Abstract LB-264: Axitinib improves radiotherapy for murine xenograft lung tumors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Biological agents are currently being tested to improve the outcome of chemo-radiotherapy for locally advanced non-small cell lung cancer (NSCLC). The anti-angiogenic drug axitinib (AG-013736, Pfizer), is a small molecule receptor tyrosine kinase (RTKs) inhibitor. Axitinib selectively targets VEGF receptors 1, 2 and 3 (VEGFR), has a high potency for VEGFR-2 and inhibits the signal transduction induced by VEGF binding to VEGFR. Axitinib used in a phase II trial for advanced NSCLC demonstrated a promising one-year survival rate with manageable toxicities. We have tested the combination of axitinib with radiotherapy in a pre-clinical model of orthotopic A549 model of human lung carcinoma xenografts in nude mice. Mice-bearing established A549 lung tumor nodules were treated orally and daily with axitinib at 25mg/kg/day concomitant with daily fractionated radiation for 5 consecutive days. Radiation was administered to the left lung at a dose 2 Gy per day and then, axitinib treatment was continued for 5 days per week for 4 more weeks. A mild decrease in overall weight was observed in mice treated with axitinib or axitinib and radiation indicating that axitinib was safe and well tolerated, probably as a result of its short-half life (2-5h). No systemic effect on the vasculature of other organs including the heart, kidney and liver was observed by histology. Axitinib caused decreased tumor cellularity in lung nodules associated with a heavy infiltration of inflammatory cells. Mice treated with axitinib and radiation had a significant decrease in the size and number of lung tumor nodules which contained degenerating giant tumor cells and inflammatory infiltrates. Morphometric measurements of tumor nodules confirmed that the size of tumor nodules was significantly smaller in the irradiated left lung and was further reduced by combination with axitinib compared to that of mice treated with single modality (p<0.05). Ki-67 staining showed a marked decrease in the number of proliferating tumor cells. In the surrounding lung tissue, scattered intra-alveolar hemorrhage was estimated to cover 10 to 20% of the lung surface in treated mice but it was comparable to that observed in untreated mice. Axitinib caused mild chronic interstitial pneumonia and combined axitinib and radiation treatment was associated with moderate interstitial pneumonia. In independent experiments, treatment of lung tumors with a single dose of radiation (10 Gy) administered to the lungs and 10 weeks of axitinib showed a complete inhibition of tumor growth in the lungs. Histology showed the presence of distinctive lymphohistiocytic nodules with no detectable viable tumor cells. This treatment was well tolerated with minimal weight loss. These findings suggest a potential novel approach for the treatment of locally advanced NSCLC by combining radiotherapy with the anti-angiogenic drug axitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-264. doi:1538-7445.AM2012-LB-264