ALUR 2018.

Study characteristics
Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Alectinib 600 mg orally, daily, continuously Median age (range): 55.5 (21 to 82) Female %: 43.1 Ethnicity Asian %: 6.9 ECOG 0 to 1 %: 91.7 Never smoked %: 48.6 Stage of disease IV at entry %: 95.8 Adenocarcinoma %: 100 Brain metastases at entry %: 65.3 Previous chemotherapy %: 100 Previous targeted therapy %: 100 Docetaxel 75 mg/m² intravenously, every 3 weeks or pemetrexed 500 mg/m² intravenously, every 3 weeks continuously Median age (range): 59 (37 to 80) Female %: 51.4 Ethnicity Asian %: 20 ECOG 0 to 1 %: 85.7 Never smoked %: 45.7 Stage of disease IV at entry %: 97.1 Adenocarcinoma %: 100 Brain metastases at entry %: 74.3 Previous chemotherapy %: 100 Previous targeted therapy %: 100 Inclusion criteria Histologically or cytologically confirmed diagnosis of advanced or recurrent (stage IIIB not amenable for multimodality treatment) or metastatic (stage IV) NSCLC that is ALK‐positive. ALK‐positivity must have been determined by a validated fluorescence in situ hybridisation (FISH) test (recommended probe, Vysis ALK Break‐Apart Probe) or a validated immunohistochemistry (IHC) test (recommended antibody, clone D5F3). Participant had received 2 prior systemic lines of therapy, which must have included 1 line of platinum‐based chemotherapy and 1 line of crizotinib. Prior CNS or leptomeningeal metastases allowed if asymptomatic. Participants with symptomatic CNS metastases for whom radiotherapy is not an option will be allowed to participate in this study. Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 prior to the administration of study treatment. ECOG PS of 0 to 2. For all females of childbearing potential, a negative pregnancy test must be obtained within 3 days before starting study treatment. Exclusion criteria Patients with a previous malignancy within the past 3 years are excluded (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, or in situ carcinoma of the cervix). Patients who have received any previous ALK inhibitor other than crizotinib. Any GI disorder that may affect absorption of oral medications. Pretreatment: higher proportion of ECOG 2, brain metastases, female gender, and Asian ethnicity in chemotherapy group Number enrolled: 107 Number in control group: chemotherapy 35 (docetaxel 25, pemetrexed 9) Number in treatment group: 72 alectinib Number of withdrawal (treatment/control): 20/10
Interventions	Intervention characteristics Alectinib 600 mg orally, daily, continuously Type: TKI Docetaxel 75 mg/m² intravenously, every 3 weeks or pemetrexed 500 mg/m² intravenously, every 3 weeks Type: chemotherapy
Outcomes	Progression‐free survival (PFS) using RECIST version 1.1 as assessed by investigator [ Time Frame: randomisation to first documented disease progression, death from any cause, or study end (up to 33 months) ] Percentage of participants with CNS objective response rate (ORR) with measurable CNS metastases at baseline using RECIST version 1.1 as assessed by Independent Review Committee (IRC) [ Time Frame: baseline through study end (up to 33 months) ] PFS using RECIST version 1.1 as assessed by IRC [ Time Frame: approximately 15 months (tumour assessments at baseline, every 6 weeks until progressive disease (PD), death, or withdrawal from study prior to PD) ] Percentage of participants with objective response of complete response (CR) or partial response (PR) using RECIST version 1.1 as assessed by investigator and IRC [ Time Frame: approximately 15 months (tumour assessments at baseline, every 6 weeks until PD, death, or withdrawal from study prior to PD) ] Percentage of participants with disease control using RECIST version 1.1 as assessed by investigator and IRC [ Time Frame: approximately 15 months (tumour assessments at baseline, every 6 weeks until PD, death, or withdrawal from study prior to PD) ] Duration of response (DOR) using RECIST version 1.1 as assessed by investigator and IRC [ Time Frame: from the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months) ] PFS in the intention‐to‐treat population with CNS metastases at baseline (C‐ITT)  using RECIST version 1.1 as assessed by investigator and IRC [ Time Frame: approximately 15 months (tumour assessments at baseline, every 6 weeks until PD, death, or withdrawal from study prior to PD) ] Time to CNS progression in C‐ITT population using RECIST version 1.1 as assessed by IRC [ Time Frame: approximately 15 months (tumour assessments at baseline, every 6 weeks until PD, death, or withdrawal from study prior to PD) ] Percentage of participants with disease control in C‐ITT population using RECIST version 1.1 as assessed by IRC [ Time Frame: from first documented CR, PR, or stable disease (SD) lasting at least 5 weeks through study end (up to 33 months) ] Percentage of participants with ORR in C‐ITT population using RECIST version 1.1 as assessed by IRC [ Time Frame: baseline through study end (up to 33 months) ] Duration of response for lesions in the CNS (C‐DOR) using RECIST version 1.1 as assessed by IRC [ Time Frame: from the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months) ] Overall survival (OS) [ Time Frame: randomisation to death from any cause, through study end (up to 33 months) ] Plasma concentration of alectinib Compliance of EORTC QLQ‐C30 over time [ Time Frame: baseline through Week 138 ] Percentage of participants with adverse events (AEs) [ Time Frame: baseline through study end (up to 33 months) ]
Identification	Trial name: ALUR Sponsorship source: Hoffmann‐La Roche Country: multinational (Europe, Asia)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Central randomization was performed via a block‐stratified randomization procedure (block size 6) using an interactive voice or web‐based response system"
Allocation concealment (selection bias)	Low risk	Quote: "The following steps were taken to keep the study team blinded: no aggregate review of patients indicating the treatment allocation was performed"
Blinding of participants and personnel for objective outcomes	High risk	Investigator‐assessed PFS, therefore outcome could have been influenced by blinding Comment: this was judged to be high risk
Blinding of participants and personnel for subjective outcomes	High risk	Open‐label
Blinding of outcome assessment for objective outcomes	High risk	OS not influenced by blinding.  Investigator‐assessed PFS, therefore outcome could have been influenced by blinding Comment: this was judged to be high risk
Blinding of outcome assessors for subjective outcomes	High risk	Open‐label study, outcomes could have been influenced by blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The ITT population comprised all patients randomized. The safety population comprised all patients who received 1 dose of assigned study medication."
Selective reporting (reporting bias)	Low risk	Trial date listed prior and all outcomes reported, and all prespecified outcomes reported from trial.
Other bias	Low risk	Baseline characteristics well balanced.