Alectinib-Bevacizumab Combination Shows Superior Efficacy in ALK-Positive Lung Cancer
A recent phase 2 clinical trial has revealed promising results for patients with ALK-positive non-small cell lung cancer (NSCLC), demonstrating that combining the ALK inhibitor alectinib with the anti-angiogenic agent bevacizumab significantly improves outcomes compared to historical data for ALK inhibitor monotherapy.
The ALEK-B trial, conducted at the Instituto Nacional de Cancerología in Mexico, enrolled 41 treatment-naïve patients with metastatic ALK-positive NSCLC. After a median follow-up of 34.5 months, the combination therapy achieved impressive progression-free survival (PFS) rates of 97.1% at 12 months and 64.2% at 36 months.
"These results are particularly striking when compared to historical data from the ALEX trial, which reported 12-month and 36-month PFS rates of 76% and 46.4%, respectively, with alectinib monotherapy," said lead investigator Dr. Oscar Arrieta. "Our findings suggest that adding bevacizumab may mitigate primary resistance or delay early resistance mechanisms associated with second-generation ALK-TKIs."
Remarkable Response Rates and CNS Efficacy
The combination therapy demonstrated robust efficacy across multiple endpoints. All patients achieved an objective response, with 87.8% experiencing partial responses and 12.2% complete responses. The median time to response was 1.34 months, with a median time to best overall response of 13.7 months.
Notably, the regimen showed exceptional efficacy in preventing central nervous system (CNS) progression. The 36-month intracranial progression-free survival rate was 87.8%, and the cumulative incidence of new brain metastases was only 8.8% after 34.4 months of follow-up. Among the seven patients who presented with brain metastases at baseline, the intracranial response rate reached 85.7%, with three patients achieving complete intracranial responses.
"The CNS efficacy results are particularly important given that approximately 60% of ALK-positive NSCLC patients develop brain metastases within six years of diagnosis," explained Dr. Arrieta. "The combination's ability to prevent CNS progression represents a significant advancement in addressing this critical aspect of disease management."
Safety Profile and Quality of Life
The safety profile of the combination therapy showed increased toxicity compared to alectinib monotherapy, with 97.5% of patients experiencing adverse events of any grade. The most common adverse events included diarrhea (75.6%), proteinuria (70.7%), anemia (58.5%), and peripheral edema (41.5%).
Grade ≥3 adverse events affected 46.3% of patients, with proteinuria (22.0%), ALT increase (17.1%), and AST increase (9.8%) being the most frequent. Notably, 43.9% of patients discontinued bevacizumab due to adverse events, primarily grade 3 proteinuria, but continued with alectinib as monotherapy.
Despite these challenges, patient-reported outcomes showed significant improvements in global quality of life and functioning scales throughout the treatment period. The global Quality of Life score improved from a baseline mean of 65.2 to 77.4 at 12 months (p = 0.0116) and was maintained at 75.98 at 36 months (p = 0.07).
Implications for Clinical Practice
The ALEK-B trial results suggest that combining alectinib with bevacizumab could represent a promising strategy for patients with ALK-positive NSCLC, particularly for preventing early progression and CNS metastases.
Dr. Benjamin Besse, a lung cancer expert not involved in the study, commented: "These findings are intriguing and warrant further investigation in a randomized controlled trial. The combination appears to enhance the already impressive efficacy of alectinib, especially in preventing CNS progression, which remains a significant challenge in this patient population."
However, experts caution that the single-arm design and relatively small sample size of the study limit definitive conclusions. Additionally, the high rate of bevacizumab discontinuation raises questions about the optimal dosing and duration of the antiangiogenic component.
"The optimal dose and duration of antiangiogenic therapy in ALK-positive NSCLC patients remain to be elucidated, especially considering that more than one-third of patients discontinued bevacizumab due to toxicity," noted Dr. Arrieta. "Future studies should explore whether limiting the number of antiangiogenic cycles could mitigate these issues while maintaining efficacy."
Future Directions
The promising results of the ALEK-B trial have prompted discussions about potential phase 3 randomized controlled trials to definitively determine whether adding an antiangiogenic agent to ALK-TKI therapy provides significant benefits over monotherapy.
Of particular interest is whether this combination approach could also enhance the efficacy of third-generation ALK inhibitors like lorlatinib, which has shown impressive 60-month PFS rates of 60% in the CROWN trial.
"While lorlatinib has demonstrated superior efficacy compared to second-generation ALK-TKIs, specific populations may not be eligible due to comorbidities or may face access limitations," explained Dr. Arrieta. "The alectinib-bevacizumab combination could represent an alternative strategy for these patients."
The researchers are continuing to follow the ALEK-B trial participants, with planned evaluations extending to 60 months post-treatment initiation. Additional analyses of resistance mechanisms and subsequent therapy outcomes will provide further insights into the long-term benefits of this combination approach.
As the landscape of ALK-positive NSCLC treatment continues to evolve, the ALEK-B trial represents an important step toward optimizing outcomes for this patient population through rational combination strategies targeting both the oncogenic driver and the tumor microenvironment.
