose of 150 mg twice daily, and one patient received 100 mg three times daily. The median duration on treatment was 8.4 months with range from 0.3 to 23.2 months, and seven (50%) patients received treatment for longer than 10 months (Figure 1). Table 2 shows the most common treatment-related adverse events noted at a frequency of 10% or higher in patients with thyroid carcinoma. The toxicity profile observed in this analysis is similar to the adverse events observed in the parent study.

The most common treatment-related adverse events observed were skin papillomas (n=8, 57%), hyperkeratosis (n=5, 36%), and alopecia (n=4, 29%), all of which were grade 1. Treatmentrelated adverse events of grade 3 or higher included grade 4 elevated lipase (n=1), grade 3 elevated amylase (n=1), grade 3 fatigue (n=1), grade 3 febrile neutropenia (n=1), and grade 3 cutaneous squamous cell carcinoma (n=1).

Treatment-related serious adverse events were noted in two patients, including febrile neutropenia (n=1) and squamous cell carcinoma (n=1). Adverse events that resulted in dose reduction occurred in two patients, including influenza like illness and pyrexia in one patient and arthralgia in one patient. Dose interruptions were necessary in seven (50%) patients because of a total of 13 adverse events, of which the most common were fatigue (n=3, 21%) and chills (n=2, 14%). No patients discontinued treatment due to adverse event. No deaths resulted from adverse events, and 10 patients (71%) had no drug-related adverse events higher than grade 2. A full list of serious adverse events (both treatment-related and –unrelated) observed in thyroid cancer patients treated on this trial are described in Supplementary Results.

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Among the 14 patients with papillary thyroid cancer, four (29% and 95% CI, 8%, 58%) partial responses were observed (Figures 2, 3), six patients achieved stable disease, and three patients had progressive disease as best response. One patient withdrew consent after only 11 days of treatment, before having any post-baseline disease assessment. Among the three patients with progressive disease as best response, one patient had anaplastic thyroid cancer, one patient had concurrent papillary and Hürthle cell features, and one patient had prior MEK inhibitor treatment. No deaths occurred while on the study. Nine of the 14 patients achieved at least a 10% decrease by RECIST, including the four patients with partial responses. Thyroglobulin response data was available for 13 of the 14 patients (Figure 4).

In the patient with anaplastic thyroid cancer who had a best response of progressive disease, the patient’s original pathology had a mixed histology, with both differentiated and anaplastic features. Soon after starting dabrafenib, all of the patient’s palpable tumors began to decrease except one new lesion, which was biopsied and demonstrated anaplastic features. By RECIST, the patient had a 66% decrease in measurable tumor, but best response was determined to be progressive disease because of the development of the new lesion. Because the anaplastic features were present before enrolling on the trial, the progressive disease from anaplastic thyroid carcinoma was not attributed to dabrafenib.

Among the responders, at the time of data cut off only one responder developed progressive disease, with duration of response of 9.3 months, and the other three responders had not progressed, with duration of response 4.6+, 10.4+ and 21.4+ months. Six patients who had not developed progressive disease, including the three remaining patients with partial responses, were permitted to continue receiving treatment on a subsequent rollover study, which was created in order to permit for patients who were receiving clinical benefit to continue the study treatment.

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12 The median progression-free survival was 11.3 months with 95% CI lower limit of 2.1 months and the upper limit could not be determined. Among the seven patients who had not progressed, five patients had censored value of progression-free survival >11.3 months.

The four patients with variant histologies (i.e. poorly differentiated / high grade, follicular variant, oncocytic features) had a trend of less response (response rate 0% vs. 40%) and smaller median percentage decrease in size (13% vs. 23%) compared to the ten patients with conventional (welldifferentiated) histology. All of the durable responses were observed in patients with differentiated histology.

DISCUSSION

We report detailed efficacy and safety results of the largest group of BRAF-mutant thyroid carcinoma patients treated with a selective BRAF inhibitor. Our findings show that dabrafenib has good clinical activity in patients with metastatic radioiodine-refractory BRAF-mutant thyroid carcinoma, with a 29% response rate and 64% of patients achieving at least a 10% reduction in tumor size.

The antitumor activity observed in this study corroborates thyroid carcinoma preclinical models, which suggested that selective targeting of mutant BRAF V600E would inhibit cell proliferation, decrease phosphorylation of downstream MEK and ERK, induce a G(1) block, and alter expression of genes involved in the control of G(1)-S cell-cycle transition (18). Similar to BRAF-mutant melanoma cells, which display features of oncogene addiction in vitro, these data suggest that BRAF-mutant thyroid cancer cells may depend on activated BRAF for cell survival and growth (24).

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This study expands the previous very limited published clinical experience of selective BRAF inhibitors used for the treatment of BRAF-mutant thyroid cancer. In the first-in-human phase 1 trial of the selective BRAF inhibitor vemurafenib, antitumor activity was observed in the three patients with papillary thyroid cancer who enrolled, including an objective response lasting eight months in one patient (who was progression free for 12 months), and stable disease lasting 11 and 13 months in each of the other two patients (25,26).

In contrast to the antitumor activity observed with BRAF inhibition in this study, MEK inhibition monotherapy as a strategy to target the MAPK pathway has yielded only modest success. Despite preclinical studies of MEK inhibitors demonstrating potent inhibition of proliferation and tumor growth in BRAF-mutant thyroid cell lines and xenografts, clinical trials of MEK inhibitor monotherapy have not yet demonstrated robust response rates in thyroid cancer (27-30). However, a recent study demonstrated that the MEK inhibitor selumetinib can produce clinically meaningful increases in iodine uptake and retention in a subgroup of patients with iodinerefractory thyroid cancer (31).

Importantly, dabrafenib was well tolerated and resulted in mostly mild, manageable toxicity. Adverse events noted in patients with thyroid carcinoma mirrored those of the parent study (20). Proliferative skin lesions such as papillomas and hyperkeratosis, the most frequent treatmentrelated adverse events, were controlled with conservative measures for most individuals.

Even long-term treatment with dabrafenib was well-tolerated, as evidenced by the six patients who had not developed progressive disease at the time of study completion and who have continued receiving dabrafenib treatment in a rollover study, which was created in order to permit patients who were receiving clinical benefit to continue the study treatment. At the time of this

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14 publication, all six of these patients are still receiving dabrafenib without progressive disease, and four of them have been receiving dabrafenib for more than 2.5 years. A side effect profile of minimal toxicity is an especially important feature of dabrafenib which may facilitate its development as a potential therapy for papillary thyroid cancer, in which future clinical trials may investigate the potential benefit of dabrafenib in the adjuvant and neoadjuvant settings. In addition, many patients with papillary thyroid carcinoma have an indolent, chronic natural history of their disease, which might require prolonged systemic therapy. Whereas such patients are typically reluctant to undergo aggressive treatment with conventional cytotoxic chemotherapy, dabrafenib has the potential to be an acceptable alternative which could be offered as chronic treatment for such patients.

Similar to melanoma, development of resistance to BRAF inhibitors in thyroid carcinoma may be mediated through various mechanisms, including acquired mutations, such as in MEK or NRAS, or via acquired bypass pathways, such as overexpression of COT or PDGFR-beta (32). MonteroConde et al. recently demonstrated that inhibition of BRAF in thyroid cancer cell lines leads to a rebound in ERK signaling which is associated with HER2/HER3 expression (33). Translational studies designed to identify other mechanisms of resistance in thyroid carcinoma are needed and will provide the basis for future clinical trials that would combine BRAF inhibitors with other therapeutic agents.

The patient with anaplastic thyroid carcinoma who experienced a 66% decrease in target lesions by RECIST, but who developed a new lesion, highlights the difficulty of managing patients with mixed responses. Although mixed responses are common in clinical practice and have been attributed to heterogeneous clonal subsets within tumors, a systematic approach to studying the phenomenon on a large scale is needed. Considering the considerable decrease of size observed

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15 in the target lesions in this patient, strategies to maximize clinical benefit in similar, future patients could include radiation or surgical excision of a solitary, progressing lesion.

Our study is limited by small sample size, as is expected in this first-in-human phase 1 study, which was open to all BRAF-mutant solid tumor malignancies. Further trials to investigate dabrafenib’s efficacy in thyroid cancer are underway, including (1) a randomized phase II trial study of dabrafenib with or without the MEK inhibitor trametinib in patients with recurrent thyroid cancer (NCT01723202) and (2) a clinical trial to investigate whether dabrafenib can resensitize iodine-refractory papillary thyroid cancer patients to radioactive iodine therapy (NCT01534897). Because of dabrafenib’s known activity against melanoma brain metastases (20,34), further trials should also be considered to investigate dabrafenib activity against brain metastases in BRAF-mutant thyroid cancer, which although is a uncommon event occurring in approximately 1.2% of patients with differentiated thyroid cancer, is associated with a poor prognosis, including a median survival of 12.4 months and very limited treatment options (35).

In conclusion, the selective BRAF inhibitor dabrafenib is well-tolerated and active against BRAFmutant differentiated thyroid cancer, and it is a promising treatment for further development in this patient population. Further monotherapy trials, novel combination trials, and translational studies should be pursued to identify and overcome mechanisms of resistance. In addition, future trials may consider investigating the potential role for dabrafenib treatment in the adjuvant and neoadjuvant setting.

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16 ACKNOWLEDGEMENT

We thank the patients and their families. We also thank Rosa Mostorino, Quan Lin, and Judith Christmas for clinical trial coordination and Adrienne Howard for regulatory protocol assistance. This work was supported by the NIH Clinical and Translational Science Award UL1 RR024148 and by the NIH Cancer Center Support Grant (CCSG) award CA016672 to MD Anderson Cancer Center. The parent study NCT00880321 was sponsored by GlaxoSmithKline.

DISCLOSURE GSF has received research funding and travel reimbursement from GlaxoSmithKline; MM has participated in advisory boards for GlaxoSmithKline; DH, AN, SP-P, SGW have no conflict of interest to declare; MEC has received grant funding for her institute from Roche, Exelixis and Eisai, and has received personal fees (e.g. honoraria, consultancy fees etc) from Exelixis and Eisai; SIS has received grant funding to his institute from Genzyme and Pfizer, and has received personal fees from Exelixis, Bayer, Eisai, AstraZeneca, Roche, Genzyme, Pfizer and Veracyte; BM is an employee of GlaxoSmithKline; MC and VG are employees of, and hold stocks of, GlaxoSmithKline; RK has received research funding from GlaxoSmithKline.

Corresponding author: Gerald Falchook, MD, MS Director, Drug Development Program Sarah Cannon Research Institute – Denver 1800 Williams Street Denver, CO 80218 United States of America

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Email: [email protected]

Tel: 281-221-0693

Fax: 713-794-4130

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33. Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale A, Sherman EJ, Ryder M, Ghossein RA, Rosen N, Fagin JA 2013 Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov 3:520–533.

34. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D 2012 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 13:1087-1095.

35. Chiu AC, Delpassand ES, Sherman SI 1997 Prognosis and treatment of brain metastases in thyroid carcinoma. J.Clin.Endocrinol.Metab. 82:3637-3642.

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24

Figure 1: Duration on treatment for 14 patients with V600E BRAF-mutant thyroid cancer treated with dabrafenib

Footnote: ► Indicates the first occurrence of PR * Indicates time of PD → Patient continued treatment in the rollover study. ¥ Patient received prior MEK inhibitor treatment. # Patient received 100 mg TID , all other subjects received 150 mg BID † Patient with concurrent papillary and Hurthle cell features. ‡ Patient with anaplastic histology. This patient had a 66% decrease in target lesions but developed a new lesion at first restaging.

Note 1: Six patients had not developed progressive disease at the time of study completion and continued receiving treatment in a rollover study. At the time of this publication, all six of these patients are still receiving dabrafenib, and four of them have been receiving dabrafenib for more than 2.5 years.

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25

Note 2: One patient withdrew consent before having any post-baseline disease assessment.

Note 3: Duration on treatment is defined as the time interval from the first dose to the last dose on the phase 1 study, regardless of dose interruption.

Abbreviations: BID, twice a day; PD, progressive disease; PR, partial response; SD stable disease; TID, three times a day; UNK, unknown response.

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26

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27

Figure 2: Change in tumor size in 14 patients with V600E BRAF-mutant thyroid cancer treated with dabrafenib

Footnote: * Patient received prior MEK inhibitor treatment. † Patient with concurrent papillary and Hurthle cell features. # Patient received 100 mg TID. All other patients received 150 mg BID. ‡ Patient with anaplastic histology. This patient had a 66% decrease in target lesions but developed a new lesion at first restaging.

Note 1: One patient withdrew consent before having any post-baseline disease assessment, so was not included in the plot.

Note 2: The patient with the largest reduction experienced reduction in her target lesion but disease progression in a non-target lesion at the same disease assessment. Subsequent biopsy of the progressing non-target lesion demonstrated anaplastic carcinoma histology, rather than papillary carcinoma.

Abbreviations: BID, twice a day; TID, three times a day.

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28


29

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30

Figure 3: Partial response in a V600E BRAF-mutant papillary thyroid cancer treated with dabrafenib. This patient achieved a 38% decrease in tumor size and received treatment for 12 months before progressing.

(Panel A) Baseline (Panel B) After 9 weeks of treatment (Panel C) After 39 weeks of treatment

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31

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32

Figure 4. Best percentage change in thyroglobulin in patients with V600E BRAF-mutant thyroid cancer treated with dabrafenib.

Footnote: * Patient experienced radiological progression on study, with thyroglobulin level increasing from 7 μg/L at baseline to 79 μg/L on progression. † Patient underwent total thyroidectomy; this patient had a best response by RECIST of PD.

Note 1: Of the 14 patients in the study, thyroglobulin response data was not available in 1 patient with baseline thyroglobulin values only (best response by RECIST, unknown).

Note 2: Two additional patients were excluded for reasons that might interfere with interpretation of thyroglobulin levels: one patient had a baseline thyroglobulin level that was assessed more than 3 months before starting dabrafenib (best response, PR), and one patient had antithyroglobulin antibodies (best response, SD).

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33 Table 1: Baseline demographic and clinical characteristics

Patients (n=14) Age (years)

Median (range)

61 (44-83)

Gender

Male

5 (36%)

Female

9 (64%)

BRAF Mutation

V600E

14 (100%)

ECOG PS

0

3 (21%)

1

11 (79%)

Prior radioactive iodine treatment (131I)

13 (93%)

Prior surgery

13 (93%)

Prior external beam radiation

1 (7%)

Prior non-131I systemic

0

9 (64%)

regimens in the

1

2 (14%)

metastatic setting

2

2 (14%)

>3

1 (7%)

150mg BID

13 (93%)

100mg TID

1 (7%)

Dabrafenib dose received

Prior MEK inhibitor treatment

1 (7%)

Histology

Conventional (well differentiated)*

9 (64%)

Poorly differentiated** or high-grade***

3 (21%)

Follicular variant**

2 (14%)

Oncocytic and Hurthle cell features

1 (7%)

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34

* One patient’s histology was mistakenly entered as poorly differentiated into database and is correctly listed here as well differentiated. ** One patient had concurrent poorly differentiated features and follicular variant histology. *** Includes one patient with anaplastic features.

Abbreviations: BID, twice a day; ECOG, Eastern Cooperative Oncology Group; PS, Performance status; TID, three times a day

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35 Table 2: Treatment-related adverse events with frequency of 10% or higher in patients with thyroid cancer

Grade 1

Grade 2

Grade 3

Grade 4

Total

Skin papilloma

8 (57%)

0

0

0

8 (57%)

Hyperkeratosis

5 (36%)

0

0

0

5 (36%)

Alopecia

4 (29%)

0

0

0

4 (29%)

Arthralgia

1 (7%)

1 (7%)

0

0

2 (14%)

Hair texture abnormal

2 (14%)

0

0

0

2 (14%)

Pyrexia

1 (7%)

1 (7%)

0

0

2 (14%)

Seborrhoeic keratosis

2 (14%)

0

0

0

2 (14%)

Skin hypertrophy

2 (14%)

0

0

0

2 (14%)

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36

Supplementary Material

Supplementary Methods

Eligibility criteria Inclusion criteria A patient was eligible for inclusion in this study only if all of the following criteria applied. 

Written informed consent provided.



Aged 18 years or older.



Histologically or cytologically confirmed diagnosis of a solid tumour that is not responsive to standard therapies or for which there is no approved or curative therapy. Presence of a BRAF mutation was initially optional in the doseescalation cohorts but later required in both the dose-escalation and expansion cohorts due to absence of activity in BRAF wild-type tumours.



Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group scale. Patients with performance status of 2 may be enrolled with approval of the GSK Medical Monitor.



Able to swallow and retain oral medication.

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37 

Male patients must agree to use acceptable contraception methods. This criterion must be followed from the time of the first dose of study medication until 16 weeks after the last dose of study medication.



A female patient is eligible to participate if she is of: – non-childbearing potential, defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal, defined as 12 months of spontaneous amenorrhoea (in questionable cases a blood sample with simultaneous follicle stimulating hormone >40 MlU/ml and 47 oestradiol 3xULN and total bilirubin >2xULN (>35% direct bilirubin; bilirubin fractionation required) or INR >1.5 without evidence of biliary obstruction or progressive disease would be considered an untoward medical occurrence, and therefore an SAE. Other hepatic events should be documented as an AE or an SAE as appropriate. Disease-Related Events or Outcomes Not Qualifying as SAEs An event which is part of the natural course of the disease under study (i.e., disease progression) should not be reported as a SAE. Progression of the subject's neoplasia will be recorded in the clinical assessments in the eCRF. Death due to disease progression is to be recorded on the Record of Death eCRF page and not as a SAE. However, if the progression of the underlying disease is greater than that which would normally be expected for the subject, or if the Investigator considers that there was a causal relationship between treatment with GSK2118436 or protocol design/procedures and the disease progression, then it must be reported as a SAE. Any new primary cancer must be reported as a SAE.

Definition of dose-limiting toxicity An event was considered to be a dose-limiting toxicity if it occurred within the first cycle of treatment with dabrafenib and met at least one of the following criteria. 

Grade 4 haematological toxicity.

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47 

Grade 3 or 4 non-haematological toxicity (excluding alopecia). Grade 3 nausea, vomiting, and diarrhoea were considered dose limiting if uncontrolled with standard supportive measures.



Treatment delay of >14 consecutive days due to unresolved toxicity.



A grade 2 non-haematological toxicity or greater that, in the judgment of the investigator and GSK Medical Monitor, was dose limiting.



Troponin level greater than the upper limit of normal (ULN) and >10% coefficient of variance (CV) level with other clinical signs, symptoms, labs, or tests consistent with cardiac toxicity.



Troponin value >ULN and >10% CV level, and increased by >50% from baseline for >3 days.



Ejection fraction less than the lower limit of normal with a relative decrease of >20% from baseline with confirming assessment within 7 days.



Significant alteration in cardiac valve morphology from baseline, including any new grade 2 or higher valvular heart disease, as defined by Common Terminology Criteria for Adverse Events v.3 (asymptomatic moderate regurgitation or stenosis by imaging or worse).



Patients with clinical laboratory values that met dose-limiting toxicity criteria were required to have those laboratory tests repeated and verified. Patients with abnormal troponin values were required to have appropriate work-up as clinically indicated. Troponin elevation caused by disease progression or an acute event 47


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48 such as sepsis or pulmonary embolism was not considered to be a dose-limiting toxicity. Troponin dose-limiting toxicity determination required central lab confirmation of the local lab troponin changes.

BRAF testing Tumour tissue genotyping for BRAF was performed with accredited assays using allelespecific polymerase chain reaction (PCR). The main methods of tumour tissue genotyping for BRAF varied slightly at each site and at RGI, as follows. 

University of Texas MD Anderson Cancer Center: the analysis was limited to codons 468–474 of exon 11 and codons 595–600 of exon 15 of the BRAF gene.



RGI: an allele-specific PCR was used to detect the specific mutations Val600Glu: 1799T>A and Val600Lys: 1798_99GT>AA in exon 15 of the BRAF gene.

Dose Adjustment Criteria In the event of a DLT or other clinically significant adverse event (during any cycle), treatment may be withheld and supportive therapy administered as clinically indicated. If the toxicity or event resolves to baseline or Grade 1 in less than or equal to 14 days of stopping therapy, treatment with GSK2118436 may be restarted. Dose reduction should be considered as clinically indicated. Any dose adjustment or interruption will be recorded. If the toxicity does not resolve to at least Grade 1 in less than or equal to 14 days, withdrawal from the trial is recommended. However, if the investigator and GSK 48


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49 Medical Monitor agree that further treatment will benefit the subject, treatment can continue with at least 25% dose reduction.

Stopping Criteria Liver Chemistry Stopping Criteria Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology during administration of GSK2118436 and the follow-up period. GSK2118436 will be stopped if any of the following liver chemistry stopping criteria is met: • ALT >8xULN

• ALT >5xULN for more than 2 weeks

• ALT >3xULN and bilirubin >2xULN (>35% direct bilirubin, bilirubin fractionation required) without evidence of biliary obstruction

• ALT >3xULN with the appearance or worsening of eosinophilia   Refer to Section 12, Liver Chemistry Testing Procedures, for details of the assessments required if a subject meets any of the above criteria in the absence of disease progression.  

QTc Stopping Criteria  

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50 A subject that meets the criteria below will have drug stopped:

•

QTcF > 500 msec (manual overread)

•

If subject has bundle branch block, then stopping criteria is QTcF > 530 msec  

If an ECG demonstrates a prolonged QTc interval, obtain two more ECGs over a brief period, and then use the averaged, manually read, QTc values of the three ECGs to determine whether the subject should be discontinued from the study. If the QTc prolongation resolves to grade 1 or baseline, the subject may continue on therapy if the investigator and GSK medical monitor agree that the subject will benefit from further treatment.

Left Ventricular Ejection Fraction Stopping Criteria

Subjects who have an ejection fraction below the LLN with a > 20% (relative) decrease must have the ECHO repeated within one week. If the repeat ECHO confirms the initial findings, the investigational product should be held. Any decision to restart with or without dose reduction must be discussed with the GSK medical monitor. Treatment can only be restarted if LVEF resolves to the normal range. Subjects who have other signs or symptoms of cardiac toxicity in conjunction with LVEF withdrawal criteria should be taken off study unless the investigator and GSK medical monitor agree that the subject will benefit from further treatment. 50


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51

Valvular Toxicity Stopping Criteria Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO (Grade 2 mitral/tricuspid/aortic valvular toxicity per CTC AE v4.0) should temporarily discontinue GSK2118436 and have a repeat evaluation by ECHO within 1 week. ECHO should be repeated every 1-2 weeks for 4 weeks or until valve recovery to baseline. • If the valve recovers to baseline any time during the next 4 weeks, after consultation and approval of the GSK medical monitor, the subject may be restarted on GSK2118436 at a reduced dose(s). For such subjects, monitoring of the valve via ECHO will then be performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 12 weeks and then per protocol.

• If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the subject should permanently discontinue GSK2118436. The valve should continue to be monitored via ECHO every 4 weeks for 16 weeks or until recovery to baseline. 

Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging, with symptoms controlled by medical intervention) valvular toxicity must discontinue GSK2118436. Valvular toxicity should continue to be monitored every 4 weeks for  16 weeks or until recovery to baseline. If recovery occurs (return to baseline via imaging AND symptom resolution) within 4 weeks, the subject may restart GSK2118436 at a reduced dose after consultation and approval of the GSK medical monitor.   51


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52 ECHO must be performed at baseline and at follow-up visit(s). Copies of all ECHO(s) and cardiology consultations performed on subjects who experience a valvular toxicity will be required by GSK for review.

Troponin Stopping Criteria

Abnormal troponin test must be repeated and verified. A subject with elevated troponin (>ULN) must have appropriate work-up as clinically indicated. Further treatment must be discussed with the GSK medical monitor. A subject that meets the DLT criteria for troponin will have drug stopped. Further treatment can only be considered if troponin returns to normal or baseline and if the investigator and GSK medical monitor agree that further treatment will benefit the subject.

Supplementary Results

Serious adverse events (SAEs) in patients with thyroid cancer, N=14 Number of subjects (%) Abdominal pain

1(7%)

Constipation

1 (7%)

Febrile neutropenia*

1(7%)

Pancreatitis

1(7%)

52


53

Pneumonia 1(7%)

Pyrexia 1(7%)

Squamous cell carcinoma* 1(7%)

Staphylococcal bacteremia 1(7%)

* Treatment-related serious adverse event.

53

Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib.

Panniculitis With Necrotizing Granulomata in a Patient on BRAF Inhibitor (Dabrafenib) Therapy for Metastatic Melanoma.

Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.

Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436).

Multiple BRAF Wild-Type Melanomas During Dabrafenib Treatment for Metastatic BRAF-Mutant Melanoma.

Dabrafenib in an elderly patient with metastatic melanoma and BRAF V600R mutation: a case report.

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib.

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.

Dabrafenib and trametinib activity in a patient with BRAF V600E mutated and microsatellite instability high (MSI-H) metastatic endometrial cancer.

Effective treatment with Dabrafenib and Trametinib for a BRAF-mutated metastatic dedifferentiated malignant spindle cell neoplasm.

MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E.

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma.

Dabrafenib: A New Therapy for Use in BRAF-Mutated Metastatic Melanoma.

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma.

Comparative safety of BRAF and MEK inhibitors (vemurafenib, dabrafenib and trametinib) in first-line therapy for BRAF-mutated metastatic melanoma.

Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

Dabrafenib for treatment of BRAF-mutant melanoma.

NICE guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma.

Clinical observation of panniculitis in two patients with BRAF-mutated metastatic melanoma treated with a combination of a BRAF inhibitor and a MEK inhibitor.

BRAF-Directed Therapy in Metastatic Colorectal Cancer.

Primary Meningeal Pleomorphic Xanthoastrocytoma With Anaplastic Features: A Report of 2 Cases, One With BRAF(V600E) Mutation and Clinical Response to the BRAF Inhibitor Dabrafenib.

Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites.

BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer.

Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer.