Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAFmutated melanoma. N Engl J Med 2017;377: DOI: /NEJMoa (PDF updated January 24, 2018)

2 Table of Contents PART I. ADDITIONAL METHODS... 3 Full inclusion criteria... 3 Full exclusion criteria... 3 Dose adjustment guidelines... 4 Full definition of the primary efficacy endpoint... 4 Definitions of secondary endpoints... 4 Additional details on study assessments and statistical analyses... 4 Part II. SUPPLEMENTARY TABLE... 6 Table S1. Patient Disposition... 6 Part III. SUPPLEMENTARY FIGURES... 7 Figure S1. Trial Consort Diagram... 7 Figure S2. Kaplan-Meier Estimate of Distant Metastasis Free Survival... 8 Figure S3. Kaplan-Meier Estimate of Relapse-Free Survival

3 PART I. ADDITIONAL METHODS Full inclusion criteria In addition to the criteria listed in the main text, patients were required to have adequate organ function, including hematologic (absolute neutrophil count /L, hemoglobin 9 g/dl, platelet count /L, prothrombin time/international normalized ratio and partial thromboplastin time 1.5 upper limit of normal), hepatic (albumin 2.5 g/dl, total bilirubin 1.5 upper limit of normal, aspartate aminotransferase and alanine aminotransferase 2.5 upper limit of normal), renal ( 1 of the following: serum creatinine 1.5 mg/dl or creatinine clearance 50 ml/min), and cardiac (left ventricular ejection fraction lower limit of normal by echocardiography) function. Tumor BRAF V600 mutation testing was conducted using the biomérieux BRAF THxID IUO assay in a central laboratory. Women of childbearing potential must have had a negative serum β-hcg pregnancy test within 7 days of the first dose of study treatment and agreed to use effective contraception from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment. Full exclusion criteria Patients were excluded if they had mucosal or ocular melanoma. Patients presenting with initial resectable lymph node recurrence after a diagnosis of stage I or II melanoma were eligible; however, patients with an unknown primary melanoma were not eligible. Prior radiotherapy or systemic therapy (ie, chemotherapy, immunotherapy, biologic therapy, vaccine therapy, targeted therapy, or investigational treatment) for melanoma was not allowed. Patients were also ineligible if they had received an investigational anticancer drug within 28 days or 5 half-lives, whichever is longer, prior to randomization, or if they had current or expected use of a prohibited medication (other anticancer therapies, other investigational drugs, antiretroviral drugs, herbal remedies, and drugs that are strong inhibitors or inducers of CYP3A and CYP2C8). Women who were pregnant or nursing, patients with known human immunodeficiency virus, patients with history of another malignancy (including melanoma) or concurrent malignancy (exceptions included patients who were disease free for 5 years following any other malignancy without a confirmed RAS mutation, and those with a history of completely resected nonmelanoma skin cancer, successfully treated in situ carcinoma, or presenting with multiple concurrent primary melanomas), patients with known immediate or delayed hypersensitivity or idiosyncratic reaction to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide, and patients with a history or evidence of cardiovascular risk 3

4 were excluded. Patients were also excluded if they had a history of clinically significant or active interstitial lung disease or pneumonitis, history of or current evidence/risk of retinal vein occlusion or central serous retinopathy, or any serious or unstable preexisting medical condition. Dose adjustment guidelines If a dose adjustment was required, doses of both treatments were reduced simultaneously, with the exception of dose reductions for pyrexia, hypertension, or valvular toxicity (reduce and/or interrupt dabrafenib dose), and dose reductions for visual changes (including retinal vein occlusion and central serous retinopathy), left ventricular ejection fraction reduction, rash, or pneumonitis (reduce and/or interrupt trametinib dose). For dabrafenib, the dose was reduced to 100 mg on first reduction and 75 mg on second reduction; however, the dose was not reduced to <75 mg. Trametinib was reduced to 1.5 mg on first reduction and 1 mg on second reduction; however, the dose was not reduced to <1 mg. Full definition of the primary efficacy endpoint Recurrence of or death from the same cancer and all deaths from other causes were considered as events. Treatmentemergent malignancies other than second melanomas were not considered as events, and losses to follow-up were censored. Patients without recurrence-free survival events were censored at the last adequate assessment. Definitions of secondary endpoints Overall survival was defined as the interval from randomization to the date of death, irrespective of the cause of death; patients still alive were censored at the date of the last contact. An additional OS interim analysis will be performed when 50% of the target number of OS events have occurred (ie, 299 events), and the final OS analysis will be conducted at 597 events. An O Brien-Fleming type stopping boundary was used for all planned OS tests to maintain the cumulative type-i error rate at 2.5% (one-sided). For distant metastasis free survival, patients alive and without distant metastasis were censored at the date of last assessment. For freedom from relapse, patients alive without recurrence or with a second primary cancer were censored at the date of last assessment. Additional details on study assessments and statistical analyses The study was designed to provide evidence with respect to RFS to support the null hypothesis (H 0 : λ = 1) or reject it in favor of the alternate hypothesis (H A : λ 1), where λ is the HR of combination therapy relative to 2 matched 4

5 placebos. For the primary endpoint of RFS, the Pike estimator, which is a nonparametric estimator of the HR, has been specifically developed for survival data and is used as a measure of the relative survival experience of 2 groups. Within the range of values of the ratio of the HRs of interest in clinical trials, the Pike estimator is more efficient in terms of mean square error than the Cox proportional hazards method. 16,17 All baseline medical history, physical examination, laboratory, demographic, cardiac, and radiological tumor assessments were performed within 28 days before the first dose of study drug. Disease assessments included clinical examination performed at screening, on the date of randomization, and once per month through month 12, and radiological assessments, performed at screening and every 3 months through month 12; thereafter, clinical examination and radiological assessments were performed every 3 months through month 24, then every 6 months until disease recurrence or study completion. Radiological efficacy assessments were primarily performed by contrast-enhanced computed tomography (CT) scans of the chest, abdomen, and pelvis (magnetic resonance imaging [MRI] was also acceptable if scanning sequences were optimized for disease type). A contrast-enhanced MRI scan of the brain (contrastenhanced CT was allowed only if MRI was contraindicated or unavailable) was required for all patients at baseline, and subsequent scans were performed only as clinically indicated. Whenever possible, the same diagnostic method, including use of contrast when applicable, was used throughout the study. For cases of disease recurrence, patients were managed per institutional practice. 5

6 Part II. SUPPLEMENTARY TABLE Table S1. Patient Disposition Placebo to Placebo to Match Match Dabrafenib Trametinib Dabrafenib Trametinib n = 435 n = 435 n = 432 n = 432 Patients treated, n (%) Treatment ongoing as of data cutoff date* End of treatment 435 (100) 435 (100) 432 (100) 432 (100) Treatment status, n (%) Completed scheduled treatments 272 (63) 277 (64) 227 (53) 227 (53) Prematurely discontinued treatment 163 (37) 158 (36) 205 (47) 205 (47) Primary reason for premature treatment discontinuation, n (%) Adverse event 108 (25) 104 (24) 12 (3) 12 (3) Protocol deviation 2 (<1) 2 (<1) Loss to follow-up Investigator discretion 2 (<1) 2 (<1) 5 (1) 5 (1) Decision by patient or proxy 27 (6) 26 (6) 11 (3) 11 (3) Disease recurrence 23 (5) 23 (5) 175 (41) 175 (41) * Data cutoff date, 30 June

7 Part III. SUPPLEMENTARY FIGURES Figure S1. Trial Consort Diagram 7

8 Figure S2. Kaplan-Meier Estimate of Distant Metastasis Free Survival NR, not reached. 8

9 Figure S3. Kaplan-Meier Estimate of Freedom from Relapse NR, not reached. 9