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Vismodegib: The first drug approved for advanced and metastatic basal cell carcinoma AK Dubey1, S Dubey2, SS Handu1, MA Qazi11 Department of Pharmacology, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India 2 Department of Pathology, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 23525058
Treatment of basal cell carcinoma (BCC) usually involves surgical interventions and laser ablation, but in locally advanced BCC, which arise either from earlier untreated lesions or from recurrence of aggressive BCC, surgery and radiotherapy are not helpful. Vismodegib, the first oral-targeted therapy for locally advanced and metastatic BCC, unsuitable for surgery or radiotherapy, was recently approved by US Food and Drug Administration (FDA). The drug was under the priority review program of FDA and was approved on the basis of promising results of phase II trial. Vismodegib acts by targeting the hedgehog pathway, which is activated abnormally in most BCCs. Approval of vismodegib is a big step ahead in the treatment of advanced BCC, where there was no other effective drug therapy till now. Keywords: Basal cell carcinoma, hedgehog, vismodegib
Basal cell carcinoma (BCC) is the most common malignant neoplasm of the skin worldwide, varying with the geographical location and skin complexion. Though more common in Caucasians, the incidence of BCC has been on the rise worldwide. [1] These are slow- growing tumors, that do not metastasize often, are locally invasive, cause destruction and severe morbidity. Treatment of BCC usually involves surgical interventions such as excision and curettage with or without cautery, cryotherapy, and laser ablation. Radiotherapy, photodynamic therapy, and topical therapy with imiquimod or 5-Fluorouracil are a few nonsurgical options to manage BCC. For most inoperable BCCs, radiotherapy has become the preferred alternative option where recurrence following treatment is common. [2] In locally advanced BCC, which arise either from earlier untreated lesions or from recurrence of aggressive BCC, surgery and radiotherapy are not considered to be helpful. [3] A better understanding of the pathogenesis of BCC at the molecular level has helped in the quest for nonsurgical targeted therapies to effectively treat BCC. On the January 30 2012, the US Food and Drug Administration (FDA) approved vismodegib, the first oral-targeted therapy for locally advanced BCC, not suitable for surgery or radiotherapy. It is also the first drug approved for treating metastatic BCC. The drug was reviewed under the FDA's priority review program, which allows a fast 6-month review of drugs offering major advances in treatment. [4] Pathophysiological basis of vismodegib therapy in basal cell carcinoma Vismodegib acts by targeting the hedgehog (Hh) pathway, which is activated in most BCCs. Hh signaling pathway is an important cascade for cellular growth and differentiation during the embryonic development. The pathway was first identified in the fruit fly, Drosophila and the name Hh was given to the pathway because of the spiky appearance of those fruit fly embryos which had mutated Hh gene, the initial binding factor or the ligand in the pathway. [5] Apart from the Hh ligand, the two receptor proteins involved in the cascade are, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1 is a suppressor or inhibitory protein and forms an inactive complex with SMO, in the absence of Hh. When Hh binds with PTCH1 and prevents its inhibitory action, SMO becomes free to act. Activated SMO is then involved in promoting the transcription of different genes, which, during the embryonic development, are responsible for cellular growth and differentiation, and in adults, are involved in tissue repair and stem cell maintenance. [6] A dysregulated Hh signaling pathway has now been linked not just to BCC, but also medulloblastoma, and many other cancers such as those of gastrointestinal tract, brain, lung, breast, and prostate. [7] Aberrant activation of the Hh pathway has been found to cause cellular proliferation and stimulate cancer stem cells. In the stratified epithelium, this disturbs the equilibrium between cellular proliferation and cell cycle arrest, causing epidermal hyperplasia along with uncontrolled proliferation of basal cells leading to BCC. [8] Inactivation of PTCH1 or oncogenic activation of SMO is a common feature in most of the BCCs. So increasing the inhibitory action of the PTCH1 or suppressing the activation of SMO can be targeted for the treatment of BCC and other tumors with hyperactivated Hh pathway. [6] Vismodegib, a 2-pyridyl amide small molecule, blocks Hh signaling by selectively inhibiting SMO, and thus prevents the consequent induction of target genes which could lead to BCC. [9]
Structural modifications of benzimidazole led to the discovery of a functionalized 2-pyridyl amide moiety, which could inhibit the Hh pathway. Further, optimization of pharmacokinetic and pharmacodynamic properties of this molecule finally culminated in the development of vismodegib. When tried in a medulloblastoma allograft mouse model, which was totally dependent on the Hh pathway, vismodegib was seen to produce complete tumor regression at a low dose of 12.5 mg/kg twice daily. [10] Human clinical development Phase I trial An open label multicenter phase I trial was conducted in 68 patients, which included 33 patients of advanced BCC, to evaluate the drug's safety and tolerability. In the early stage of the trial, there were only three patients of advanced BCC, but the evidence of clinical benefit in two of these, prompted the investigators to add a further cohort, increasing the final number of such patients. Patients who had metastatic disease showed an overall response rate of 50% and those with locally advanced disease showed 60% response rate. Safety and pharmacokinetic studies were carried out for three different daily doses of 150, 270, and 540 mg. The 150 mg daily dose was recommended for the phase II trials, as the higher doses did not produce higher plasma concentration of the drug and the safety profile was found to be acceptable, with no dose limiting toxic effect. [11],[12] Phase II trials A multicenter open label phase II study was conducted in patients with metastatic BCC and those with inoperable locally advanced BCC. Daily oral dose of vismodegib, 150 mg, was given to the patients. Response rate was 30% in patients with metastatic BCC ( n=33) and 43% in patients with locally advanced BCC ( n=63). Complete response was seen in 13 patients (21%) with locally advanced BCC. The results of this trial, named Erivance BCC trial, prompted the FDA to grant approval of the drug, as no other effective therapy for such patients was available earlier. [13] Another phase II multicentric randomized, double-blind, placebo-controlled trial ( n=41), tested the efficacy of vismodegib in basal cell nevus syndrome. Basal cell nevus syndrome is an autosomal dominant disorder that results in numerous BCCs along with other facial and skeletal abnormalities. In this trial, the incidence of new BCC in patients on vismodegib was significantly lower as compared to placebo (2 vs. 29 cases per group per year). The reduction in the size of already existing BCC was also significantly greater with vismodegib than with the placebo (-65% vs. −11%). None of the patients on vismodegib showed progression of the BCC and in some patients there was complete clinical regression of the tumor. Biopsy from the clinically regressed tumors could not detect any residual BCC in 83% of the samples. [14]
Vismodegib has saturable, solubility-limited, gastrointestinal absorption, as shown by lack of proportional increase in the plasma concentration with increase in dose after 150 mg. [15] It has high-affinity saturable binding to alpha-1-acid glycoprotein (AAG), with slow metabolic elimination. [16] Absolute bioavailability after single dose is 31.8% and volume of distribution ranges from 16.4 to 26.8 L. Half-life is 12 days for a single dose and 4 days for continuous once daily dosing. The high-affinity saturable plasma protein binding is an important reason for the nonlinear pharmacokinetics of vismodegib, evidenced by the 2.4-fold rise in the unbound fraction with continuous dosing as compared to a single dose. [17] Because of this effect on the free fraction, the drug is required to be given daily despite its long half-life.
In the early development studies, vismodegib was generally well-tolerated. The most frequently reported adverse events were muscle spasm, dysgeusia, fatigue, alopecia, and nausea. Other adverse events commonly reported are hyponatremia, abdominal pain, diarrhea, constipation, anorexia, and arthralgia. [12] Deaths have been reported in the trials in a few cases but are more likely due to progression of the cancer and other disease-related complications. Serious adverse events have been reported in 25% of patients. [13] In the trial for testing efficacy of vismodegib in basal cell nevus syndrome, 54% of patients (14 of 26) receiving vismodegib, discontinued drug treatment owing to adverse events. [14] Because of the importance of Hh pathway during embryonic development, the drug has the potential to cause fetal death or birth defects; so pregnancy prevention is necessary and breast feeding is to be avoided. The patients are also advised against donating blood or blood products while receiving the drug and for at least 7 months after the last dose of the drug. [18] There does not appear to be any significant risk of drug-drug interactions, when vismodegib is coadministered with other drugs. Therapeutic dose of vismodegib does not prolong the QTc interval. [18]
Vismodegib is available as a 150 mg capsule for once daily use in adults with metastatic BCC, or with locally advanced BCC that has recurred following surgery, or those who are not candidates for surgery and radiation. [18]
The development of vismodegib has been hailed as the greatest advancement in therapy yet seen for advanced BCC. [3] Aberrant activation of Hh pathway has definite implications in other types of cancers too, so the targeted inhibition of this pathway has given a hope for potential therapy of such cancers. Medulloblastoma, the most common malignant brain tumor in children, has been shown to regress rapidly with vismodegib treatment. [9] Preclinical studies have shown the potential of vismodegib in treating pancreatic cancer by targeting pancreatic cancer stem cells. [19] Decreasing hepatic Hh activity by vismodegib in murine models has resulted in reversal of advanced liver fibrosis and the associated hepatocarcinogenesis. [20] The soaring hopes have, however, crashed in some cases where the rapid response to the drug could not be sustained. A patient of medulloblastoma relapsed after the initial transient drug response, and the investigations showed that the Hh pathway had acquired a mutation to stop the drug from binding to its receptor thus leading to drug resistance. [21] BCC rebound has also been reported in a nevoid BCC syndrome patient after cessation of vismodegib. [22] Intolerance to the drug, as evident from the trials, leading to high attrition rates, should also be a concern to be addressed.
Approval of vismodegib, the first in class, small molecule Hh pathway inhibitor, is a big step ahead in the treatment of advanced BCC where there was no other reliable option available till now. The drug also appears promising as an effective treatment option for other cancers, where dysregulated Hh pathway is implicated. Ongoing and future trials on Hh inhibitors should provide further impetus to develop effective and safe targeted therapies for other types of cancer.
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