Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study

Abstract

Purpose Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Patients and Methods Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Results Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Moving more potent and less toxic options to the frontline in the management of advanced lung cancer

“…Worldwide, alectinib is prescribed at 600 mg twice daily and was approved in 2015 following results from two single-arm phase-II trials [global NP28673 (NCT01801111) and the North American NP28761 (NCT01871805) studies] in patients with disease progression on or intolerance to crizotinib. These studies confirmed ORRs of approximately 50% or higher for systemic and intracranial sites of tumor burden (13,45).…”

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

“…In the dose-finding portion of the AF-002JG trial, a phase I/II study performed in the United States in ALK-positive NSCLC patients previously treated with crizotinib, alectinib allowed a RR of 55% (74). In a global phase II study testing alectinib in crizotinibrefractory ALK-rearranged NSCLC (NP28673), the RR was 50% in the whole study population (including both patients pretreated with chemotherapy and chemotherapynaive) and 45% in the subgroup of patients pretreated with chemotherapy (76). In an ongoing phase II study enrolling 87 ALK-positive patients who had progressed on crizotinib (NP28761), at the time of the primary analysis (median follow-up 4.8 months), 33 out of 69 patients (48%) with measurable disease at baseline had a confirmed partial response with alectinib (75).…”

“…At a median follow-up >30 months, Ohe et al showed that seven out of 14 patients with baseline brain metastases were still in the study without CNS or systemic progression; PFS of patients with or without brain metastases was similar. Moreover, in the recently published phase II NP28763 trial (76), among the 84 crizotinib-resistant patients with baseline CNS metastases, 23 patients obtained a CNS complete response (27%); the overall intracranial DCR was 83% and the median duration of CNS response was 10.3 months. Considering only the 35 patients with measurable brain lesions at baseline, CNS objective RR was 57%, including achievement of seven CNS complete responses.…”

“…In the USA phase II study NP28761, constipation (31 patients, 36%) represented the most common all-grade toxicity, and increase in creatinephosphokinase (CPK; 7 patients, 8%), ALT (5 patients, 6%), and AST (4 patients, 5%) levels were the most frequent grade 3-4 events (75). In the global phase II study NP28763, constipation (45 patients, 33%) represented the most common all-grade toxicity; dyspnea (4 patients, 3%); ALT (2 patients, 2%), and AST (2 patients, 2%) elevations were the most frequent grade 3-4 events (76).…”

A few pills twice a day keep ALK-positive non-small-cell lung cancer at bay

“…The new generation and FDA-approved ALK-inhibitors, ceritinib, alectinib and brigatinib, are more potent and brain-penetrable than crizotinib and retain activity against a wide spectrum of ALK resistance mutations (6). In single-arm studies, all these drugs resulted effective in crizotinib-failure setting, particularly in patients with brain metastases (BMs) (7)(8)(9)(10)(11). Furthermore, sequential use of crizotinib followed by ceritinib or alectinib produced a combined PFS exceeding 18 months (12,13).…”