Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

• Published in: ESMO open 2022-02, Vol.7 (1), p.100342, Article 100342
• Main Authors: Lin, J.J., Muzikansky, A., Kennedy, E., Kuberski, H., Stober, L.L., Wanat, A.C., Azzoli, C.G., Lennes, I., Sequist, L.V., Dagogo-Jack, I., Shaw, A.T., Gainor, J.F.
• Format: Article
• Language: English
• Subjects: alectinib; anaplastic lymphoma kinase; Anaplastic Lymphoma Kinase - genetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; bevacizumab; Bevacizumab - adverse effects; Carbazoles; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; non-small-cell lung cancer; Original Research; Piperidines; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases - therapeutic use; targeted therapy; Vascular Endothelial Growth Factor A - therapeutic use
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2021.100342

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor. Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy. Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual. Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities. •Alectinib plus bevacizumab is safe in patients with advanced ALK-rearranged non-small-cell lung cancer.•Bevacizumab combined with alectinib does not increase risk of intracranial hemorrhage in patients with brain metastases.•Enrollment challenges with this trial highlight important consi