J‐ALEX 2017.

Study characteristics
Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Alectinib 300 mg orally, twice daily, continuously Median age (range): 61 (27 to 85) Female %: 60 Ethnicity Asian %: 100 ECOG 0 to 1 %: 98 Never smoked %: 54 Stage of disease IV at entry %: 74 Adenocarcinoma %: 97 Brain metastases at entry %: 14 Previous chemotherapy %: 36 Previous targeted therapy %: 0 Crizotinib 250 mg orally, daily, continuously Median age (range): 59.5 (25 to 84) Female %: 61 Ethnicity Asian %: 100 ECOG 0 to 1 %: 98 Never smoked %: 59 Stage of disease IV at entry %: 72 Adenocarcinoma %: 99 Brain metastases at entry %: 28 Previous chemotherapy %: 36 Previous targeted therapy %: 0 Inclusion criteria Histologically or cytologically confirmed ALK‐positive by immunohistochemistry and fluorescence in situ hybridisation (FISH) or reverse transcription‐polymerase chain reaction (RT‐PCR). Stage IIIB NSCLC not amenable to curative radiotherapy, stage IV NSCLC. Chemotherapy‐naive or has received 1 regimen of chemotherapy for NSCLC (continuous maintenance is included in the initial therapy). Note that neoadjuvant or postoperative adjuvant chemotherapy will only be counted as 1 regimen if the cancer recurs within 6 months after finishing therapy. Response Evaluation Criteria in Solid Tumours (RECIST) (v1.1) measurable disease. Exclusion criteria Treated with an ALK inhibitor in the past. Meningeal metastases, or brain metastases that are symptomatic or require treatment. Pleural effusion, ascites, or pericardial effusion requiring drainage. Concurrent or prior radiographically evident interstitial lung disease. HIV antibody‐positive, hepatitis B surface or hepatitis C virus (HCV) antigen‐positive, or HCV antibody‐positive. Another primary cancer with a disease‐free interval of less than 5 years Number eligible: 234 Number enrolled: 207 Number in control group: 104 Number in treatment group: 103 Number of withdrawal (treatment/control): 24/61
Interventions	Intervention characteristics Alectinib 300 mg orally, twice daily, continuously Type: TKI Crizotinib 250 mg orally, twice daily, continuously Type: TKI
Outcomes	Primary outcome Progression‐free survival as assessed by the Independent Review Facility Secondary outcomes Investigator‐assessed progression‐free survival Overall survival Proportion of participants who achieved an objective response Duration of response Time to response Time to progression of brain metastatic lesions in participants who had them at baseline Time to onset of brain metastatic lesions in participants who did not have them at baseline Health‐related quality of life Safety Pharmacokinetics
Identification	Trial name: J‐ALEX Sponsorship source: Chugai Pharmaceutical Co, Ltd. Country: Japan
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned in a 1:1 ratio, using a stratified permuted‐block method"
Allocation concealment (selection bias)	Low risk	Quote: "an interactive web response system (IxRS; EPS Corporation, Tokyo, Japan) using a randomisation code generated independently by the IxRS vendor."
Blinding of participants and personnel for objective outcomes	Low risk	Quote: "Members of the Independent Review Facility (IRF) who assessed the primary endpoint were masked to treatment and to the investigators’ assessment for each patient."
Blinding of participants and personnel for subjective outcomes	High risk	Open‐label
Blinding of outcome assessment for objective outcomes	Low risk	Quote: "Members of the Independent Review Facility (IRF) who assessed the primary endpoint were masked to treatment and to the investigators’ assessment for each patient."
Blinding of outcome assessors for subjective outcomes	High risk	Quote: "open‐label design" ; "Secondary endpoints were investigator‐assessed
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals stated in text; see CONSORT diagram in figure.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Low risk	Balanced baseline characteristics