Correlation of baseline molecular and clinical variables with ALK inhibitor efficacy in ALTA-1L.

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Background: Efficacy of ALK TKIs in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) varies. We evaluated the impact of EML4-ALK fusion variants and other baseline (BL) molecular and clinical variables on clinical efficacy of brigatinib (BRG) vs crizotinib (CRZ) as first ALK TKI therapy in pts with ALK+ NSCLC in the phase 3 ALTA-1L (NCT02737501) trial. Methods: Plasma samples were collected at screening for molecular genetic analysis of ALK and other genes implicated in NSCLC by next-generation sequencing. Exploratory analyses were performed to identify associations of clinical outcomes with oncogenic alterations including ALK fusion variants and TP53 status. Results: 124 BL samples were collected from 136 BRG-treated pts and 127 from 137 CRZ-treated pts. Pts with plasma samples were representative of the intent-to-treat population. BL ALK fusion detection rate was 52% (65/124) and 54% (68/127) in the BRG and CRZ arms, respectively, of which 83% (54/65) and 93% (63/68) were EML4-ALK fusions. In pts with detectable EML4-ALK fusions, the three predominant EML4-ALK fusion variants (V1, V2, V3) were equally distributed between arms; V1 and V3 were most prevalent (BRG/CRZ: V1, 42%/47%; V3, 42%/33%) but V1 was more frequent than V3 in pts without BL brain metastasis (47% vs 36%) or prior chemotherapy (45% vs 35%). Gender and age did not impact variant type. BRG showed higher ORR and improved mPFS vs CRZ in all variant subgroups; pts with V3 had poorer PFS compared with V1 and V2 regardless of treatment (Table). In pts with V3, BRG showed significantly improved PFS (HR=0.273, 95% CI 0.125, 0.597) and higher ORR (84% vs 67%) vs CRZ. TP53 mutation was detected in 30% (37/124) of pts in BRG arm and 26% (33/127) in CRZ arm. In pts with detectable ALK fusion, TP53 mutation showed poorer PFS in both arms than nonmutant/undetected cases (Table). BRG had better ORR and PFS vs CRZ in pts regardless of TP53 mutation status. Additional analyses of BL variables are ongoing. Conclusions: EML4-ALK fusion variant 3 and TP53 mutation were identified as poor prognosis biomarkers in ALK+ NSCLC. BRG demonstrated better efficacy than CRZ as first-line therapy in pts regardless of EML4-ALK fusion variant and TP53 mutation status. These findings may help define areas of greatest unmet need. Clinical trial information: NCT02737501 . [Table: see text]