The highly selective second-generation TKI alectinib demonstrated a clinically meaningful improvement in overall survival compared with crizotinib in patients with ALK-positive non–small cell lung cancer.
Solange Peters, MD, PhD
The highly selective second-generation TKI alectinib (Alecensa) demonstrated a clinically meaningful improvement in overall survival compared with crizotinib (Xalkori) in patients with ALK-positive non—small cell lung cancer (NSCLC), according to updated data from the pivotal phase 3 ALEX trial presented at the 2020 ASCO Virtual Scientific Program.1
The 5-year overall survival (OS) rate with alectinib was 62.5% versus 45.5% with crizotinib; the OS data remain immature with 37% of events recorded (stratified HR, 0.67; 95% CI, 0.46-0.98).
The median duration of follow-up with alectinib was 48.2 months (range, 0.5-62.7) versus 23.3 months (range, 0.3-60.6) with crizotinib. Notably, 34.9% of patients in the alectinib arm and 8.6% of those in the crizotinib arm were still on study treatment at the time of the analysis. There were also no new safety signals with alectinib.
“The importance of this presentation is the fact that this is the first global randomized study of the next-generation ALK TKI to demonstrate clinically meaningful improvement of OS using a new ALK TKI as compared with crizotinib in [patients with] ALK-positive NSCLC,” Solange Peters, MD, PhD, lead author of the study, chair of medical oncology in the Oncology Department at CHUV Lausanne University, said in a presentation during the meeting.
In the global, open-label, phase 3 trial, 303 patients aged ≥18 years with untreated, stage IIIB/IV ALK-positive NSCLC and an ECOG performance score of 0 to 2 were randomized to receive either alectinib at 600 mg twice daily or crizotinib at 250 mg twice daily.
Those with asymptomatic central nervous system (CNS) metastases were allowed to enroll, and CNS imaging was performed in all patients at baseline and every 8 weeks until disease progression. Crossover between the 2 arms was not permitted until disease progression. Further lines of treatment following progressive disease were left to the physician’s discretion and based on treatment availability.
The primary end point of the trial was progression-free survival (PFS) per investigator assessment. Secondary end points included PFS as assessed by an independent review committee (IRC), IRC-assessed time to CNS progression, objective response rate, duration of response, OS, and safety.
In the intent-to-treat (ITT) patient population, baseline demographics were well balanced between the 2 treatment arms. A very global population of patients were included in the trial, said Peters, adding that Asian patients accounted for almost half of the ITT population. Additionally, almost 40% of the population had CNS metastases at baseline.
At the primary analysis of the trial, with a data cutoff of February 9, 2017, the rate of investigator-assessed PFS was found to be significantly higher with alectinib compared with crizotinib in the ITT population (stratified HR, 0.47; 95% CI, 0.34-0.65; P <.001).2 The median PFS with alectinib had not been reached versus 11.1 months with crizotinib.
Mature PFS findings from the trial, at a data cutoff of November 30, 2018, confirmed the significant improvement previously observed with the second-generation TKI.3 Specifically, median investigator-assessed PFS with alectinib versus crizotinib was 34.8 months and 10.9 months, respectively (ITT stratified HRR, 0.43; 95% CI, 0.32-0.58; P <.0001).
The median investigator-assessed PFS was also longer with alectinib versus crizotinib in patients with baseline CNS metastases, at 25.4 months versus 7.4 months, respectively (HR, 0.37; 95% CI, 0.23-0.58) and in those without, at 38.6 months and 14.8 months, respectively (HR, 0.46; 95% CI, 0.31-0.68). The PFS event-free rate was higher with alectinib versus crizotinib, irrespective of the presence of baseline CNS metastases, with 43.7% of patients who received alectinib event free at 4 years.
The OS data remained immature, with 32% of events recorded (stratified HR, 0.69; 95% CI, 0.47-1.02). In patients with CNS metastases at baseline, the HR was 0.60 (95% CI, 0.34-1.05) versus a HR of 0.77 in those without CNS metastases (95% CI, 0.45-1.32). The 4-year OS rate with alectinib was 64.5% (95% CI, 55.6-73.4) versus 52.2% with crizotinib (95% CI, 42.6-64.8).
With the findings presented at the 2020 ASCO Virtual Scientific Program, which included an updated data cutoff date of November 29, 2019, the median OS had not yet been reached with alectinib compared with 57.4 months with crizotinib. During the presentation, Peters reported that the OS rates at 1 to 5 years with alectinib were 84.3%, 72.5%, 67.0%, 65.3%, and 62.5%, respectively, compared with crizotinib at 82.5%, 65.3%, 57.0%, 51.2%, and 45.5%, respectively.
“The OS benefit of alectinib versus crizotinib was generally consistent across all patient subgroups,” noted Peters.
In total, 21 patients died without disease progression and without having received any follow-up therapy. Of 84 patients in the alectinib arm and 114 patients in the crizotinib arm who experienced disease progression, including symptomatic deterioration, subsequent therapy was administered in 60.7% and 63.2% of patients, respectively.
Other ALK TKIs were given to 38.1% of patients who progressed in the alectinib arm and to 53.5% of patients who progressed in the crizotinib arm. Lorlatinib (Lorbrena) and crizotinib were the most common ALK TKIs received in the alectinib arm (13.1% each) versus ceritinib (Zykadia) and alectinib in the crizotinib arm.
Beyond ALK TKIs, the most common agents received after disease progression in the alectinib and crizotinib arms were pemetrexed, carboplatin, and cisplatin. Specifically, pemetrexed was given to 26.2% versus 11.4% of those who progressed in the alectinib and crizotinib arms, respectively; carboplatin was given to 19.0% and 6.1%, respectively, and cisplatin was given to 15.5% and 6.1%.
Regarding safety, all-grade adverse events (AEs) were reported in 97% of both arms (n = 147 each). Serious AEs occurred in 39% of patients on the alectinib arm (n = 59) versus 32% of patients on the crizotinib arm (n = 48). Grade 3 to 5 AEs were reported in 52% and 56% of those in the alectinib and crizotinib arms, respectively. Seven fatal AEs were reported in each arm.
Twenty-two AEs led to treatment discontinuation in both arms; 31 events led to dose reductions in the alectinib arm versus 30 in the crizotinib arm, and 40 events in both arms led to dose interruptions.
“It’s quite important to stress that no new safety signals were observed in this updated analysis of the ALEX data, but also to keep in mind that almost a 3 times longer median treatment duration was delivered [with] alectinib as compared with crizotinib,” said Peters.
Longer follow-up is required, as OS data remain immature.