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Stivarga (Regorafenib)
Regorafenib, formerly known as BAY 73-4506 and as fluro-sorafenib, was developed by Bayer. The brand name for regorafenib is Stivarga. Regorafenib is structurally similar to sorafenib, with a change in a single atom that gives it an additional mechanism of action: a second blockade of angiogenesis via inhibition of Tie-2. For an image showing how regorafenib is related to sorafenib, see this link.
Scroll down this page for positive clinical trial results reported for regorafenib used against GIST.
FDA Approval Granted for Regorafenib against GIST and Colon Cancer
On 2/25/2013 the FDA approved regorafanib for GIST. Here are details from the FDA press release:
FDA stated "The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease..... With this new approval, Stivarga is intended to be used in patients whose GIST cancer cannot be removed by surgery or has spread to other parts of the body (metastatic) and is no longer responding to Gleevec (imatinib) and Sutent (sunitinib), two other FDA-approved drugs to treat GIST...... Stivarga was reviewed under the FDA’s priority review program, which provides an expedited six-month review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products. The drug was also granted orphan product designation because it is intended to treat a rare disease."
LINK HERE for a pdf news release from Bayer about the positive results for regorafenib against GIST in the GRID trial, which was the basis for filing for FDA approval.
On 9/27/2012 the FDA approved regorafenib (Stivarga) for treatment of colon cancer. See FDA link and Bayer press release.
Definition from NCI Drug Dictionary: An orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities. Multikinase inhibitor BAY 73-4506 binds to and inhibits vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation. VEGFRs are receptor tyrosine kinases that play important roles in tumor angiogenesis; the receptor tyrosine kinases RET, KIT, and PDGFR, and the serine/threonine-specific Raf kinase are involved in tumor cell signaling.
Mode of action: inhibitor of vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, plus the angiogenesis-related Tie2 kinase.
Information at manufacturer website:
http://www.bayerhealthcare.com/html/pdf/DAST_190607_EN.pdf
Clinical trials relevant to GIST:
Note: the trial listed above provides a mechanism for GIST patients to obtain regorafenib prior to its FDA-approval application being considered by the FDA.
Contact: Bayer Clinical Trials Contact clinical-trials-contact@bayerhealthcare.com
Contact: For trial location information (Phone Menu Options '3' or '4') (+)1-888-84 22937
Open Label Regorafenib Study to Evaluate Cardiovascular Safety Parameters, Tolerability, and Anti-tumor Activity. NCT01339104.
Study of Regorafenib as a 3rd-line or Greater Treatment for Gastrointestinal Stromal Tumors (GIST) (GRID) a Phase III trial, NCT 01271712. This trial is no longer recruiting but is ongoing.
Regorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor, NCT01068769 This trial is no longer recruiting but is ongoing.
Clinical trial results and other sources of information about regorafenib:
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators.
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
Lancet. 2013 Jan 26;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1.
PubMed PMID: 23177515
Demetri et al (2013) reported results from the Phase III trial of regorafenib in patients with metastatic or unresectable GIST. This study included 133 patients in the regorafenib arm and 66 in the placebo arm (who could cross over to receive regorafenib upon progression). All subjects had previously taken at least imatinib and sunitinib, and over 40% had received prior third or higher line therapies. Median progression-free survival was 4.8 months in the regorafenib arm, with an interquartile range of 1.4 to 9.2 months, which was significantly longer than the 0.9 months PFS in the placebo arm. Placebo subects who crossed over to receive regorafenib had a median 5.0 months PFS after crossover. The disease control rate (partial response or stable disease) was 56% in the regorafenib group. The most common side effects of regorafenib were hand-foot skin reaction, hypertension, and diarrhea. The investigators did not report results separately by tumor genotype, but they plan to conduct this analysis later.
Abstract No: LBA10008
Citation: J Clin Oncol 30, 2012 (suppl; abstr LBA10008)
Author(s): George D. Demetri, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Heikki Joensuu, Robert G. Maki, Piotr Rutkowski, Peter Hohenberger, Hans Gelderblom, Michael Gordon Leahy, Margaret von Mehren, Patrick Schoffski, Martin E. Blackstein, Axel Le Cesne, Giuseppe Badalamenti, Jian-Ming Xu, Toshirou Nishida, Dirk Laurent, Iris Kuss, Paolo Giovanni Casali, on behalf of GRID Investigators;
Dr. Demetri presented the Phase III results of the randomized, double-blind, placebo-controlled GRID (GIST-Regorafenib in Progressive Disease) trial, which evaluated the efficacy and safety of Bayer’s new multikinase inhibitor, regorafenib (REG), in patients with metastatic and/or unresectable GIST whose disease had progressed despite prior treatment with IM and SU. Patients were randomized 2:1 to receive best supportive care plus either REG 160 mg once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was PFS. Secondary endpoints included OS, disease control rate (DCR, defined as rate of partial response plus stable disease lasting for ≥12 wks), response rate and duration, safety and correlative genotypic analyses. Patients who progressed during the trial period were eligible for crossover to open-label REG. A total of 234 patients were screened and199 were randomized (REG: 133, PL: 66). Median PFS was 4.8 months for REG vs 0.9 months for PL – satisfying the primary endpoint. The most common >grade 3 toxicities in the REG arm were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). The investigators concluded that REG had significantly improved both PFS and DCR, with toxicities as expected for this drug class.
Nancy’s comment: Regorafenib targets C-Kit, VEGFR. PDGFR, RET, RAF-1, BRAF, p38 MAP, and a bunch of other kinases – thus, audience expectations were extremely high. Those hoping to come away from the presentation with news of a dramatic breakthrough were disappointed…but these are early days. Unquestionably, some patients will do very well on this drug. Whether the median PFS can be further improved -- and OS increased -- remain to be seen.
A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU).
Authors: S. George, M. von Mehren, M. C. Heinrich, Q. Wang, C. L. Corless, J. E.
Butrynski, J. A. Morgan, A. J. Wagner, E. Choy, W. D. Tap, J. Manola,
J. T. Yap, A. D. Van Den Abbeele, S. Solomon, J. A. Fletcher, and G. D. Demetri
ASCO Meeting Abstracts. 2011; 29(15_suppl): p. 10007
http://en.wikipedia.org/wiki/Regorafenib
http://www.medicalnewstoday.com/articles/164835.php
http://prod2.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=33859
