Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial

Abstract

Background: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.

Methods: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.

Findings: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).

Interpretation: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

Funding: F Hoffmann-La Roche.

Figure 1. Best overall systemic responses according to IRC at the time of primary analysis

This waterfall plot illustrates the best overall responses among 69 patients with baseline measurable disease according to the IRC. A total of 33 patients achieved a partial response (PR) as their best response, and 22 patients achieved stable disease (SD). Eleven patients had progressive disease (PD) as their best response. The responses of three patients are unknown due to unavailable or unevaluable post-baseline restaging scans.

Figure 2. Best overall systemic responses according to IRC at the updated analysis

This waterfall plot illustrates the best overall responses among 67 patients with baseline measurable disease according to the IRC. A total of 35 patients achieved a partial response (PR) as their best response, and 18 patients achieved stable disease (SD). Eleven patients had progressive disease (PD) as their best response. The responses of three patients are unknown due to unavailable or unevaluable post-baseline restaging scans.

Figure 3. Progression-free survival by IRC

Shown is the Kaplan-Meier curve for estimated PFS among 87 patients treated with alectinib. PFS is defined as the time from first alectinib dose to disease progression or death from any cause. 44% of patients were censored at the time of data cut-off. Vertical lines on the PFS curve indicate censored patients.

Figure 4. Best overall CNS response to alectinib

This waterfall plot illustrates the best overall intracranial responses among 16 patients with baseline measurable CNS disease according to the IRC. Four patients achieved a complete response (CR), and eight patients achieved a partial response (PR). The remaining four patients had stable disease (SD) as their best response. Asterisks indicate those patients who did not receive prior radiation therapy for their CNS disease.

Figure 5. Cumulative incidence curves of CNS and non-CNS progression rates

Shown is the cumulative incidence of CNS and non-CNS progression, plotted using a cumulative incidence curve. CNS progression was defined as a new CNS lesion or progression of pre-existing CNS lesions, according to the IRC.