Page 31 - Demo

Panitumumab and chemoradiation for inoperable pancreatic cancer292affect H-RAS or N-RAS and concentrate almost exclusively on the K-RAS locus, with reports of mutation rates up to 95% (17). Interestingly, several studies have shown that EGFR pathway inhibition can improve the antitumor efficacy of RT independent of the K-RAS mutation status of a tumor (18, 19). Furthermore, preclinical in vivo studies indicated that the radiosensitizing activity of gemcitabine may be enhanced by specific EGFR inhibition (20) and also showed, in a pancreatic tumor model, that treatment with panitumumab, a fully human anti-EGFR monoclonal antibody (mAb), enhanced the antitumor efficacy of gemcitabine monotherapy (61% vs. 38% growth inhibition; ref. 21). Panitumumab is generally well tolerated. Skin toxicity, hypomagnesaemia, and diarrhoea are the most common toxicities observed (22). Based on these promising preclinical data in favour of combining EGFR pathway inhibition (independent of K-RAS mutational status) with both gemcitabine and radiation therapy and the nonoverlapping toxicity profiles of gemcitabine and panitumumab, we designed a phase I/II feasibility trial evaluating the addition of panitumumab to gemcitabinebased CRT in patients with LAPC. Here, we report the phase I feasibility part of this study. The primary endpoint was to determine the maximum tolerated dose (MTD) of panitumumab to be used in combination with gemcitabine-based CRT in patients with LAPC. Secondary endpoints included early signs of clinical activity of the study treatment, clinical response rate, progression free survival (PFS), and overall survival (OS). Patients and Methods Eligibility Adult patients with untreated LAPC were eligible for this phase I trial. Encasement >270 of the superior mesenteric or portal vein or >90 tumor contact with the superior mesenteric artery, celiac trunk, or common hepatic artery in the absence of distant metastasis was considered in a multidisciplinary team as LAPC. Histologic or cytologic confirmation of pancreatic cancer was required. Patients with imminent bowel obstruction, active bleeding, uncontrolled infection, or a second current malignant disease (except basal cell carcinoma of the skin) were not eligible. Inclusion criteria also included measurable or evaluable disease as defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria, an