Abstract
Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor–mutated (EGFR-mutated) advanced non–small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib. The distribution of erlotinib in their tumours at different times after erlotinib administration was analysed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). We also analysed the distribution of erlotinib metabolites and the distribution of erlotinib in tumours refractory to erlotinib, which were established by long-term treatment with erlotinib. We found that erlotinib was broadly diffused in the tumours from B901L-implanted xenograft mice, independently of bevacizumab treatment. We also found that erlotinib metabolites were co-localized with erlotinib and that erlotinib in erlotinib-refractory tumours was broadly distributed throughout the tumour tissue. Multivariate imaging approaches using MALDI MSI as applied in this study are of great value for pharmacokinetic studies in drug development.
Highlights
Erlotinib in combination with bevacizumab was shown in the JO25567 study to improve progression-free survival (PFS) in patients with epidermal growth factor receptor–mutated (EGFR-mutated) advanced non–small-cell lung cancer (NSCLC) compared with treatment with erlotinib alone[1]
Quantitation of erlotinib in tumours by LC-MS/MS revealed that treatment with PTK787 improved delivery of erlotinib to tumours derived from a lung cancer cell line[22], and use of MALDI MSI revealed that inhibition of angiogenesis by bevacizumab improved paclitaxel distribution in tumours derived from an ovarian cancer cell line[23]
The microvessel density in tumours treated with erlotinib following bevacizumab was significantly lower than that in tumours treated with erlotinib following human IgG (Fig. 1)
Summary
Erlotinib in combination with bevacizumab was shown in the JO25567 study to improve progression-free survival (PFS) in patients with epidermal growth factor receptor–mutated (EGFR-mutated) advanced non–small-cell lung cancer (NSCLC) compared with treatment with erlotinib alone[1]. One proposed mechanism is that normalization of microvessels in tumours by bevacizumab results in improvement of drug delivery to tumours[7,8,9]. Bevacizumab treatment is known to normalize interstitial pressure and microvessel structure in tumours[12,13], and as a result, drug delivery to and distribution within tumours are thought to be improved. Quantitation of erlotinib in tumours by LC-MS/MS revealed that treatment with PTK787 (an inhibitor of VEGFR tyrosine kinase, PDGFRβ tyrosine kinase, and c-Kit) improved delivery of erlotinib to tumours derived from a lung cancer cell line[22], and use of MALDI MSI revealed that inhibition of angiogenesis by bevacizumab improved paclitaxel distribution in tumours derived from an ovarian cancer cell line[23]. There is currently insufficient data to conclude that combination therapy with bevacizumab improves delivery and distribution of erlotinib in patients with EGFR-mutated NSCLC. Unlike with a cytotoxic drug such as paclitaxel, time-dependent distribution due to interactions with EGFR might need to be considered
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