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Regorafenib

 

  1. What is Regorafenib?
  2. Why is Regorafenib Approved by FDA?
  3. How Does Regorafenib Work?
  4. What is Regorafenib Main Used For?
  5. What Benefits of Regorafenib have been shown in Studies?
  6. What Risks/Side effects does Regorafenib May Bring?
  7. How do I store and/or throw out Regorafenib?
  8. Future directions of Regorafenib
  9. Conclusion

 

What is Regorafenib?

Regorafenib(CAS: 755037-03-7), sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types.By 2015 it had two US approvals for advanced cancers.

 

Why is Regorafenib Approved by FDA

The European Medicines Agency decided that Regorafenib’s benefits are greater than its risks and recommended that it be approved for use in the EU. The Committee noted that in colorectal cancer the benefits in terms of extending patient survival were modest, but considered that they outweighed the risks in patients for whom there are no other remaining treatment options. However, given the side effects, the CHMP considered it important to find ways to identify any subgroups of patients who are more likely to respond to Stivarga.

With regard to GIST and HCC, the Committee noted that the outlook is poor for patients whose disease gets worse despite previous treatment. Stivarga had been shown to delay the worsening of the disease in these patients. For patients with HCC, this led to an improvement in the length of time patients lived. The side effects of Stivarga are manageable.

 

How Does Regorafenib Work? 

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

AASraw is the professional manufacturer of Regorafenib.

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What is Regorafenib Main Used For?

Regorafenib is a cancer medicine that contains the active substance regorafenib powder. It is used on its own to treat the following cancers:

① Colorectal cancer (cancer of the bowel and rectum) that has spread to other parts of the body;

② Gastrointestinal stromal tumour (GIST, a cancer of the stomach and bowel) that has spread or cannot be surgically removed;

③ Hepatocellular carcinoma (HCC, a cancer of the liver).

Regorafenib is used in patients who have already been treated with, or who cannot be given, other available treatments. For colorectal cancer, these include chemotherapy based on medicines called fluoropyrimidines and treatment with other cancer medicines known as anti‑VEGF and anti‑EGFR therapies. Patients with GIST should have tried treatment with imatinib and sunitinib and patients with HCC should have tried sorafenib before starting treatment with Regorafenib.

 

Regorafenib

 

What Benefits of Regorafenib have been shown in Studies?

 Colorectal cancer

In a main study involving 760 patients with metastatic colorectal cancer which had progressed after standard therapy, Regorafenib was compared with placebo (a dummy treatment) and the main measure of effectiveness was overall survival (the length of time that patients lived). All patients also received supportive care, including pain medicines and treatment for infections. The study showed that Regorafenib improved survival, with treated patients living for 6.4 months on average, compared with 5 months for those given placebo.

 

 GIST(Advanced Gastrointestinal Stromal Tumours)

In another main study, Regorafenib was compared with placebo in 199 patients with GIST that had spread or was inoperable and who were also given best supportive care. Supportive care included treatments like pain relief, antibiotics, and blood transfusions that help the patient but without treating the cancer. The study showed that Regorafenib with supportive care was effective at prolonging the length of time patients lived without their disease getting worse. Patients treated with Regorafenib lived on average for 4.8 months without their disease getting worse compared with 0.9 months for patients taking placebo and supportive care.

 

 HCC(Advanced Hepatocellular Carcinoma)

In a main study involving 573 patients with HCC that had worsened after treatment with sorafenib, Regorafenib was compared with placebo and the main measure of effectiveness was overall survival. All patients also received supportive care. The study showed that Stivarga increased the length of time that patients lived overall, with patients treated with Regorafenib living for 10.6 months on average, compared with 7.8 months for those given placebo.

 

What Risks/Side effects does Regorafenib May Bring?

Infection. Regorafenib may lead to a higher risk of infections especially of the urinary tract, nose, throat and lung. Regorafenib may lead to a higher risk of fungal infections of the mucous membrane, skin or the body. Tell your healthcare provider right away if you get fever, severe cough with or without an increase in mucus (sputum) production, severe sore throat, shortness of breath, burning or pain when urinating, unusual vaginal discharge or irritation, redness, swelling or pain in any part of the body

Severe bleeding. Regorafenib can cause bleeding, which can be serious and sometimes lead to death. Tell your healthcare provider if you have any signs of bleeding while taking Regorafenib, including: vomiting blood or if your vomit looks like coffee grounds, pink or brown urine, red or black (looks like tar) stools, coughing up blood or blood clots, menstrual bleeding that is heavier than normal, unusual vaginal bleeding, nose bleeds that happen often, bruising, and lightheadedness.

A tear in your stomach or intestinal wall (bowel perforation). Regorafenib may cause a tear in your stomach or intestinal wall that can be serious and sometimes lead to death. Contact your healthcare provider immediately if you notice severe pains or swelling in your stomach area (abdomen), fever, chills, nausea, vomiting, or dehydration.

A skin problem called hand-foot skin reaction and severe skin rash. Hand-foot skin reactions are common and sometimes can be severe. Tell your healthcare provider right away if you get redness, pain, blisters, bleeding, or swelling on the palms of your hands and soles of your feet, or a severe rash.

High blood pressure. Your blood pressure should be checked every week for the first 6 weeks of starting Regorafenib. Your blood pressure should be checked regularly and any high blood pressure should be treated while you are receiving Regorafenib. Tell your healthcare provider if you have severe headaches, light-headedness, or changes in your vision.

Decreased blood flow to the heart and heart attack. Get emergency help if you have chest pain, have shortness of breath, feel dizzy, or feel like passing out.

A condition called reversible posterior leukoencephalopathy syndrome (RPLS). Call your healthcare provider right away if you get severe headaches, seizure, confusion, change in vision, or problems thinking

Risk of wound healing problems. Wounds may not heal properly during Regorafenib treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with Regorafenib.

▪ You should stop taking Regorafenib at least 2 weeks before planned surgery.

▪ Your healthcare provider should tell you when you may start taking Regorafenib again after surgery.

The most common side effects with Regorafenib include pain including stomach-area (abdomen); tiredness, weakness, fatigue; diarrhea (frequent or loose bowel movements); decreased appetite; infection; voice change or hoarseness; increase in certain liver function tests; fever; swelling, pain, and redness of the lining in your mouth, throat, stomach, and bowel (mucositis); and weight loss.

AASraw is the professional manufacturer of Regorafenib.

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How do I store and/or throw out Regorafenib?

♦ Store tablets in the original container at room temperature. Keep the cap tightly closed. Do not take out the antimoisture cube or packet.

♦ Throw away any part not used 7 weeks after opening the bottle.

♦ Store in a dry place. Do not store in a bathroom.

♦ Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.

♦ Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

 

Regorafenib

 

Future directions of Regorafenib

Five years after its approval, regorafenib remains a drug with limited clinical handling. Approved use in colorectal cancer, GIST and HCC is only for advanced metastatic disease. Combined with high cost, there is currently little clinical benefit for patients. Moreover, distinct trials are being conducted in order to define it as a new treatment option. Future directions for this drug include the management of osteosarcoma. A recent placebo-controlled, double blind trial in France has shown an increase in progression-free survival by a factor of 3 in patients with metastatic osteosarcoma that have failed every line of treatment. Compellingly, these new data show benefit on advanced metastatic disease as a last resort, similarly to all current approved uses.

Recent data suggest a possible synergic effect between regorafenib and immune checkpoint inhibitors, as has been shown in the REGONIVO trial.A phase Ib trial comparing regorafenib and its combination with nivolumab in patients with advanced gastric cancer or colorectal cancer, demonstrated 38% objective response rate (44% in gastric cancer and 36% in colorectal cancer) and a tolerable side effects profile in the combination group. This intriguing benefit may be due to reduction of tumour-associated macrophages by regorafenib, increasing the tumour’s sensitivity to nivolumab. Currently, the REGONIVO phase II trial is under way and could soon corroborate this hypothesis. Additionally, a latter phase II clinical trial has demonstrated that regorafenib is superior to lomustine in advanced and relapsed glioblastoma.The REGOMA trial, in Italy, has indicated a significant improvement in overall survival (hazard ratio 0.50; 95% confidence interval 0.33–0.75; log-rank p=0.0009) as compared with lomustine therapy.

The REVERSE studies have been conducted with regorafenib and cetuximab in the treatment of metastatic colorectal cancer. The results obtained on the sequence of the use of such drugs in the treatment of this cancer suggest that the ideal order would be the initial administration of regorafenib followed by cetuximab, different from the standard protocol currently used. The results showed improved overall survival of the patients and the benefit seemed to be driven mostly by greater activity of cetuximab than regorafenib as the second treatment.

The INTEGRATE trial of regorafenib monotherapy in gastric cancer showed that this drug was well tolerated and that there was no damage in patients’ quality of life compared to those who received placebo and that it did not appear to have an excessively negative effect on those parameters from toxicity. Research projects highlighted that baseline levels of pain, appetite, constipation, and physical functioning were found to be significant prognostic factors for survival.Also, this trial demonstrated that regorafenib had considerable activity in the primary progression-free survival endpoint.Additionally, the phase II REDOS trial was performed from 2015–2018 and authors showed that a dose-escalation strategy for regorafenib is an achievable alternative to the standard regorafenib dosing strategy of 160 mg/day, especially in patients with metastatic colorectal cancer. It was also found that patients treated with dose escalation had a higher frequency of post-progression treatment and numerically longer overall survival.

Regarding tolerability of regorafenib when employed to treat colorectal cancer, limited data are available on the tolerance in the older patient population, and the decision must be made considering the minimal survival benefit and the toxicity profile. Considering this drug in HCC treatment, research projects emphasize that there is an acceptable tolerance profile and that regorafenib provides a survival benefit.For GIST treatment, several authors state that regorafenib is well tolerated with no unexpected toxicities.

Further research is needed to determine which patients can benefit the most from this drug. As of 2019, ongoing trials are testing whether regorafenib can improve outcomes in soft tissue sarcomas, such as osteogenic sarcoma, liposarcoma, Ewing sarcoma and rhabdomyosarcoma.

 

Conclusion

Despite 5 years of approval and promising pharmacodynamics, regorafenib has shown limited, yet statistically significant, benefit for various types of solid tumours. Labelled indications comprise colorectal cancer, GIST and HCC. Advanced phase II trials have shown significant improvements in survival for gastric cancer, glioblastoma and osteosarcoma, which may indicate future inclusion in labelled indications.

Combination therapy with immune checkpoint inhibitors has been demonstrated as beneficial in phase I trials, and phase II trials are being performed. Currently, regorafenib is being investigated for other cancers as well. Many individual side effects can be used as markers for better outcomes with treatment. Among those, hand–foot syndrome and hypothyroidism are the most related to improved survival. In summary, studies have shown that regorafenib can significantly improve survival with an acceptable tolerance in a variety of solid tumours.

AASraw is the professional manufacturer of Regorafenib.

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Reference

[1] Krishnamoorthy SK, Relias V, Sebastian S, et al. Management of regorafenib-related toxicities: a review. Ther Adv Gastroenterol. 2015;8:285–97.

[2] Thangaraju P, Singh H, Chakrabarti A. Regorafenib: a novel tyrosine kinase inhibitor: a brief review of its therapeutic potential in the treatment of metastatic colorectal carcinoma and advanced gastrointestinal stromal tumors. Indian J Cancer. 2015;52:257–60.

[3] Grünewald FS, Prota AE, Giese A, Ballmer-Hofer K. Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta Proteins Proteomics. 2010;1804:567–80.

[4] Shinkai A, Ito M, Anazawa H, et al. Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor. J Biol Chem. 1998;273:31283–8.

[5] Fuh G, Li B, Crowley C, et al. Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J Biol Chem. 1998;273:11197–204.

[6] Eriksson A, Cao R, Roy J, et al. Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation. 2003;107:1532–8.

[7] Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.

[8] Emuss V, Garnett M, Mason C, Marais R. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 2005;65:9719–26.

[9] Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.

[10] Martin AJ, Gibbs E, Sjoquist K, et al. Health-related quality of life associated with regorafenib treatment in refractory advanced gastric adenocarcinoma. Gastric Cancer. 2018;21:473–80.

[11] Heo YA, Syed YY. Regorafenib: a review in hepatocellular carcinoma. Drugs. 2018;78:951–8.

[12] Yin X, Yin Y, Shen C, Chen H, Wang J, Cai Z, et al. Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials. Onco Targets Ther. 2018;11:6405–14.

[13] Lombardi G, De Salvo GL, Brandes AA, et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019;20:110–9.

[14] Bekaii-Saab T. A closer look at regorafenib. Clin Adv Hematol Oncol. 2018;16:667–9.

[15] Yoshino K, Manaka D, Kudo R, et al. Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report. J Med Case Rep. 2017;11:227.

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