Giving high, intermittent doses of the anti-cancer drug sunitinib was well-tolerated and improved survival in patients with advanced tumors, according to a study presented at the 2020 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. The treatment strategy not only resulted in high concentrations of the drug in patient blood, but even higher concentrations in their tumors.
"This is the first time it has been shown that high concentrations of sunitinib in the tumor, in contrast to concentrations in blood, are associated with an improved clinical outcome for patients treated with high-dose intermittent sunitinib," said Sophie Gerritse, a PhD medical oncology student in the Department of Medical Oncology at Radboud University Medical Center, Nijmegen, The Netherlands, who presented results at the meeting.
Emiliano Calvo, MD, PhD, Co-Chair of the EORT-NCI-AACR symposium and Director of the START Madrid Group in Spain added: "The finding that intermittent high doses of sunitinib increased concentrations in the tumors and was associated with improved survival is also important as patients with these types of advanced cancers are urgently in need of optimized treatments, as sometimes the tumor progresses not due to primary resistance, but instead due to insufficient drug levels in the patient to fight against his or her cancer." Calvo did not participate in the study.
Sunitinib is one of several approved drugs classified as tyrosine kinase inhibitors, which play a significant role in the development and progression of cancer cells. The recommended dosage of 50 mg per day has produced durable clinical responses and survival benefits initially in patients for several cancers, particularly kidney, pancreatic, and sarcomas of the digestive system.
However, for its anti-cancer activities to work effectively, the drug concentration needs to be prolonged over time to inhibit angiogenesis and specific intracellular kinase signaling. Unfortunately, higher dosage has led to toxic side effects and eventually drug resistance in all patients.
In a Phase I trial published in the February 2019 issue of the Journal of Clinical Oncology (JCO), the Netherlands research team described an alternate treatment strategy, escalating dosage of sunitinib intermittently until they reached a maximum tolerable dose-the highest dose level at which less than or equal to 33 percent of patients experienced dose-limiting toxicities (doi: 10.1200/JCO.18.00725).
In a cohort of 69 patients pre-treated for advanced cancer, predominantly colorectal cancer (42%), Gerritse and colleagues found that a maximum tolerated dose of 300 mg once weekly or 700 mg once every 2 weeks resulted in a nine- and-18-fold higher maximum blood plasma concentration respectively compared to the standard 50 mg daily dose.
What's more, the intermittent, high-dose sunitinib exhibited a toxicity profile comparable to the standard 50 mg daily dose. Common observed adverse events for any grade were fatigue, nausea, and anorexia. Two patients who received prior radiotherapy developed severe bowel toxicity, excluding these patients from future clinical trials.
"The underlying mechanisms (for severe bowel toxicity) are still to be elucidated," the researchers wrote in the JCO article. "The working hypothesis assumes inadequate capability of tissue repair after radiation-induced bowel injury because of impaired VEGF (vascular endothelial growth factor) response."
Study Details
In the study presented at the EORTC-NCI-AACR symposium, Gerritse and colleagues sought to evaluate whether high concentrations of sunitinib in the blood led to higher concentrations in the tumor and what the effect might be on patient outcomes.
As outlined in her presentation, the team collected and analyzed blood samples from 82 patients in the Phase I trial, conducted between 2014 and 2018 at the Amsterdam University Medical Center. Blood samples were taken before treatment with sunitinib and then several times after treatment began. On day 17 after the launch of treatment, the researchers took skin biopsies from 36 of these patients, and tumor biopsies from 22 of the 36 patients. Blood plasma analyses, using liquid chromatography-mass spectrometry, were performed in collaboration with Nielka van Erp, PharmD, PhD, also from Radboud.
Findings yielded a maximum tolerated dose for sunitinib of 300 mg once a week or 700 mg every 2 weeks, with adverse effects comparable to the normal schedule of 50 mg daily.
"With this schedule, we were able to create very high peaks of sunitinib concentrations in blood samples-up to 18 times higher than with daily doses of 50 mg," said Gerritse. "We were able to achieve very high concentrations of sunitinib in the tumor. However, we found that the maximum concentration of sunitinib in blood plasma underestimated concentrations in the tumor by a factor of 19. In fact, there was no relationship between concentrations in the blood and skin concentrations in the tumor."
In the tumor biopsies from the small group of 22 patients, the team also found a significant relationship between tumor concentrations achieved and overall survival and length of time before the cancer progressed.
"Our findings have the potential to change the dose and schedule of multi-targeting TK inhibitors, like sunitinib, and thereby enhance their clinical efficacy," Gerritse said. "An important result of this study is that the concentration of sunitinib in the blood underestimates the corresponding concentration of the drug in the tumor."
And added by Calvo: "It has the potential to transform the use of TK inhibitors and possibly other drugs as well, because when we speak about precision oncology, it is not only about the right drug for the specific patient and tumor, but also choosing the right dose for each patient through methods like these. It would be interesting to know if this effect is also seen with other classes of anti-cancer drugs and, of course, to validate these data prospectively."
Warren Froelich is a contributing writer.