Tanios Bekaii-Saab, MD: Mechanisms of Action in Regorafenib

How does regorafenib differ in its mechanism of action from other anti-VEGF therapies (eg; bevacizumab)?

Regorafenib is an oral agent and is what we call an inhibitor of multiple tyrosine kinases, which essentially means it targets multiple proteins other than just VEGF. As such, it is not a pure antiangiogenic agent and will hit other targets that are important to tumor proliferation and tumor spread. It also affects the microenvironment other than just VEGF.

Case 1: mCRC

Marie K. is a 61-year-old female from Indianapolis, Indiana, who works as a corporate IT consultant. In July of 2013, she was diagnosed with mCRC after presenting to her PCP with symptoms of abdominal fullness and abnormal bowel movements of several weeks’ duration.

Medical history is notable for hip replacement in 2011, and mild GERD

CT scans of the abdomen and pelvis suggest presence of multiple peritoneal implants with mild ascites

Her initial biopsy showed a well-differentiated adenocarcinoma with molecular testing showed RAS-WT and BRAF- WT disease

She received initial therapy with FOLFIRI and cetuximab, and showed good response after 4 cycles

In March of 2014, she returned to her oncologist for a follow-up, and her CT scan showed evidence of progression, with visceral peritoneal metastases and ascites, as well as increasing CEA levels (40.2 ng/mL); her ECOG performance status at time of progression was 0

She was switched to FOLFOX and bevacizumab, with a good response. She had a marked decrease in CEA levels and improvement in her abdominal ascites after 3 cycles of therapy

In January of 2015, she returned for follow up with symptoms of abdominal fullness, increasing fatigue, and declining performance status (PS 1); PET/CT scan at that time showed marked progression of multiple target lesions.

She began treatment with regorafenib at a dose of 160 mg, but treatment was interrupted for 1 week after she developed moderate fatigue and grade 3 hand-foot skin reaction (HFSR); her liver function tests were within normal limits before and during treatment

Her condition improved, and treatment with regorafenib was re-initiated at a dose of 120 mg

Patient tolerated the reduced dose, with some mild fatigue, through 8 cycles of treatment; her disease remained stable on PET/CT at her 2-, 4-, and 6-month assessments, and performance status improved (PS 0)

She was scheduled to undergo oral surgery (dental implants) in October of 2015, and her treatment was interrupted 2 weeks prior to surgery

She returns for follow up 4 weeks after the procedure, with good wound healing and a PS of 0. Her PET/CT scan shows moderate progression of the peritoneal metastases and several new hepatic lesions. Her CEA has also increased to 27.7 ng/mL. Liver and kidney function remain within normal limits.