ASCEND‐4 2017.

Study characteristics
Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Ceritinib 750 mg orally, daily, continuously Median age (range): 55 (22 to 81) Female %: 54 Ethnicity Asian %: 40 ECOG 0 to 1 %: 94 Never smoked %: 57 Stage of disease IV at entry %: 95 Adenocarcinoma %: 95 Brain metastases at entry %: 31 Previous chemotherapy %: 0 Previous targeted therapy %: 0 Cisplatin 75 mg/m²/pemetrexed 500 mg/m² or carboplatin area under the curve (AUC) 5‐6/pemetrexed 500 mg/m² x 4 intravenously every 3 weeks followed by maintenance pemetrexed 500 mg/m² every 3 weeks Median age (range): 54 (22 to 80) Female %: 61 Ethnicity Asian %: 44 ECOG 0 to 1 %: 93 Never smoked %: 65 Stage of disease IV at entry %: 97 Adenocarcinoma %: 98 Brain metastases at entry %: 33 Previous chemotherapy %: 0 Previous targeted therapy %: 0 Inclusion criteria Patient has a histologically or cytologically confirmed diagnosis of NSCLC that is ALK‐positive as assessed by the Ventana immunohistochemistry (IHC) test. The test will be performed at Novartis designated central laboratories. Patient has newly diagnosed stage IIIB (who is not a candidate for definitive multimodality therapy) or stage IV NSCLC or relapsed locally advanced or metastatic NSCLC not previously treated with any systemic anticancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not), with the exception of neo‐adjuvant or adjuvant therapy. Patient has at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Exclusion criteria Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate). Patient with a history of severe hypersensitivity reaction to platinum containing drugs, pemetrexed, or any known excipients of these drugs. Patient with symptomatic CNS metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms. Number eligible: 425 Number enrolled: 376 Number in treatment group: 189 ceritinib Number in control group: 187 chemotherapy Number of withdrawals (treatment/control): 94/145 Number completing trial (treatment/control): 95/30
Interventions	Intervention characteristics Ceritinib 750 mg orally, daily, continuously Type: TKI Cisplatin 75 mg/m²/pemetrexed 500 mg/m² or carboplatin AUC 5‐6/pemetrexed 500 mg/m² x 4 intravenously, every 3 weeks, followed by maintenance pemetrexed 500 mg/m² every 3 weeks, continuously Type: chemotherapy
Outcomes	Progression‐free survival by blinded independent review committee Overall survival Overall response rate Duration of response Disease control rate Time to response Patient‐reported outcomes with time to deterioration for quality of life Adverse events
Identification	Trial name: ASCEND‐4 Sponsorship source: Novartis Country: multinational (Europe, Asia, South/Central America)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was done via interactive response technology"
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was done via interactive response technology"
Blinding of participants and personnel for objective outcomes	Low risk	Quote: "Intracranial response was assessed based on images collected for the blinded independent review committee, by an independent central neuroradiologist" Overall survival would not be influenced by blinding.
Blinding of participants and personnel for subjective outcomes	High risk	Open‐label
Blinding of outcome assessment for objective outcomes	Low risk	Quote: "Intracranial response was assessed based on images collected for the blinded independent review committee, by an independent central neuroradiologist" Overall survival would not be influenced by blinding.
Blinding of outcome assessors for subjective outcomes	High risk	Open‐label
Incomplete outcome data (attrition bias) All outcomes	Low risk	Any withdrawals were stated in text.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	High risk	Quote: "overall intracranial response rate; intracranial disease control rate; duration of intracranial response; intracranial clinical benefit rate (this was added post hoc)" Comment: post hoc analysis for intracranial outcomes; this was deemed as high risk