Brigatinib for anaplastic lymphoma kinase-tyrosine kinase inhibitor naïve anaplastic lymphoma kinase-positive advanced non-small cell lung cancer: an effective but still broken option

Abstract

Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur in approximately 5% of non-small cell lung cancers (NSCLCs), in which they identify a distinct subtype of lung tumor that shows exquisite sensitivity to therapy with ALK tyrosine kinase-inhibitors (ALK-TKIs) (1).Despite durable responses to the first-generation ALK-TKI crizotinib, the development of acquired resistance occurs in virtually all patients (2). From a biological standpoint, resistance to crizotinib develops either by 'on target' (ALK secondary mutations in the tyrosine kinase domain or ALK amplification) or 'off target' mechanisms (activation of signaling pathways other than ALK) (3). The novel second-generation ALK-TKI brigatinib has shown preclinical activity against a wide spectrum of ALK secondary mutations associated with resistance to crizotinib, and consistently, it proved to be clinically effective in crizotinib-refractory patients (4-6). Against this background, in September 2018, Camidge and colleagues reported in the New England Journal of Medicine the eagerly awaited results of the 'ALTA-1L' trial, which compared brigatinib with crizotinib in ALK-TKI naïve patients with ALK-positive advanced NSCLC (7). Study overview'ALTA-1L' is a multicenter, randomized, open-label, phase 3 trial that allocated 275 patients with ALK-TKI naïve ALK-positive advanced NSCLC in a 1:1 ratio to either brigatinib 180 mg once daily (after a 7 days lead-in phase at 90 mg; N=137) or crizotinib 250 mg twice daily (N=138) (7). Crossover to brigatinib was allowed for patients in the crizotinib arm, upon confirmation of disease progression by blinded independent review assessment. The primary endpoint of the study was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), intracranial ORR (IORR), intracranial PFS, and overall survival. The first pre-specified interim analysis was performed at 50% of expected events (99/198). With a median follow-up of 11.0 months in the brigatinib group and 9.3 months in the crizotinib group, blinded independent review-assessed PFS was significantly longer for brigatinib [median PFS not reached versus 9.8 months (95% CI, 9.0-12.9 months), respectively], with an estimated 12-month progression-free rate of 67% (95% CI, 56-75%) versus 43% (95%, CI, 32-53%), respectively, and a hazard ratio (HR) for progression or death of 0.49 in favor of brigatinib [(95% CI, 0.33-0.74), P<0.001]. The subgroup analysis showed that brigatinib was superior to crizotinib across several clinical characteristics, including performance status (0 or 1), presence of brain metastases (BMs) at baseline, and prior exposure to chemotherapy for advanced disease (the study allowed

Primary resistance to ALK inhibitors in KLC1/ALK-rearranged pleural metastatic lung adenocarcinoma: a case report

“…Sensitivity to ALK inhibitors remains unclear in these cases. Mechanisms of acquired resistance to ALK inhibitors have been identified, such as ALK mutations (L1196M, I1171T, D1203N, G1269A/F1174L, G1202R, W1295C, G1202R/L1196M, G1202R/G1269A) and bypass mutations in other genes, such as NRAS G12V, EGFR R108K, PIK3CA E545K, EGFR P753S, BRAF V600E, and MET D1246N ( 7 - 9 ).…”