Morphological response of tumor histology in a phase I trial of sorafenib and bevacizumab
Authors: Ryan Henning, Elise Kohn, Minshu Yu, Nilofer Azad
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

234 

Introduction: Angiogenesis is an important factor in the growth and development of most cancers. Sorafenib and bevacizumab are two antiangiogenic agents approved for certain types of cancer. Here we analyze the effects on tumor histology of targeting serial points in the VEGF pathway in our phase I clinical trial of these two drugs in combination for refractory solid tumors.    Methods: Eligible pts had an advanced solid tumor that was metastatic or unresectable for which curative therapies do not exist or are no longer effective. The study was divided into two cohorts. Pts on cohort 1 were treated with both agents initially. On cohort 2 pts began with four weeks of single agent therapy followed by introduction of the second agent. Cohort 2 was divided into two arms; pts on arm A began treatment with four weeks of sorafenib prior to combination therapy and Arm B is the opposite. Tissue core needle biopsies (18g) were acquired at three time intervals: prior to beginning treatment, after two weeks of single agent therapy, and after two weeks of combined therapy (~C2D15). Biopsies were immediately imbedded in OCT, frozen, and stored at -80°C. Sections were analyzed cytologically for apoptosis, necrosis, percent viable tumor cells, and tissue size. We defined a morphological response (MR) as tissue samples showing an apoptotic change or necrotic change resulting in less than 60% tumor cells being viable in the final biopsy, and nonmorphological response (nMR) as tissue showing solid and healthy tumor cells or with greater than 60% viable tumor cells in biopsy 3.    Results: 18 pts were included in this study, 7 pts from arm A and 11 pts from arm B. 11/18 pts fell into the MR category and 7/18 were nMR. There was no difference in MR or nMR between arms A and B. 1/11 MR patients had progressive disease (PD), 6/11 had stable disease (SD) and all 4/11 pts with a partial response (PR) to treatment were in this group. 1 nMR pt had PD and 6 pt had SD while none reached a PR. There was no statistically significant difference between median sizes of biopsies taken at each time interval. Biopsies taken prior to treatment had median sizes of 2.2 mm2 (n=47, 0.50 - 5.0), 2.5 mm2 (n=34, 0.18 - 7.8) after two weeks of single agent therapy, and 1.9 mm2 (n=37, 0.18 - 6.9) for the biopsy on combination therapy. A significant difference in tissue size was observed comparing the 3rd biopsy of MR vs. nMR pts (performed when pts were on combination therapy). MR pts had a median tissue size of 1.4 mm2 (p = 0.01, n=24, 0.18 - 4.9), while nMR pts showed a median tissue size of 3.0 mm2 (n=12, 0.40 - 6.9).    Conclusions: The results of this study show that a combination of treatment with sorafenib and bevacizumab can induce a morphological response of histology that may correlate with disease behavior in patients with a solid tumor malignancy. This qualitative analysis may provide useful and possibly predictive information and should be tested in a larger patient cohort.