A recent multi-trial analysis has revealed that bevacizumab (Avastin) provides survival benefits in patients with colorectal cancer (CRC) for approximately two years after initial administration, after which its efficacy appears to diminish significantly. These findings, presented at the 2025 ASCO Gastrointestinal Cancers Symposium, may explain why studies with median follow-ups of 24 months show positive outcomes with bevacizumab, while those extending beyond 30 months fail to demonstrate sustained benefits.
Time-Limited Efficacy Pattern Identified
Researchers conducted a comprehensive review of several major clinical trials including PARADIGM (NCT02394795), FIRE-3 (NCT00433927), CALGB 80405 (NCT00265850), PEAK (NCT00819780), AVANT (NCT00112918), and NSABP-08 (NCT00096278) to evaluate the time-related effects of bevacizumab.
The analysis revealed a consistent pattern across studies. In the NSABP-08 trial, bevacizumab initially reduced time to relapse for approximately six months, but this effect diminished and disappeared by the 12-month mark. More concerning, at 24 months post-initiation, patients treated with bevacizumab began showing a steadily increasing risk of relapse compared to control groups.
"The biologic explanation of the clinical data is that short-term treatment with bevacizumab (plus chemotherapy) induces initial tumor stasis and shrinkage, followed by selection and emergence of more aggressive and resistant tumor clones, characterized by an accelerated growth, invasiveness and metastasis shifting the overall tumor growth kinetics to a steeper angle," the researchers explained in their abstract.
Cross-Cancer Consistency
Importantly, the researchers observed identical kinetics in the AVANT study involving patients with metastatic ovarian cancer, suggesting this time-dependent effect is not limited to colorectal cancer but may represent a broader pattern in bevacizumab's mechanism of action across different malignancies.
The review also examined bevacizumab's effects in breast and renal cancers, finding significant progression-free survival benefits initially, but without corresponding improvements in overall survival. Even more concerning, the AVANT and NSABP-08 studies showed detrimental effects on survival when bevacizumab was used in the adjuvant setting.
Explaining the PARADIGM Crossover
These findings provide a potential explanation for the puzzling results observed in the PARADIGM trial, where the survival curve for bevacizumab crossed below that of panitumumab (Vectibix) at approximately 28 months. After this crossover point, bevacizumab's survival curve continued to decline, eventually showing up to 11% worse survival compared to panitumumab by the 5-year mark.
Similar patterns were observed in other comparative trials including FIRE-3, CALGB-80405, and PEAK, with differences becoming apparent around the 20-month timepoint. This consistent finding across multiple studies strongly suggests a previously unrecognized time-dependent effect of bevacizumab.
Biological Mechanisms and Clinical Implications
The researchers propose that bevacizumab is most effective during the period of active administration, followed by what they describe as a "slow rebound" after discontinuation. By 20-24 months post-initiation, the initial survival benefits appear to be completely lost.
To explain these clinical observations, the researchers connected their findings to preclinical data on intratumor heterogeneity, clonal evolution, tumor biology, and interactions between bevacizumab and diverse tumor microenvironments.
This temporal pattern may also explain why bevacizumab shows greater benefits in specific patient populations, particularly those with high tumor burden, shorter expected survival, and those receiving the drug in second- and third-line treatment settings for colorectal cancer.
Future Directions
These findings raise important questions about optimal treatment duration and sequencing strategies for anti-angiogenic therapies like bevacizumab. They suggest that clinicians may need to consider time-limited use of bevacizumab, potentially switching to alternative therapies before the two-year mark to avoid the diminishing returns and possible negative effects observed after this period.
Further research is needed to determine whether intermittent dosing strategies, combination approaches, or biomarker-guided treatment selection might help overcome these temporal limitations and improve long-term outcomes for patients with colorectal cancer receiving bevacizumab.
