Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501)

Abstract

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

Case report: Acquired resistance to crizotinib from a MET Y1230H mutation in a patient with non-small cell lung cancer and KIF5B-MET fusion

“…A multicenter Phase 3 study (CTONG1509) ( 13 ) reported that bevacizumab plus erlotinib provides superior progression-free survival compared to erlotinib alone in Chinese patients. In addition, bevacizumab with alectinib has been proven to be a safe and highly effective first-line therapy ( 14 ). Bevacizumab is a monoclonal antibody against VEGF; thus, VEGFR2 inhibition enhances the anti-tumor effect of molecularly targeted drugs in various oncogene-driven NSCLC models by inhibiting tumor angiogenesis and exerting a direct antiproliferative effect on cancer cells ( 15 ), which suggests that combination therapy with bevacizumab and molecularly targeted agents is a promising strategy for patients with NSCLC harboring oncogenic driver genes.…”

Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory

“…Other localized lesion control can also rely on radiotherapy ( 48 , 49 ). When there is progression of multiple lesions or resistance occurs outside the kinase domain, despite oligoprogression, CNS progression rather than systemic progression, systemic treatments such as chemotherapy and antiangiogenesis therapy will likely need to be considered to control all lesions ( 18 , 23 ). Additionally, it is worth further exploration in future studies to determine the most appropriate treatment strategy by exploring the synergistic effects of alectinib and radiotherapy, chemotherapy, or antiangiogenic drugs to make an accurate decision.…”

“…However, several studies have indicated that sequential ALK-TKI treatment may ultimately result in the development of highly resistant complex ALK mutations, which could potentially limit the survival benefits of patients ( 22 ). Fortunately, some clinical studies have shown the superiority of continuing the original ALK-TKI treatment combined with other treatments after the progression of next-generation ALK-TKI ( 18 , 23 ). Lin et al demonstrated that in patients who underwent chemotherapy in combination with ALK-TKI after developing resistance to next-generation ALK-TKI, the mPFS was 6.8 months, which was significantly longer than the patients who received chemotherapy alone (6.8 vs. 3.2 months).…”

“…Lin et al demonstrated that in patients who underwent chemotherapy in combination with ALK-TKI after developing resistance to next-generation ALK-TKI, the mPFS was 6.8 months, which was significantly longer than the patients who received chemotherapy alone (6.8 vs. 3.2 months). In a Phase II clinical trial investigating non-squamous NSCLC patients with combined alectinib and bevacizumab following resistance to alectinib, the study resulted in an mPFS of 3.1 months ( 23 ). The above studies suggest that even if disease progression occurs, tumors can remain responding to TKIs ( 18 , 23 ).…”

“…In a Phase II clinical trial investigating non-squamous NSCLC patients with combined alectinib and bevacizumab following resistance to alectinib, the study resulted in an mPFS of 3.1 months ( 23 ). The above studies suggest that even if disease progression occurs, tumors can remain responding to TKIs ( 18 , 23 ). This may be due to the persistence of TKI-sensitive clones ( 24 ).…”