In a North American phase II trial reported in The Lancet Oncology, Shaw et al found that alectinib (Alecensa), which is active against acquired crizotinib (Xalkori) resistance mutations and exhibits high central nervous system (CNS) penetration, was associated with considerable activity in crizotinib-refractory ALK-positive non–small cell lung cancer (NSCLC), including CNS metastases. Findings in this study and those in a recently reported global phase II study support the recent approval of alectinib in this setting.
In the study, 87 patients with stage IIIB to IV ALK-positive NSCLC who had disease progression after crizotinib from 27 sites in the United States and Canada were enrolled between September 2013 and August 2014 and treated with oral alectinib at 600 mg twice daily until disease progression, death, or withdrawal.
The primary endpoint was the proportion of patients achieving an objective response on independent review committee (IRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) 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 performed in the intent-to-treat population. The study is ongoing, and patients are still receiving treatment.
Patients had a median age of 54 years, 55% were women, 84% were white, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 62% were never-smokers, 99% had stage IV disease, 94% had adenocarcinoma, 60% had CNS metastases, and 74% had received prior chemotherapy. Of 34 patients (39%) who had received prior brain radiotherapy, treatment had occurred more than 6 months before starting alectinib in 16 of them (47%).
At the time of primary analysis, at median follow-up of 4.8 months, 33 of 69 patients with measurable disease had confirmed partial response, yielding a response rate of 48% (95% confidence interval [CI] = 36%–60%); an additional 22 patients (32%) had stable disease. At updated analysis at a median of 9.9 months, 35 (52%, 95% CI = 40%–65%) of 67 patients with measurable disease had IRC-assessed objective response. Among the 35 patients with objective response, the median duration of response was 13.5 months (95% CI = 6.7 months to not estimable), with data from 21 of these patients censored at the time of data cutoff.
Estimated median progression-free survival among all 87 patients was 8.1 months (95% CI = 6.2–12.6 months), with data from 38 patients censored at the time of data cutoff. Estimated overall survival rate at 12 months was 71% (95% CI = 61%–81%).
Among 16 patients with measurable CNS disease at baseline, 4 (25%) achieved a complete CNS response and 8 (50%) had a partial response, for an overall response rate of 75% (95% CI = 48%–93%); median duration of CNS response was 11.1 months (95% CI = 5.8–11.1 months). All 16 patients had disease control in the CNS. Among 52 patients with measurable or nonmeasurable CNS disease, 21 (40%, 95% CI 27%–55%) had an objective response, including 13 (25%) with a complete response; 33 (63%) had a noncomplete response or stable disease; median duration of response was 11.1 months (95% CI = 10.8 months to not estimable). Disease control was achieved in 46 (89%, 95% CI = 77%–96%). Among 18 of the 52 who had not received previous brain radiation therapy, objective response occurred in 12 (67%), including a complete response in 10; 5 had stable disease.
The most common adverse events of any grade were constipation (36%), fatigue (33%), myalgia (24%), and peripheral edema (23%). The most common grade 3 or 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (8%), increased alanine transaminase (ALT; 6%), and increased aspartate transaminase (AST; 5%), and dyspnea (3%). Serious adverse events occurred in 15%.
Dose interruption occurred in 36%, and dose reduction occurred in 16%. Death due to adverse events occurred in two patients and was considered possibly related to study treatment in one patient (due to hemorrhage in a patient on anticoagulant therapy).
The investigators concluded: “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.”
The study was funded by F. Hoffmann-La Roche.
Alice T. Shaw, MD, of Massachusetts General Hospital, is the corresponding author of The Lancet Oncology article.
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