Regorafenib Prior to Selective Internal Radiation Therapy Using 90Y-Resin Microspheres for Refractory Metastatic Colorectal Cancer Liver Metastases: Analysis of Safety, Dosimetry, and Molecular Markers

Abstract

Background: This Phase II, open-label, study examined the safety of regorafenib followed by selective internal radiation therapy (SIRT) with regorafenib re-initiation in the treatment of metastatic colorectal cancer (mCRC) patients with liver metastases who are not surgical candidates. Methods: Patients received 160 mg regorafenib daily on a 21-day course followed by a 1 week washout prior to SIRT. Liver function was evaluated at 2 and 4 weeks after SIRT, and regorafenib re-initiated if liver function was normal. Patients were evaluated for safety, and restaged at weeks 6 and 12 following SIRT. In addition, protein and cytokine assays of blood were performed to identify candidate molecular biomarkers associated with outcomes. Individual patient voxel-based dosimetry assessment was performed post-SIRT. Results: Twenty-Five patients were enrolled and received a median 11 weeks regorafenib. Three patients received regorafenib, but not SIRT due to disease progression. The remaining 22 patients received SIRT with a median activity delivered to the liver of 38 mCi, mean normal liver dose of 14.98 Gy and tumor mean dose of 29.0 Gy with a tumor to normal ratio mean of 2.42. There were four treatment-related serious AEs and no treatment-related deaths. Median progression-free survival was 3.7 months and the median overall survival was 12.1 months. The relative densities of several biomolecules changed significantly during the course of treatment, most notably post-treatment increases in levels of sex-hormone binding globulin ( SHBG ) and decreased levels of the cytokine MIG (CXL9) . Decreases in von Willebrand factor ( VWF ), the ankyrin repeat domain ( ANKRD26 ), and MIG were associated with improved survival times. Post-treatment increases in alpha-2-macroglobulin ( A2M ) and the cytokine intercellular adhesion molecule ( ICAM-1) were associated with reduced overall survival time, while increases in Eotaxin ( CCL14) predicted longer overall survival times. Conclusions: The treatment of mCRC patients with liver metastases using regorafenib followed by SIRT was tolerable in this patient population. Further efficacy analysis of this treatment schema and analysis of potential molecular biomarkers using larger sample sizes is merited.

Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a retrospective cohort study

“…The ORR advantage obtained from regorafenib combined with radiotherapy in this study also translated into a survival advantage. The patients achieved a mPFS of 7.89 months and a mOS of 16.85 months; these figures are superior to those previously reported for regorafenib combined with selective internal irradiation radiotherapy ( 27 ) (i.e., a mPFS of 3.7 months and a mOS of 12.1 months). This may be related to the patients’ baseline data; the enrolled patients in previous study had liver metastasis.…”

Novel Gene Signatures Predictive of Patient Recurrence-Free Survival and Castration Resistance in Prostate Cancer

“…The Von Willebrand Factor ( VWF ) is a marker for angiogenesis, and it has been suggested as a predictive biomarker for therapeutic response in pancreatic cancer [ 76 ]. A decrease in VWF expression is associated with improved survival in patients with colorectal cancer and liver metastases [ 77 ], and a single nucleotide polymorphism in VWF (rs73049469) is associated with overall survival in NSCLC [ 78 ]. VWF is also upregulated in androgen-independent prostate cancer cells [ 79 ].…”

Radioembolization in the Setting of Systemic Therapies

“…30 In a phase II trial, 22 patients with unresectable mCRC of the liver received 160 mg regorafenib daily for 21 days, followed by a 1-week washout prior to Y90 administration; if liver function remained normal 4 weeks after Y90, regorafenib was reinitiated. 31 Dose adjustments and delays were allowed per the discretion of the treating physicians. 68% of the cohort required dose reductions and 80% required dose interruptions.…”

“…The authors concluded that addition of regorafenib to Y90 was safe and tolerable, with a safety profile comparable to regorafenib monotherapy. 31 The molecular agent cetuximab is a potent radiosensitizer, although there are no clinical studies focused on its safety and toxicity when used in combination with Y90. As mentioned previously, bevacizumab, also frequently used in the treatment of mCRC, may not necessarily have synergistic toxic effects with Y90, but it may increase the risk of arteriography complications.…”