Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study

295

227

Purpose: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.Patients and Methods: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).Results: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).Conclusion: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors. Clin Cancer Res; 18(9); 2658-67. Ó2012 AACR.

Section: Discussionmentioning

confidence: 99%

A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors

Mross¹,

Frost²,

Steinbild³

et al. 2012

295

227

“…In this respect, regorafenib inhibits multiple cell membrane tyrosine kinase receptors that are involved in key processes of cancer development and progression, including angiogenesis (17). Furthermore, regorafenib antitumor activity could be also due in part by its ability to inhibit RAF serine/threonine kinase (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Napolitano

Martini

Rinaldi³

et al. 2015

Purpose: In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximabsensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximabresistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.Conclusions: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. Clin Cancer Res; 21(13); 2975-83. Ó2015 AACR.

“…These findings might result from the variable and low incidence of KIT expression in colon cancers, marked intratumoral heterogeneity of KIT expression in colon cancers, requirement of continuous SCF stimulation to the KIT expressing tumors, and varying concomitant activations of endogenous KIT and PKC-d in human colorectal cancers. These considerations make it difficult, if not impossible, to carry out a in vivo validation study of the antitumor effect of KIT inhibitors in colon cancers expressing WT-KIT and exemplify why the results for tyrosine kinase inhibitors in clinical trials in colon cancers are unimpressive, except for regorafenib, a multi tyrosine kinase inhibitor (40). However, continuous downstream signal activation through SCF binding to WT-KIT may be present in some colorectal cancers, and these cancers are expected to exhibit rapid progression.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

Park

Kim

Song

et al. 2013

Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis.Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation.Results: We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-d in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-d and that expression of KIT is correlated with poor patient survival (P ¼ 0.004).Conclusions: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-d-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT.