medwireNews: Combined treatment with durvalumab plus bevacizumab could benefit women with HER2-negative advanced breast cancer who have progressed on bevacizumab maintenance, shows a phase 1b trial.
In addition to promising efficacy and tolerability data, the researchers also report on correlative studies, which they say “agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs [regulatory T] cells both systemically and in tumor tissue.”
The study authors explain in Breast Cancer Research that “[p]reclinical evidence in breast, pancreatic, and brain tumors and melanoma and clinical results in renal cell cancer have shown that antiangiogenic treatment was followed by more efficient T cell extravasation and tumor infiltration, turning immunologically ‘cold’ into ‘hot’ tumors.”
They continue: “Particularly, the sequence in which these agents are administered (sequential versus concurrently with immunotherapy) might be of key importance.”
The investigator-initiated study included 25 patients with locally advanced or metastatic breast cancer who had received maintenance treatment with single-agent bevacizumab for at least 6 weeks as a part of any bevacizumab-containing regimen prior to enrollment. Participants were aged a median of 54.1 years and had received up to seven previous lines of therapy for advanced disease.
Treatment with durvalumab 10 mg/kg plus bevacizumab 10 mg/kg every 2 weeks for a median 13 weeks achieved a median progression-free survival duration of 3.5 months, while median overall survival was 11.0 months.
The objective response rate was “low,” with just 8% of patients having a partial response to the combination, but the clinical benefit rates at 8 and 16 weeks were 60% and 44%, respectively, report Miguel Quintela-Fandino (Spanish National Cancer Research Center, Madrid) and co-workers.
Analysis of peripheral blood mononuclear cells from samples obtained after maintenance bevacizumab but before durvalumab initiation showed a significant increase in CD4+ T cells in individuals who derived clinical benefit from the combination at week 16 (nonprogressors) versus those who did not (progressors).
Nonprogressors also had significantly lower baseline levels of immunosuppressive TREG cells than progressors, and numerically higher levels of effector memory and central memory CD8+ T cells at the 4-week timepoint after the first dose of durvalumab plus bevacizumab.
Moreover, morphologic analysis of biopsy samples from three nonprogressors and three progressors at baseline revealed “vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors,” say Quintela-Fandino et al.
This finding “further supports the hypothesis that antiangiogenics can exert an immunopriming effect, at least in some cases,” they add.
The researchers note that the small sample size and patient heterogeneity, including the “highly variable” duration of bevacizumab maintenance (1.6–24.7 months), are the main weaknesses of the study. They also highlight that the study design “does not distinguish between ‘priming’ effects (versus no-priming) or even whether it is justified or not to maintain bevacizumab in the combination phase.”
Nonetheless, the team concludes: “Taken together the positive efficacy signal, the low toxicity rates, the finding of candidate biomarkers of activity in peripheral blood, and the biological rationale, our data justify a larger prospective clinical trial aiming to define the magnitude of the benefit derived from antiangiogenic priming in this setting.”
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