Alectinib in combination with bevacizumab as first-line treatment in ALK-rearranged non-small cell lung cancer (ALEK-B): a single-arm, phase 2 trial

Introduction

Anaplastic lymphoma kinase (ALK) rearrangements drive 3–9% of non–small cell lung cancers (NSCLC)^1,2. ALK oncoproteins promote cell survival and growth through aberrant activation of intracellular signaling, including the PI3K/AKT/mTOR and RAS/Raf/MEK/ERK pathways³. NSCLC cancers harboring ALK rearrangements (ALK-positive) are highly sensitive to ALK-tyrosine kinase inhibitors (ALK-TKIs), which can induce apoptosis. In the last decade, the development of ALK-TKIs has significantly improved the survival outcomes of patients with ALK-positive NSCLC. Next-generation ALK-TKIs have become the standard first-line treatment option for patients with advanced ALK-positive NSCLC because of their greater potency, selectivity, and central nervous system (CNS) penetration compared to crizotinib.

Alectinib, a second-generation ALK-TKI, has demonstrated a prolonged progression-free survival (PFS) compared to crizotinib. Initial results from the ALEX trial reported a 12-month PFS of 68.4% for alectinib versus 48.7% for crizotinib⁴. The median PFS, as assessed by independent review, was 25.7 months for alectinib compared to 10.4 months for crizotinib⁴. The median PFS assessed by independent review was of 25.7 months versus 10.4 months. However, despite the initial efficacy of ALK-TKIs, the development of drug resistance and subsequent disease progression inevitably occur⁵, with the CNS being a common site of relapse. Therefore, exploring biologically synergistic combinations to enhance efficacy and overcome resistance to ALK-TKIs is a crucial goal in translational research.

Vascular endothelial growth factor (VEGF) plays a crucial role in promoting primary tumor growth, and metastasis in NSCLC⁶. Bevacizumab, a recombinant, humanized, anti-VEGF monoclonal antibody, has shown efficacy in combination with platinum chemotherapy for advanced non-squamous NSCLC⁷. Recently, the combination of epidermal growth factor receptor TKIs plus antiangiogenic monoclonal antibodies has overcome acquired resistance to and improve PFS among this subset of patients^{8, 9–10}, especially for those with co-mutations such as TP53¹¹.

Based on preclinical findings, the dual blockade of ALK and VEGF signaling enhances antitumor effects and overcomes resistance by preventing the activation of MAPK, PI3K/AKT, and hypoxia pathways^12,13. In a phase I/II study, the combination of alectinib and bevacizumab demonstrated safety in patients with advanced ALK-positive NSCLC, including those with baseline brain metastases (BM)¹⁴. Given...