We are aware that sorafenib binds to plasma proteins. At steady state, when sorafenib is orally administered at 800 mg/d, accumulation ratios are 5.7 to 6.4, indicating that it has a good distribution range. Of note, 90% of sorafenib is bound to the plasma proteins (1), but the large distribution volume indicates that this binding does not affect the body distribution. Moreover, binding to plasmatic proteins is not predictive at all of the tissue distribution of a given drug; rather, the affinity of this binding could be an issue. Furthermore, the recent publication by Villarroel and colleagues states that “the binding of sorafenib in plasma is concentration-independent, indicating a low-affinity, and nonspecific and nonsaturable process” (2), showing that the sorafenib affinity for plasmatic proteins is lower than its affinity for cell membranes [sorafenib displays a high lipophilicity (log P = 3.8)]. Pharmacokinetic studies are performed using total (bound + unbound) drug concentrations as a variable further strengthening that it is not the free concentration in plasma but the total concentration of the drug that is a better representative of the drug effect. Thus, levels of plasmatic proteins are not predictive for pharmacodynamic effects of tyrosine kinase inhibitors and there is no reason to argue that our preclinical observations are not relevant for subsequent clinical trials.
We have conducted a phase I/II trial, precisely based on our preclinical results showing that combination induced significantly better responses in vivo as compared with each drug alone, with some complete tumor regression in mice. The aim of this trial was to assess the feasibility and efficacy of the irinotecan–sorafenib combination (180 mg/m2 and 400 mg twice a day) in patients with Kras mutated metastatic colorectal cancer who had progressed after irinotecan-based chemotherapy. The results are now accepted in the British Journal of Cancer (3) and were presented at the American Society of Clinical Oncology (4). Disease control rate of 65% with a median progression-free survival and overall survival of 3.7 months and 8 months, respectively, further confirmed the potential synergy between sorafenib and irinotecan.
We believe that the arbitrary nature of the last comment made by the author is seriously deleterious for the field. The results of our phase I/II clinical trial are the most compelling evidence that, conversely to what is stated, our lines of research (that took into account accumulating evidence in both cell lines and animal models) did not end in failure and will certainly contribute to the improvement of treatments for patients with metastatic colon cancer or colorectal cancer.
See the original Letter to the Editor, p. 763
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.