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

Abstract

Erlotinib (Tarcevat, 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 ¼ 0.008) and phospho-extracellular signal-regulated kinase (ERK) (P ¼ 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.

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

“…8,54 Support for this notion is gained from studies demonstrating that in cancer patients treated with targeted TKIs, tumor tissue exhibited lower levels of pERK post-treatment. Specifically, significant correlations between reduced pERK and disease stabilization or partial responses were observed after therapy with sorafenib 55 and erlotinib 56 in patients with metastatic carcinomas of the head, neck, 55 and colon, 56 respectively. In summary, the results of the current study indicate that pERK-1/2 is an independent prognostic biomarker that significantly predicts the onset of metastasis in clinically confined RCC.…”

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

“…Erlotinib monotherapy has shown modest activity in patients with many solid tumors including refractory colorectal cancer with a response rate of 8% in one study; although results have been variable (121,122). Preliminary results from phase I/II studies of erlotinib plus FOLFOX or XELOX (Xeloda plus oxaliplatin) in advanced refractory colorectal cancer suggest that the addition of erlotinib to standard chemotherapy has some beneficial effects (123)(124)(125).…”

Biologics in bowel cancer

“…Small molecule EGFR inhibitors including erlotinib have been studied in colorectal cancer, however results were modest with limited rationale for larger studies (22).…”