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Efficacy and safety of the ALK inhibitor alectinib in <i>ALK</i>+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673).
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2015
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PathologyPharmacotherapyPre-clinical PharmacologyTranslational PharmacologyMolecular PharmacologyOncologyMetronomic TherapyClinical TrialsAlk Inhibitor AlectinibRadiation OncologyNovel TherapyPrior CrizotinibHealth SciencesClinical TherapeuticAlk Inhibitor CrizotinibAlk+ Nsclc PtsGlobal Phase 2Cancer TreatmentPharmacologyLung CancerBronchial NeoplasmClinical PharmacologyMedicineCns MetsDrug Discovery
8008 Background: The ALK inhibitor crizotinib is approved for patients (pts) with ALK-rearranged (ALK+) NSCLC, but most pts progress within a year and CNS progression is common. The NP28673 study (NCT01801111) investigated the efficacy and safety of alectinib, a highly selective, CNS-active ALK inhibitor, in ALK+ NSCLC pts who had progressed on crizotinib. Methods: Eligible pts ( ≥ 18 yrs; locally advanced or metastatic ALK+ NSCLC [by FDA-approved FISH test]; failed on/intolerant to crizotinib) received alectinib 600mg p.o. BID until progression, death or withdrawal. Crizotinib was the only prior ALK inhibitor permitted. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included ORR by investigator; duration of response (DOR); CNS ORR and DOR; progression-free survival (PFS); disease control rate (DCR), CNS progression rate, overall survival, and safety. Results: 138 pts from 16 countries were enrolled by the 18 Aug 2014 cut-off. Median age 52 yrs; 80% had prior chemo; 60% had baseline CNS mets (60/83 treated). Median follow-up was 30 wks. In the response-evaluable population assessed by IRC (122 pts with measurable disease at baseline), ORR was 49.2% (95% CI 40.0–58.4; all PRs); DCR was 79.5% (95% CI 71.3–86.3). For patients with prior chemo and crizotinib (n = 96), ORR was 43.8% (95% CI 33.6–54.3); DCR was 78.1% (95% CI 68.5–85.9). For patients with baseline measurable CNS disease (n = 34), IRC-assessed CNS ORR was 55.9% (95% CI 37.9–72.8), including five CRs. Updated ORR, DOR and PFS data will be presented. Overall, 27.5% of pts had grade 3–5 adverse events (AEs), most commonly dyspnea (3.6%) and pulmonary embolism (2.2%); low rates of dose interruptions (19.6%), reductions (8.7%), and withdrawals (8.0%) due to AEs were seen. Conclusions: Alectinib was well tolerated and achieved a robust treatment response, including excellent intracranial activity, in ALK+ NSCLC pts who had progressed on crizotinib; most had also failed prior chemo and had CNS mets. A phase 3 trial of first-line alectinib vs crizotinib and an expanded access program are ongoing. Clinical trial information: NCT01801111.