Important new data from two trials evaluating different treatment approaches in metastatic colorectal cancer provide reassurance for clinicians that current treatment choices are valid, and confirm that molecular characterisation of such tumours is vital, experts have said.
The latest results of the phase III, randomized FIRE-3 and CALGB/SWOG 80405 trials were presented at the ESMO 2014 Congress in Madrid, Spain.1 The trials evaluated different approaches to first line treatment in colorectal cancer patients with normal or “wild type” versions of the RAS gene.
Specifically, they compared adding either the epidermal growth factor receptor (EGFR)-blocker cetuximab or the anti-vascular endothelial growth factor (VEGF) inhibitor bevacizumab to combination chemotherapy.
“Surprisingly, the smaller FIRE-3 trial showed a clear overall survival gain by adding the anti-EGFR antibody cetuximab to FOLFIRI chemotherapy for the patients with RAS wild type tumours, but overall survival was a secondary endpoint. RECIST response rate, their primary endpoint, and progression free survival (PFS) did not show any difference,” commented Professor Dirk Arnold, director of the Department of Medical Oncology, Klinik für Tumorbiologie in Freiburg, Germany.
The FIRE-3 study authors suggest that improvements in tumour burden reduction, measured in parameters such as ‘early tumour shrinkage’ and ‘depth of response’ (which refers to the relative decrease in tumour shrinkage compared to the initial tumour diameter) may help explain the improvements in overall survival, Arnold said.
“However, the results of the larger CALGB trial, which failed to show an overall survival difference with cetuximab versus bevacizumab, raise questions about this theory,” Arnold said.
Arnold said the findings suggest that more biomarkers are needed beyond expanded RAS testing, to determine the best treatment strategy in metastatic colorectal cancer.
“Both trials provide analyses in the right cohort of patients, defined by expanded RAS testing, but the CALGB trial is the first to have overall survival as the primary endpoint. Their conflicting results suggest that molecular testing of RAS status and making treatment decisions on this parameter alone is not the best way to decide the best treatment for our patients.”
Commenting on the likely response of the clinical and research community to the findings, Arnold said: “The results confirm that both treatment strategies are an option, as we have not yet found the ultimate predictive biomarker for selection of the optimal treatment in metastatic colorectal cancer - and we also need to consider other additional factors when choosing the most appropriate treatment for a particular patient.”
Treatment decisions in oncology almost always require a review of a number of factors, including molecular biology and biomarkers, but also patient characteristics (comorbidities, age, etc.) and treatment goal (such as tumour resection or relief of symptoms).
Professor Fortunato Ciardiello from Second University of Naples, Italy, ESMO President-Elect, commented: “These types of studies contribute to our concept of ‘precision medicine’, in the search for the best treatment for patients with advanced colorectal cancer. RAS testing should be considered mandatory before initiating first line treatment for all patients with metastatic colorectal cancer.”
Arnold noted: “In terms of molecular biology, the current situation of using only RAS testing is not satisfactory. In future we need more precise biomarker definitions - and possibly also smaller biomarker-defined subgroups of patients. RAS testing is the beginning - but not the end - of the biomarker story in metastatic colorectal cancer. This is not a time for simple answers. Choosing the most appropriate first line therapy in colorectal cancer remains a complex and multifactorial decision.”
“However, each of the examined strategies resulted in an overall survival of more than 30 months, in all treatment arms in both trials. This is the longest overall survival reported, and beyond the promising activity in first-line treatment, it is related to the factor that most patients also had active second and/or further line regimens with the complementary strategy. This sets the standard, and the ‘winners’ in these trials are the patients. The findings underline that treatment with any monoclonal antibody should be regarded as the standard,” Arnold said.
Concluding, Ciardiello said: “The information provided by these studies is important because it represents an effort to understand the characteristics of the tumour, and it confirms that there are two good opportunities for treating these patients. These results open a door to better understanding of the heterogeneity of metastatic colorectal cancer, and re-emphasise the role of RAS testing as a first step to offering proper treatment.”