A targeted approach to maintenance of tumour response. Clinical and translational studies in metastatic colorectal cancer

Abstract: In metastatic colorectal cancer (mCRC) chemotherapy +/- targeted therapy with palliative intent aims at prolonging survival with sustained quality of life. Maintenance of tumour response by a period of less intense treatment maydelay progression and accumulation of unacceptable toxicity. We studied the combination of targeted treatment with the angiogenesis inhibiting antibody bevacizumab (bev) and the epidermal growth factor tyrosine kinase inhibitorerlotinib (erlo) as maintenance treatment in two clinical trials.The Nordic ACT trial (paper I) included 249 mCRC patients. Following first line induction doublet chemotherapy plus bev, responding patients were randomised to maintenance treatment with bev or bev+erlo. We found no significant difference in survival outcomes between the arms. We then hypothesized that KRAS mutation of the tumour would have a negative impact on the erlo effect.In the Nordic ACT2 trial (paper II, N=233), the KRAS wildtype (wt) patients were randomised in the same manner as in Nordic ACT. The KRAS mutated (mut) patients recieved bev alone or metronomic low dose capecitabine and arms were compared without significant difference in effect or safety. The KRASwt patient cohorts from the both Nordic ACT trials were pooled in an analysis of survival outcomes (N=126) with no statistically significant gain from the addition of erlo to bev as maintenance.There are no validated biomarkers of anti-angiogenic therapy. Treatment induced hypertension has been associated with better response to angiogenesis inhibition. The vasoactive peptides (VPs) atrial natriuretic peptide, adrenomedullin, and copeptin are linked to regulation of blood pressure and angiogenesis. In paper III, the stablepro-peptides of each VP were analysed in plasma from ACT2 study patients with documented progressive disease (N=97). IncreasingVP levels during the first six weeks of induction chemotherapy + bev were significantly associated with better clinical outcome. In paper IV, we collected serum samples at start of induction, start of maintenance and at progression from ACT2 patients (N=22). Analyses of 55 circulating, angiogenesis-related proteins were performed at each time point byantibody array membrane technology. Levels of some, mostly pro-angiogenic, proteins decreased significantly during response and/or increased at progression.In summary, these studies demonstrate that mCRC patients may not benefit from bev+erlo as maintenance therapy in terms of efficacy, and that the clinical benefit can be further questioned due to tocixity concerns. KRAS status is not likely a predictive biomarker for erlo in mCRC. Microarray methodology for simultaneous detection of multiple proteins in serum is convenient for exploration of signalling patterns related to the response and resistance to angiogenesis inhibition. Our translational results support the evidence of an interaction between host-related vascular effects and response to chemotherapy plus bev. Both VPs and other counterbalancing pro-angiogenic factors are promising biomarkers that warrant further studies in this setting.