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

Abstract

Background 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 and methods 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. Results 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. Conclusions Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

High incidence and reversible bradycardia events following alectinib initiation

“…Although alectinib‐related bradycardia is mostly asymptomatic and not life‐threatening, there are patients who encounter dose reduction, drug discontinuation, or even death due to severe bradycardia. The newly prospective combination of alectinib and the anti‐angiogenic agent bevacizumab has obtained positive results, along with the risk of cardiovascular adverse events increasing 29 . When this therapy mode is practiced in patients, clinicians need to pay attention to the cardiovascular toxicity.…”

“…The newly prospective combination of alectinib and the anti‐angiogenic agent bevacizumab has obtained positive results, along with the risk of cardiovascular adverse events increasing. 29 When this therapy mode is practiced in patients, clinicians need to pay attention to the cardiovascular toxicity. Considering the increasing number of people taking alectinib, profound exploration to characterize the mechanisms and treatment of alectinib‐related SB is significant.…”

Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease

“…To delay treatment resistance, combination therapy with a backbone of ALK inhibition has been explored. In light of the complementary action and potential efficacy of anti-VEGF therapy in reducing brain metastasis proliferation, a small, single institution phase 1/2 study recently evaluated the combination of alectinib and bevacizumab in 11 patients with ALK rearranged NSCLC ( 97 ). Of the 9 patients with CNS disease at baseline, iORR was 77.8% (7/9) with 44.4% (4/9) demonstrating complete CNS response; median CNS progression-free survival was not reached ( 97 ).…”

Targeting ALK Rearrangements in NSCLC: Current State of the Art

“…A single-arm study of involving 12 patients of ALK+ NSCLC demonstrated that crizotinib plus bevacizumab showed benefit in first-line ALK+ NSCLC, with an acceptable safety profile ( 104 ). In another phase 1/2 single-arm trial, alectinib plus bevacizumab was also well tolerated ( 105 ).…”