A strategy for giving intermittent, high doses of the tyrosine kinase inhibitor sunitinib seemed to be well tolerated by patients with advanced cancer and increased drug concentrations in solid tumors, which was associated with improved survival. This research was presented by Gerritse et al at the 32th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (Abstract 42).
Patients with a range of advanced cancers—particularly kidney cancer, pancreatic neuroendocrine tumors, and gastrointestinal stromal tumors—can be treated with sunitinib. Although many patients respond well at first to the drug, they may eventually develop resistance to it. Giving large daily doses of the drug to achieve higher concentrations in the tumor itself is also limited by serious toxic side effects.
First study author, Sophie Gerritse, MD, MSc, a PhD candidate in the Department of Medical Oncology at Radboud University Medical Center, Nijmegen, The Netherlands, said: “Unfortunately, durable clinical benefit from sunitinib is hampered by intrinsic and acquired drug resistance in all patients. We need to exploit the full potential of sunitinib and other tyrosine kinase inhibitors in order to increase their efficacy in cancers where they are already [used]—and to repurpose them for other types of cancer.”
“We have already shown in a phase I trial [published by Rovithi et al in the Journal of Clinical Oncology] that giving high-dose, intermittent sunitinib at 300 mg once a week or at 700 mg once every 2 weeks to patients with advanced [solid] tumors was safe, resulted in higher peak concentrations of the drug in blood plasma samples compared with regular dosing, and…had promising clinical benefit.”
“In this most recent research, we evaluated whether high concentrations of sunitinib in the blood led to higher concentrations in the tumor and what the effect on patient outcomes might be.”
Study Methods
Dr. Gerritse and her colleagues collected and analyzed blood samples from 82 patients in the phase I trial, which was conducted at the Amsterdam University Medical Center between 2014 and 2018. The blood samples were taken before treatment with sunitinib and then several times after treatment began. On the day 17 after the start of treatment, they also took skin biopsies from 36 of these patients, and tumor biopsies from 22 of the 36 patients.
“There are five important findings from this trial,” said Dr Gerritse. “The maximum tolerated dose for sunitinib is 300 mg once a week or 700 mg once 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. We were also able to achieve very high concentrations of sunitinib in the tumor. However, we found that the maximum concentrations 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 with concentrations in the tumor.”
“In this small group of 22 patients, we found a statistically significant relationship between the tumor concentrations achieved and overall survival and length of time before the cancer progressed. This is the first time it has been shown that high concentrations of sunitinib in the tumor, in contrast to concentrations in the blood, are associated with an improved clinical outcome for patients treated with high-dose intermittent sunitinib. This interesting finding has to be validated further in large clinical trials.”
“Our findings have the potential to change the dose and schedule of multitargeting tyrosine kinase inhibitors, like sunitinib, and thereby enhance their clinical efficacy. An important result in this study is that the concentration of sunitinib in the blood underestimates the corresponding concentration of the drug in the tumor.”
Based on these results, the principal investigator of the study, Henk Verheul, MD, PhD, also of Radboud, has initiated two further phase II/III clinical trials:
- SUNRISE-CRC: For patients with metastatic colorectal cancer who will be dosed with 700 mg of sunitinib once every 2 weeks vs trifluridine/tipiracil (ClinicalTrials.gov identifier NCT03909724)
- STELLAR: For patients with advanced, recurrent glioblastoma who will be dosed with 700 mg of sunitinib once every 2 weeks vs standard treatment with lomustine (NCT03025893).
The team is also researching other potentially interesting tyrosine kinase inhibitors in the lab using the intermittent high-dose strategy.
