Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer

Abstract

Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.

Figure 1

Progression-free survival of patients on this phase II study of erlotininb with 95% CI.

Figure 2

Overall survival, as of December 2004, of patients on this phase II study of erlotinib in weeks with 95% CI.

Figure 3

Pharmacokinetic analysis of erlotinib and its metabolite.

Figure 4

EGFR signalling pathway, including downstream markers and the proposed effects of erlotinib.

Figure 5

(A) Core biopsies obtained from liver metastases pretreatment (left panels) and post-treatment (right panels), showing haematoxylin and eosin staining by transmitted light, and dual fluorescence staining for cytokeratin (red) and phosphorylated ERK1/2 (green). The fluorescence images have been false coloured and contrast enhanced for visual inspection. (B) Image processing used to quantify phosphospecific antibody labelling. The images were analysed by first converting the cytokeratin image into a binary (false coloured yellow), and overlaying this onto the linked phosphorylated protein image in order to outline the tumour area. After background subtraction, the mean pixel grey-scale values within these areas were used as a measurement of the extent of phosphorylated protein expression.

Figure 6

Whisker plot of change in markers pre- and on-treatment.