ALEX is a global, Phase III trial evaluating the use of ALECENSA and crizotinib in ALK+ NSCLC.⁷ Results so far confirm nearly three years mPFS with ALECENSA, alongside leading 5-year overall survival rates, as well as favourable safety and tolerability vs crizotinib.^7,8

Study design: A Phase III, multicentre, global, randomised, open-label trial evaluating ALECENSA against crizotinib in treatment-naïve patients with Stage IIIB/IV ALK+ NSCLC.² The primary endpoint was to assess the PFS using RECIST v1.1 (investigator assessment).² Secondary endpoints were independent review committee-assessed PFS, time to CNS progression, objective response rate, and overall survival.² A total of 303 patients were enrolled, 122 patients with CNS metastases and 181 without were included in the clinical trial.²

The updated data (data cut-off: November 30, 2018) confirmed the superior efficacy of ALECENSA with the primary endpoint being met [mature, final ITT stratified mPFS of 34.8 months with ALECENSA vs 10.9 months with crizotinib; HR=0.43 (95% CI: 0.32, 0.58) p<0.0001] and the risk of disease progression or death reduced by 57% (ITT; stratified HR=0.43, 95% CI: 0.32, 0.58).⁸ Even with significantly longer treatment duration with ALECENSA (28.1 months vs 10.8 months), the proportion of patients with Grade 3–5 AEs (52% vs 56%), AEs leading to dose reduction (20% vs 20%) or interruption (26% vs 26%) was similar with ALECENSA vs crizotinib.⁸
 

Additional 12-month follow-up from the final PFS cut-off (November 29, 2019) confirmed clinically meaningful superiority of ALECENSA vs crizotinib in regard to OS rates at 5 years (62.5% [95% CI: 54.3, 70.8] with ALECENSA vs 45.5% [95% CI: 33.6, 57.4] with crizotinib).⁸ The OS benefit of ALECENSA was generally consistent across all patient subgroups with 34.9% and 8.6% of patients remaining on their respective study treatment at cut-off.⁸ OS data for ALECENSA remain immature with 37% of events recorded (stratified HR=0.67 [95% CI: 0.46, 0.98]).⁸ The median duration of follow-up was 48.2 months (range 0.5–62.7) with ALECENSA and 23.3 months (range 0.3–60.6) with crizotinib.⁸ No new safety signals were detected.⁸

The first Phase III randomised trial to evaluate the efficacy and safety of ALECENSA vs crizotinib in Asian patients.⁹
 

This study is the first Phase III randomised trial recruiting only Asian patients to compare ALECENSA with crizotinib as a first-line treatment for ALK+ NSCLC.9 This study assessed consistency of the PFS benefit with the global Phase III ALEX study.⁹
 

Study design: A randomised, open-label, Phase III study done at 21 investigational sites in China, South Korea, and Thailand.⁹ 187 Asian patients, aged 18 years or older, with ALK+ NSCLC were randomly assigned to ALECENSA or crizotinib.⁹ Patients with asymptomatic CNS metastases were permitted.⁹ The primary endpoint was investigator-assessed PFS.⁹ The primary analysis population for efficacy was the ITT population, defined as all randomly assigned patients.9 The primary analysis population for safety was defined as all patients who received at least one dose of study medication.⁹
 

The data confirmed alignment with the ALEX trial.⁹ Investigator-assessed PFS was significantly prolonged with ALECENSA versus crizotinib (HR=0.22, 95% CI: 0.13, 0.38; p<0.0001).⁹ Independent review committee-assessed PFS was also significantly longer for ALECENSA vs crizotinib group (HR=0.37, 95% Cl: 0.22, 0.61; p<0.0001).⁹ 91% of ALECENSA patients vs 77% crizotinib patients achieved an objective response, with a longer duration of response for ALECENSA than crizotinib (HR=0.22, 95% CI: 0.12, 0.40; p<0.0001).⁹ Time to CNS progression (cause-specific HR=0.14) and the percentage of patients who achieved a CNS objective response with measurable or non-measurable baseline CNS lesions were improved; 73% of ALECENSA patients vs 22% crizotinib patients.9 Even with longer treatment duration with ALECENSA than crizotinib (14.7 months vs 12.6 months, respectively), fewer patients had Grade 3–5 (29% vs 48%, respectively) or serious AEs (15% vs 26%, respectively).⁹

The first head-to-head comparison of ALECENSA and crizotinib.¹⁰ 

Based in Japan, this study directly compared the efficacy, safety and tolerability of ALECENSA against crizotinib.¹⁰ For the first time, large-scale findings evidenced superior median PFS in patients receiving ALECENSA vs crizotinib.¹⁰

Study design: A randomised, open-label, Phase III trial in Japanese ALK-inhibitor-naïve patients with ALK+ NSCLC, who were chemotherapy-naïve or had received one previous chemotherapy regimen, at 41 study sites in Japan.¹⁰ Patients were randomly assigned to ALECENSA or crizotinib until progressive disease, unacceptable toxicity, death, or withdrawal.¹⁰ The primary endpoint was PFS assessed by an independent review facility.¹⁰ The efficacy analysis was done in the ITT population, and safety analyses were done in all patients who received at least one study drug dose.¹⁰

At final PFS analysis (data cut-off: June 2018), median PFS was 34.1 months with ALECENSA (95% Cl: 22.1, NE) and 10.2 months (95% CI: 8.3–12.0) with crizotinib.¹¹ 12 ALECENSA patients had discontinued treatment vs 24 in the crizotinib group, due to AEs.11 Grade 3 or 4 events occurred at a greater frequency with crizotinib (60.6%) than ALECENSA (36.9%).¹¹ Dose interruptions due to AEs were also more prevalent with crizotinib than with ALECENSA.¹¹