Just Accepted by Current Medical Research & Opinion Review A comprehensive review of the role of Hedgehog pathway and Vismodegib in the management of Basal Cell Carcinoma Gökmen Umut Erdem; Mehmet Ali Nahit Sendur; Nuriye Yıldırım Ozdemir; Ozan Yazıcı; Nurullah Zengin doi: 10.1185/03007995.2015.1018988
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Abstract Background: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease. Scope: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords; “vismodegib”, “pathway”, “inhibitor”, and “Targeted therapies for BCC”. The last search was done on September 1, 2014. The most of the data of vismodegib depend on to phase I and II trials. Findings: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy has not been completely known. Although conventional chemotherapies like cisplatin increased the response rate of BCC, the improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib can be a new treatment strategy for patients with locally advanced and metastatic BCC. As previous published phase I trials, in ERIVANCE BCC study, the primary endpoint objective response rate significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. According to the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who is not suitable for surgery or radiotherapy or relapsed locally advanced disease following surgery or metastatic disease. Conclusion: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
REVIEW A comprehensive review of the role of Hedgehog pathway and Vismodegib in the
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
management of Basal Cell Carcinoma 1
Gökmen Umut Erdem; 2Mehmet Ali Nahit Sendur; 2Nuriye Yıldırım Ozdemir; 1Ozan Yazıcı;
1
Nurullah Zengin
1
Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara,
Turkey 2
Yıldırım Beyazıt University, Department of Medical Oncology, Ankara, Turkey
Address correspondence to: Mehmet Ali Nahit Şendur, M.D., Yıldırım Beyazıt University, Faculty of Medicine, Department of Medical Oncology, 06800, Bilkent, Ankara-TURKEY. Tel: +90 312 2912525; Fax: +90 312 2912726; [email protected]
ABSTRACT Background: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease.
Scope: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords; “vismodegib”, “pathway”, “inhibitor”, and “Targeted therapies for BCC”. The last search was done on September 1, 2014. The most of the data of
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
vismodegib depend on to phase I and II trials.
Findings: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy has not been completely known. Although conventional chemotherapies like cisplatin increased the response rate of BCC, the improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib can be a new treatment strategy for patients with locally advanced and metastatic BCC. As previous published phase I trials, in ERIVANCE BCC study, the primary endpoint objective response rate significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. According to the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who is not suitable for surgery or radiotherapy or relapsed locally advanced disease following surgery or metastatic disease.
Conclusion: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways.
Keywords: Basal cell carcinoma; Hedgehog pathway; vismodegib; GDC-0449; non-melanoma
Introduction Basal cell carcinoma is a serious economic burden for the health care systems, with a high incidence and morbidity rate1, 2. Basal cell carcinoma, which was firstly defined in 1827, is rarely
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
reported in cancer registry systems3. Therefore, it is difficult to determine the real incidence of BCC. In the United States it was estimated that 80% of the 2.1 million new patients treated for non-melanoma skin cancers were BCC4. The estimated real incidence of BCC is 0.1-0.5% in worldwide5, 6. During the last 30 years, the incidence of BCC has rapidly increased in worldwide1, 5.In the United States, the total number of women diagnosed with BCC under 40 years of age has doubled in recent years7. In the world, Australia has the highest ratio of diagnosed BCC with its reported incidence of 726/100.0006,8. Although BCC is mostly caused by radiation exposure, other risk factors such as fair skin, light colored hair, a family history of skin cancer and a weakened immune system are still present.9-13. Many hereditary syndomes like nevoid BCC syndrome (Gorlin Syndrome), Bazex-Dupré-Christol syndrome, Rombo syndrome, Oley syndrome and Xeroderma pigmentosum might also cause BCC14. Basal cell carcinoma can be detected anywhere in the body, but it is most commonly seen in the head and neck region6. Although BCC is a slowly progressing disease, in rare cases it invades local tissues and can metastasize to other regions of the body11, 15-17. The average age of BCC diagnosis is usually in between 45 and 56 years old. Metastases of BCC can be usually detected with an average of 9 years after diagnosis18, 19. Many risk factors leading to BCC metastasis have been defined; male gender, primary lesion located on ear or face, large and local invasive primary tumor, relapsed or recurrent disease and impaired cellular immunity (acquired
immune deficiency syndrome, treatment-induced immunosuppression). Despite different treatment modalities, the median overall survival of metastatic BCC is 8 months16-22. In early stage BCC, surgery is the indispensable and essential treatment modality. Following the surgery, relapse rate is between 1-5% per year23. Most cases of BCC are treated
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumor might have potential to progress. If the patients are unsuitable or contraindicated for surgery and radiotherapy, topical therapies like 5-Fluorouracil (5-FU), İmiquimod (3M/Medicis), photodynamic therapy and cryotherapy can be applied. However, these treatments are less effective than surgery and radiotherapy15, 16, 21, 24, 25. In this patient group, there is no standardized treatment approach. Multiple BCCs may develop in Gorlin syndrome and studies have shown the mutation in the patched homologue 1 (PTCH1) gene (9th chromosome)26. It has been demonstrated that 90% of sporadic BCC cases had at least one allelic function loss mutation of PTCH1 gene, whereas 10% of them had activated mutation of the smoothened homologue (SMO) gene26, 27. These mutations initiate the signaling of the Hh pathways that cause uncontrolled proliferation of skin basal cells. Therefore, blocking of the Hh pathways might be beneficial for the treatment of BCC26, 28, 29. Cyclopamine is a teratogenic steroidal alkaloid that causes midline defects in the embryonic period. It blocks the Hh signaling by binding the SMO gene and blocks the activation of Hh target genes30, 31. While low concentrations (98% of vismodegib stays as major drug. Few minor metabolites undergo oxidation or glucorinodation reactions in plasma. In vitro studies have shown that CYP3A4/5 ve CYP2C9 are the major enzymes that produce the oxidative metabolites55. The orally administered vismodegib and metabolites are eliminated by the liver. Most of the orally taken dose was excreted in feces and urine, 82% and 4.4%, respectively. Estimated half-life of a single dose and continuous daily dose of vismodegib were 12 and 4 days, respectively61. In vitro studies showed that vismodegib is a substrate of P-glycoprotein. When vismodegib is administered together with the Claritomycin, Eritomycine or Azitromycine (which are the inhibitors of P-glycoprotein), the incidence of vismodegib side effects and systemic exposure can be increased61. Drugs affecting pH of the upper gastrointestinal system, such as proton pump inhibitors, histamine H2-receptor antagonists and antacids, can also change the solubility and decrease the bioavalibility of vismodegib. However, none of the studies evaluated the drug-drug interactions between the drugs effecting gastric pH and vismodegib61.
Safety data of Vismodegib The pregnancy category of Vismodegib is D. Before Vismodegib therapy, women should be checked for possible pregnancy and warned about contraception necessity during the treatment.
Male patients should be informed that they can expose their female partners to vismodegib via cemen. It is not yet known whether vismodegib is excreted in human breast milk or not. During breast feeding period, the potential benefits of vismodegib should be considered. Depending on
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
these benefits, the doctor should make a decision whether to discontinue nursing or to discontinue the drug61. In case of side effects, patient intolerance or drug-drug interactions with vismodegib, there have been no standardized dose reduction schedule yet. None of the studies evaluated the safety profile of vismodegib in patients with renal failure and liver function abnormalities. The patients are advised to have no blood or blood product donation following (at least) 7 months vismodegib administration61.
Clinical Trials of Vismodegib The clinical effectiveness of vismodegib was demonstrated in only in phase I62-65 and phase II6669
studies. In a phase I trial of vismodegib in patients with locally advanced or metastatic BCC, the
safety and pharmacokinetic properties were assessed65. In the first period of the trial 20 patients were enrolled and the maximum tolerated dose of vismodegib was investigated. In the first part of this phase 1 trial; 7, 9 and 4 patients recieved vismodegib 150 mg, 270 mg and 540 mg, respectively. In the pharmacokinetic study of this trial, vismodegib did not reach the high plasma concentration over the 150 mg dose. Therefore, the recommended dose of vismodegib for the second part of the trial was found to be 150 mg. In these BCC patients, 18 (54.5%) of them had metastatic and 15 (45.5%) of them had locally advanced disease. 17, 15 and 1 patients were
treated with 150 mg, 270 mg and 540 mg per day, respectively with a median of 9.8 month vismodegib treatment. In this phase I study, objective response rate (ORR), partial response (PR), complete response (CR) and stable disease (SD) rates were 54.5%, 48.4%, 6.1% and 33.3%, respectively. Progressive disease was observed only in 12.1% of the patients treated with
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
vismodegib. The ORR was 50.0% and 60% in metastatic and locally advanced BCC tumors, respectively. Dose limiting adverse events were not reported and the most commonly reported grade 3-4 adverse events were fatique, hyponatremia, muscle spasm and atrial fibrillation. This phase I study was the first study suggesting that the inhibition of the Hh pathway can be useful in treating patients with locally advanced and metastatic BCC tumors. Amin SH. and colleagues reported a case series of 3 patients with head and neck BCC from this phase I trial70. Two patients had radiologic and clinical CR whereas one patient showed significant PR with the continuous vismodegib treatment. In further work of phase I trial that was performed by LoRusso and colleagues, 68 patients with locally advanced or metastatic solid tumors who did not have standard treatment or refractory standard treatments, were administered 3 different doses of vismodegib64. In this trial most of the patients (48.5%) were diagnosed as BCC (n=33) and the other patients were diagnosed as pancreatic cancer (n=8), medullablastoma (n=1) and other cancer types (n=17). The aim of this phase I trial was to assess the safety and the efficacy of vismodegib in patients with solid tumors. In these BCC patients, 18 (54.5%) of them had metastatic and 15 (45.5%) of them had locally advanced disease. In this study, vismodegib was given until disease progression or intolerable toxicity. In this study, responses to treatment were reported only in patients diagnosed with BCC and medullablastoma. The results of this study demonstrated a 58% ORR with 12.8 (3.7-26.4) months median response in BCC patients. In addition to this, 4 patients with solid
tumors (adenocystic carcinoma, pancreatic carcinoma and metastatic carcinoid) showed SD as best response, with a median response of 3.1 (2-8-6,5) months. The most commonly reported adverse events were muscle spasms, dysgeusia, fatigue, alopecia and nausea. Most commonly reported grade 3 and 4 adverse events were hyponatremia, fatique and abdominal pain. This
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
study also showed that the 150 mg vismodegib per day was the appropriate dose for enough effective plasma concentration, clinical effectiveness and safety. In another phase I study, a clinical drug-drug interaction between vismodegib and rosiglitazone or oral contraceptives was tested63. The aim of this study was to test pharmacokinetic parameters of vismodegib in combination with other drugs. Due to the in vitro data; vismodegib had moderate inhibition potential for cytochrome P450 (CYP) 2C8 and CYP2C9. In this study, plasma concentrations of rosiglitazone, oral contraceptives and other drugs were not altered by vismodegib co-administration. A non-randomized two-cohort, phase II trial (ERIVANCE BCC) included patients with locally advanced or metastatic BCC68. The primary endpoint of this study was independently assessed by ORR. A total of 104 patients were included in study, of which 33 had metastatic and 71 had locally advanced disease. During the efficacy analysis period, independent pathologist could not demonstrate BCC in the specimens of 8 patients so they were excluded from the study population. Thus the analysis was performed on 96 patients. In locally advanced group, surgery, radiotherapy and systemic or topical therapy was performed in 89%, 27% or 11% of the patients, respectively. In metastatic group, previous surgery, radiotherapy and systemic therapy was performed in 97%, 58% and 30% of the patients, respectively. Independently assessed ORRs were 43% (27/63) (P
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Abstract Background: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease. Scope: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords; “vismodegib”, “pathway”, “inhibitor”, and “Targeted therapies for BCC”. The last search was done on September 1, 2014. The most of the data of vismodegib depend on to phase I and II trials. Findings: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy has not been completely known. Although conventional chemotherapies like cisplatin increased the response rate of BCC, the improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib can be a new treatment strategy for patients with locally advanced and metastatic BCC. As previous published phase I trials, in ERIVANCE BCC study, the primary endpoint objective response rate significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. According to the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who is not suitable for surgery or radiotherapy or relapsed locally advanced disease following surgery or metastatic disease. Conclusion: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
REVIEW A comprehensive review of the role of Hedgehog pathway and Vismodegib in the
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
management of Basal Cell Carcinoma 1
Gökmen Umut Erdem; 2Mehmet Ali Nahit Sendur; 2Nuriye Yıldırım Ozdemir; 1Ozan Yazıcı;
1
Nurullah Zengin
1
Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara,
Turkey 2
Yıldırım Beyazıt University, Department of Medical Oncology, Ankara, Turkey
Address correspondence to: Mehmet Ali Nahit Şendur, M.D., Yıldırım Beyazıt University, Faculty of Medicine, Department of Medical Oncology, 06800, Bilkent, Ankara-TURKEY. Tel: +90 312 2912525; Fax: +90 312 2912726; [email protected]
ABSTRACT Background: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease.
Scope: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords; “vismodegib”, “pathway”, “inhibitor”, and “Targeted therapies for BCC”. The last search was done on September 1, 2014. The most of the data of
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
vismodegib depend on to phase I and II trials.
Findings: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy has not been completely known. Although conventional chemotherapies like cisplatin increased the response rate of BCC, the improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib can be a new treatment strategy for patients with locally advanced and metastatic BCC. As previous published phase I trials, in ERIVANCE BCC study, the primary endpoint objective response rate significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. According to the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who is not suitable for surgery or radiotherapy or relapsed locally advanced disease following surgery or metastatic disease.
Conclusion: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways.
Keywords: Basal cell carcinoma; Hedgehog pathway; vismodegib; GDC-0449; non-melanoma
Introduction Basal cell carcinoma is a serious economic burden for the health care systems, with a high incidence and morbidity rate1, 2. Basal cell carcinoma, which was firstly defined in 1827, is rarely
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
reported in cancer registry systems3. Therefore, it is difficult to determine the real incidence of BCC. In the United States it was estimated that 80% of the 2.1 million new patients treated for non-melanoma skin cancers were BCC4. The estimated real incidence of BCC is 0.1-0.5% in worldwide5, 6. During the last 30 years, the incidence of BCC has rapidly increased in worldwide1, 5.In the United States, the total number of women diagnosed with BCC under 40 years of age has doubled in recent years7. In the world, Australia has the highest ratio of diagnosed BCC with its reported incidence of 726/100.0006,8. Although BCC is mostly caused by radiation exposure, other risk factors such as fair skin, light colored hair, a family history of skin cancer and a weakened immune system are still present.9-13. Many hereditary syndomes like nevoid BCC syndrome (Gorlin Syndrome), Bazex-Dupré-Christol syndrome, Rombo syndrome, Oley syndrome and Xeroderma pigmentosum might also cause BCC14. Basal cell carcinoma can be detected anywhere in the body, but it is most commonly seen in the head and neck region6. Although BCC is a slowly progressing disease, in rare cases it invades local tissues and can metastasize to other regions of the body11, 15-17. The average age of BCC diagnosis is usually in between 45 and 56 years old. Metastases of BCC can be usually detected with an average of 9 years after diagnosis18, 19. Many risk factors leading to BCC metastasis have been defined; male gender, primary lesion located on ear or face, large and local invasive primary tumor, relapsed or recurrent disease and impaired cellular immunity (acquired
immune deficiency syndrome, treatment-induced immunosuppression). Despite different treatment modalities, the median overall survival of metastatic BCC is 8 months16-22. In early stage BCC, surgery is the indispensable and essential treatment modality. Following the surgery, relapse rate is between 1-5% per year23. Most cases of BCC are treated
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumor might have potential to progress. If the patients are unsuitable or contraindicated for surgery and radiotherapy, topical therapies like 5-Fluorouracil (5-FU), İmiquimod (3M/Medicis), photodynamic therapy and cryotherapy can be applied. However, these treatments are less effective than surgery and radiotherapy15, 16, 21, 24, 25. In this patient group, there is no standardized treatment approach. Multiple BCCs may develop in Gorlin syndrome and studies have shown the mutation in the patched homologue 1 (PTCH1) gene (9th chromosome)26. It has been demonstrated that 90% of sporadic BCC cases had at least one allelic function loss mutation of PTCH1 gene, whereas 10% of them had activated mutation of the smoothened homologue (SMO) gene26, 27. These mutations initiate the signaling of the Hh pathways that cause uncontrolled proliferation of skin basal cells. Therefore, blocking of the Hh pathways might be beneficial for the treatment of BCC26, 28, 29. Cyclopamine is a teratogenic steroidal alkaloid that causes midline defects in the embryonic period. It blocks the Hh signaling by binding the SMO gene and blocks the activation of Hh target genes30, 31. While low concentrations (98% of vismodegib stays as major drug. Few minor metabolites undergo oxidation or glucorinodation reactions in plasma. In vitro studies have shown that CYP3A4/5 ve CYP2C9 are the major enzymes that produce the oxidative metabolites55. The orally administered vismodegib and metabolites are eliminated by the liver. Most of the orally taken dose was excreted in feces and urine, 82% and 4.4%, respectively. Estimated half-life of a single dose and continuous daily dose of vismodegib were 12 and 4 days, respectively61. In vitro studies showed that vismodegib is a substrate of P-glycoprotein. When vismodegib is administered together with the Claritomycin, Eritomycine or Azitromycine (which are the inhibitors of P-glycoprotein), the incidence of vismodegib side effects and systemic exposure can be increased61. Drugs affecting pH of the upper gastrointestinal system, such as proton pump inhibitors, histamine H2-receptor antagonists and antacids, can also change the solubility and decrease the bioavalibility of vismodegib. However, none of the studies evaluated the drug-drug interactions between the drugs effecting gastric pH and vismodegib61.
Safety data of Vismodegib The pregnancy category of Vismodegib is D. Before Vismodegib therapy, women should be checked for possible pregnancy and warned about contraception necessity during the treatment.
Male patients should be informed that they can expose their female partners to vismodegib via cemen. It is not yet known whether vismodegib is excreted in human breast milk or not. During breast feeding period, the potential benefits of vismodegib should be considered. Depending on
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
these benefits, the doctor should make a decision whether to discontinue nursing or to discontinue the drug61. In case of side effects, patient intolerance or drug-drug interactions with vismodegib, there have been no standardized dose reduction schedule yet. None of the studies evaluated the safety profile of vismodegib in patients with renal failure and liver function abnormalities. The patients are advised to have no blood or blood product donation following (at least) 7 months vismodegib administration61.
Clinical Trials of Vismodegib The clinical effectiveness of vismodegib was demonstrated in only in phase I62-65 and phase II6669
studies. In a phase I trial of vismodegib in patients with locally advanced or metastatic BCC, the
safety and pharmacokinetic properties were assessed65. In the first period of the trial 20 patients were enrolled and the maximum tolerated dose of vismodegib was investigated. In the first part of this phase 1 trial; 7, 9 and 4 patients recieved vismodegib 150 mg, 270 mg and 540 mg, respectively. In the pharmacokinetic study of this trial, vismodegib did not reach the high plasma concentration over the 150 mg dose. Therefore, the recommended dose of vismodegib for the second part of the trial was found to be 150 mg. In these BCC patients, 18 (54.5%) of them had metastatic and 15 (45.5%) of them had locally advanced disease. 17, 15 and 1 patients were
treated with 150 mg, 270 mg and 540 mg per day, respectively with a median of 9.8 month vismodegib treatment. In this phase I study, objective response rate (ORR), partial response (PR), complete response (CR) and stable disease (SD) rates were 54.5%, 48.4%, 6.1% and 33.3%, respectively. Progressive disease was observed only in 12.1% of the patients treated with
Curr Med Res Opin Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 03/08/15 For personal use only.
vismodegib. The ORR was 50.0% and 60% in metastatic and locally advanced BCC tumors, respectively. Dose limiting adverse events were not reported and the most commonly reported grade 3-4 adverse events were fatique, hyponatremia, muscle spasm and atrial fibrillation. This phase I study was the first study suggesting that the inhibition of the Hh pathway can be useful in treating patients with locally advanced and metastatic BCC tumors. Amin SH. and colleagues reported a case series of 3 patients with head and neck BCC from this phase I trial70. Two patients had radiologic and clinical CR whereas one patient showed significant PR with the continuous vismodegib treatment. In further work of phase I trial that was performed by LoRusso and colleagues, 68 patients with locally advanced or metastatic solid tumors who did not have standard treatment or refractory standard treatments, were administered 3 different doses of vismodegib64. In this trial most of the patients (48.5%) were diagnosed as BCC (n=33) and the other patients were diagnosed as pancreatic cancer (n=8), medullablastoma (n=1) and other cancer types (n=17). The aim of this phase I trial was to assess the safety and the efficacy of vismodegib in patients with solid tumors. In these BCC patients, 18 (54.5%) of them had metastatic and 15 (45.5%) of them had locally advanced disease. In this study, vismodegib was given until disease progression or intolerable toxicity. In this study, responses to treatment were reported only in patients diagnosed with BCC and medullablastoma. The results of this study demonstrated a 58% ORR with 12.8 (3.7-26.4) months median response in BCC patients. In addition to this, 4 patients with solid
tumors (adenocystic carcinoma, pancreatic carcinoma and metastatic carcinoid) showed SD as best response, with a median response of 3.1 (2-8-6,5) months. The most commonly reported adverse events were muscle spasms, dysgeusia, fatigue, alopecia and nausea. Most commonly reported grade 3 and 4 adverse events were hyponatremia, fatique and abdominal pain. This
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study also showed that the 150 mg vismodegib per day was the appropriate dose for enough effective plasma concentration, clinical effectiveness and safety. In another phase I study, a clinical drug-drug interaction between vismodegib and rosiglitazone or oral contraceptives was tested63. The aim of this study was to test pharmacokinetic parameters of vismodegib in combination with other drugs. Due to the in vitro data; vismodegib had moderate inhibition potential for cytochrome P450 (CYP) 2C8 and CYP2C9. In this study, plasma concentrations of rosiglitazone, oral contraceptives and other drugs were not altered by vismodegib co-administration. A non-randomized two-cohort, phase II trial (ERIVANCE BCC) included patients with locally advanced or metastatic BCC68. The primary endpoint of this study was independently assessed by ORR. A total of 104 patients were included in study, of which 33 had metastatic and 71 had locally advanced disease. During the efficacy analysis period, independent pathologist could not demonstrate BCC in the specimens of 8 patients so they were excluded from the study population. Thus the analysis was performed on 96 patients. In locally advanced group, surgery, radiotherapy and systemic or topical therapy was performed in 89%, 27% or 11% of the patients, respectively. In metastatic group, previous surgery, radiotherapy and systemic therapy was performed in 97%, 58% and 30% of the patients, respectively. Independently assessed ORRs were 43% (27/63) (P
