Summary Basis of Decision for Erivedge

Clinical Pharmacology

Vismodegib, the medicinal ingredient of Erivedge, is an inhibitor of the Hedgehog pathway. Hedgehog pathway signalling through the transmembrane protein Smoothened (SMO) leads to the activation and nuclear localisation of Glioma-Associated Oncogene transcription factors and induction of Hedgehog target genes. Many of these genes are involved in proliferation, survival, and differentiation. Vismodegib binds to and inhibits SMO activity thereby preventing Hedgehog signal transduction resulting from either inactivating mutations in the Protein patched homolog 1 (PTCH1) gene or activating mutations in SMO.

The clinical pharmacology studies characterized the absorption, distribution, metabolism, and excretion of vismodegib. Vismodegib binds to serum albumin and alpha-1-acid glycoprotein (AAG) and binding is saturable at clinically relevant concentrations. The AAG concentration was considered to be the most important factor influencing steady-state plasma concentrations of vismodegib. Plasma protein binding in patients was >99%. The two most abundant oxidative metabolites of vismodegib recovered in faeces were produced by the cytochrome P450 (CYP) enzymes CYP2C9 and CYP3A4/5. Vismodegib was eliminated by a combination of metabolism and excretion of parent drug, the majority of which was eliminated by the hepatic route and recovered in the faeces (82% of the administered dose), with 4.4% recovered in the urine.

There were no major objections related to the methodology and results of the studies, however, a number of issues were identified that needed to be satisfactorily addressed. These concerns and clarification requests were addressed in the Response to the Notice of Non-Compliance (R-NON), including requests for the following study data: for patients with renal/hepatic impairment to support dosage adjustment recommendations pertaining to their condition, a drug interaction study to evaluate the impact of proton-pump inhibitors, and drug interactions studies with inhibitors of CYP2C9 and CYP3A4, as well as drug interaction studies with P-glycoprotein inhibitors. The sponsor has agreed to submit the results of these studies when they become available.

Clinical Efficacy

The clinical efficacy of Erivedge (vismodegib) was demonstrated in a pivotal, international, single-arm, multicentre, open-label, 2-cohort study. The study was conducted in 104 patients above 18 years of age with advanced basal cell carcinoma (aBCC), including metastatic BCC [mBCC, number of patients (n) = 33] and locally advanced BCC (laBCC, n = 71). Metastatic BCC was defined as BCC that had spread beyond the skin to other parts of the body, including the lymph nodes, lung, bones and/or other internal organs. Locally advanced BCC patients had cutaneous lesions that were inappropriate for surgery (inoperable, recurred in the same location after two or more surgical procedures and curative resection was deemed unlikely or for whom surgery would result in substantial deformity or morbidity) and for which radiotherapy was unsuccessful, inappropriate or contraindicated. Prior to study enrollment, diagnosis of BCC was confirmed by histology. Patients with Gorlin Syndrome who had at least one advanced BCC lesion and met inclusion criteria were eligible to participate in the study. Patients were treated with oral daily dosing of Erivedge (vismodegib) at 150 mg until disease progression or unacceptable toxicity. At the time of primary analysis, the median duration of therapy in the mBCC and laBCC cohorts was 10.0 months and 9.7 months, respectively.

Of the 104 patients enrolled, 96 patients were evaluable for objective response rate (ORR). Twenty-one percent of patients carried a diagnosis of Gorlin syndrome. All Gorlin patients enrolled in the pivotal study met the inclusion criteria.

The primary endpoint was ORR as assessed by an independent review facility (IRF). Objective response was defined as a complete or partial response determined on two consecutive assessments separated by at least 4 weeks. In the mBCC cohort, tumour response was assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. In the laBCC cohort, tumour response was assessed based on visual assessment of external tumour and ulceration, tumour imaging (if appropriate), and tumour biopsy.

A patient was considered a responder if at least one of the following criteria were met and the patient did not experience progression: (1) ≥30% reduction in lesion size [sum of the longest diameter (SLD)] from baseline in target lesions by radiography; (2) ≥30% reduction in SLD from baseline in externally visible dimension of target lesions; (3) complete resolution of ulceration in all target lesions.

Erivedge was efficacious in a significant proportion of aBCC patients as evidenced by an ORR of 30.3% in patients with mBCC and of 42.9% in patients with laBCC. The ORR was maintained for a median duration of 7.6 months for patients in both cohorts.

Recognising that Erivedge demonstrated clinical efficacy in a significant proportion of patients, there were nonetheless serious limitations and uncertainties stemming from the pivotal Phase II study. In light of the fact that the pivotal study was a Phase II study with no planned confirmatory Phase III study to follow, the assessment of the clinical benefits of Erivedge for the proposed indication relied on limited exposure (33 patients in the metastatic cohort and 71 patients in the locally advanced cohort).

Given the absence of sound historical data for aBCC, the low exposure of the patient population to the study drug, the short duration of exposure (median of 9.7 months), the high discontinuation rate (51% in the pivotal study) and the fact that only 31.7% of patients entered the survival follow-up phase of the pivotal study, further evidence of the durability of the clinical response was requested. The response to NON included an updated analysis of the primary efficacy endpoint of ORR assessed by IRF, providing an additional 12 months of follow-up. Although the discontinuation rate for the updated analysis remained high (72.1%), the ORR was maintained for patients in both cohorts. The duration of response was also maintained for mBCC patients and increased from 7.6 to 9.5 months for laBCC patients. The sponsor also addressed additional methodological concerns that were requested; especially regarding the risk of sampling error with punch biopsies and the reasons for patient decision to withdraw that were not captured in the Clinical Study Report.

Health Canada was also concerned about the lack of patient selection strategy. Erivedge is a targeted therapy for patients with dysregulated Hedgehog signaling resulting from ligand-dependant activation, activating SMO mutations or loss of PTCH mutations. Health Canada was concerned that the clinical effectiveness of Erivedge might differ between patients with Gorlin syndrome compared to patients with sporadic BCCs. The response rate of 30% (mBCC) and 42.9% (laBCC) were lower than what can be expected from tumours presumed to be molecularly homogeneous. Additionally, a significant number of patients showed only partial responses and disease progression. A patient selection strategy would help improve response rates and would prevent exposing patients that would not benefit from this therapy [that is (i.e.), patients with mutations downstream of SMO]. Health Canada's concerns for the need of a patient selection strategy are supported by the sponsor's subgroup analysis of the pivotal study results showing an ORR of 31.0% [95% Confidence Interval (CI): 18.7% - 45.6%] for patients with sporadic BCC compared to 66.7% (95% CI: 44.9% - 85.4%) for Gorlin patients. To address the safety issue of unnecessary Erivedge exposure to patients who may not benefit from the drug, the indication was revised to state that the benefit of continued treatment should be regularly assessed with the optimal duration of therapy varying for each individual patient.

The Scientific Advisory Committee recommended that the indication include confirmation of aBCC status by two specialists (head and neck surgeon and radiation oncologist). The proposed indication (for the treatment of adult patients with advanced basal cell carcinoma) was also considered too broad. The sponsor agreed to revise the indication to specify the disease setting (metastatic or locally advanced) thus better reflecting the patient population in the pivotal study. However, it was thought that a confirmation of diagnosis by two additional specialists might delay access to treatment for some patients. This was addressed by revising the labelling to state that histological confirmation of disease status is required prior to prescribing the drug to ensure that the appropriate patient population is exposed to Erivedge.

For more information, refer to the Erivedge Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety data was produced from 138 patients with aBCC treated in four open label Phase I and Phase II clinical studies. Due to the size of the pooled safety database (138 patients), the assessment of the safety profile of Erivedge was limited.

The safety of Erivedge (vismodegib) was primarily evaluated in the pivotal Phase II study described in the Clinical Efficacy section. The adverse events (AEs) most frequently reported in the 104 patients were muscle spasms (68%), alopecia (64%), dysgeusia (51%), decreased weight (46%), fatigue (36%), nausea (29%), decreased appetite (23%) and diarrhea (22%).

Vismodegib was not well-tolerated. Health Canada was concerned with the high discontinuation rate and the number of unscheduled visits; reasons were not captured in the report. Health Canada was also concerned with the high incidence of AEs in the pivotal study. A total of 100% of patients suffered an AE of any grade whereas 42.3% of these patients experienced Grade 3-5 AEs. Serious adverse events (SAEs) were reported in 25% of patients (26 patients) and 7 of those had a fatal outcome. Serious adverse events that were reported in 2 or more treated patients included death, cardiac failure, pneumonia, pulmonary embolism, and deep vein thrombosis. The following SAEs were considered as related to vismodegib: 1 event of cholestatis; 2 events of pulmonary embolism; 1 event of syncope and dehydration; and 1 event of cardiac failure and pneumonia.

The rate of death at the clinical cut-off date was 15.4% (21.2% of mBCC patients and 12.7% of laBCC patients) in the pivotal study. The most frequent cause of death for patients in the metastatic cohort was disease progression. In the locally advanced cohort, 7% of the deaths occur within 30 days of the last vismodegib dose. The causes of death within the last dose of vismodegib included AEs (hypovolemic shock, acute myocardial infarction, meningeal disorder, death of an unknown cause) and disease progression.

The rate of patient discontinuation was high in the pivotal study (51% at the clinical cut-off date). The most common reasons for discontinuation in the pivotal study were disease progression for the mBCC cohort (6/14), and patient decision (18/39) followed by AEs (11/39) for the laBCC cohort. The report showed that 28% of patients enrolled in pivotal study experienced AEs that led to treatment interruption.

To further understand the reasons for discontinuation, the sponsor conducted a survey to capture the reasons for discontinuation. The survey results were submitted with the Response to the Notice of Non-Compliance (R-NON). It is noted that results were collected retrospecively on a small number of patients. In the pivotal study, 30 patients discontinued as a result of the physician or the patient decision. The majority of these patients (36.7%) discontinued due to intolerable AEs. Nine patients had ongoing tumour responses when they discontinued therapy and 6 of these interrupted treatment due to AEs. These results suggest that Erivedge is not well-tolerated in some patients, even in patients who derive a clinical benefit. Given the toxicity profile of Erivedge and its low tolerability, patients who do not benefit from therapy should not be exposed. The sponsor agreed to include in the Indication and Clinical Use section of the Erivedge Product Monograph the following statement: "In the pivotal trial, the majority of the clinical responses occurred within 16 weeks. Benefit of continued treatment should be regularly assessed, with the optimal duration of therapy varying for each individual patient." This recommendation is intended to prevent unnecessary exposure to Erivedge. It will provide guidance to prescribers on the need to reassess the clinical benefit and as to when to expect a clinical response.

Upon review of the pivotal study, Health Canada found that the following AEs were insufficiently characterized in the study report: electrolyte imbalances (including hyponatremia, renal AEs, hepatic AEs, cardiac AEs, and gastrointestinal AEs (including intestinal obstruction). The concerns raised were addressed in the R-NON.

• A total of 5.6% of patients experienced Grade 3 hyponatremia in the pivotal study. These events were also observed in the non-clinical studies as well as in the other clinical studies of vismodegib. Electrolyte imbalances such as hyponatremia can represent SAEs with severe complications. The sponsor provided in the R-NON, the incidence rates of AEs related to electrolytes abnormalities from the pooled analysis. The rates were low and the majority were moderate in severity. A total of 14.5% of patients from the pooled safety analysis had a change from baseline in laboratory values for magnesium, 13.8% for potassium and 32.6% for sodium. It is noted that 4.3% of patients from the pooled safety population had a change from baseline to at least a Grade 3. Given that a causal association could not be ruled out, the Erivedge Product Monograph was revised to include electrolyte abnormalities in the Warnings and Precaution section
• A total of 5.6% of patients experienced Grade 3 elevations of blood urea nitrogen (BUN) levels. Grade 1 BUN elevations were observed in 51.4% of the patients whereas Grade 2 increases were seen in 14.3% of patients. Grade 1 and 2 increases in creatinine levels were also reported in 27.6% and 11.5% of patients. Although vismodegib is not renally excreted, changes in BUN and/or creatinine levels in a small size study are concerning given that kidney damage were observed in non-clinical studies (vacuolation of renal tubular epithelia). Given that a significant proportion of patients treated with vismodegib experienced electrolyte imbalances as well as changes in BUN and /or creatinine levels, that two cases of acute renal failure were reported, and that renal toxicity was observed in pre-clinical studies, the potential of vismodegib to be associated with serious renal injury is significant. The sponsor has agreed to submit results of a renal impairment study upon completion. Since a causal association between the use of Erivedge and the risk of renal AEs cannot currently be ruled out, the Erivedge Product Monograph has been revised to include a serious warning that Erivedge has not been studied in patients with renal impairment.
• Grade 3 changes in liver function tests were observed in 1 patient, and Grade 1 and Grade 2 events were reported in a fair proportion of patients treated with vismodegib. Changes in liver enzymes in a small size study might represent a safety signal for rare serious liver injury. An association of vismodegib is suggested by the observation of alanine transaminase (ALT) and aspartate aminotransferase (AST) elevations in different species in non-clinical studies and by reports of elevated liver enzymes in other vismodegib studies. It should be noted that the efficacy and safety of vismodegib in patients with liver impairment is currently being assessed and the results are not yet available.The uncertainty regarding the risk of liver injury with the use of Erivedge has been addressed in the labelling as a serious warning.
• Cardiotoxicity was a concern. The pivotal study showed changes in heart rhythm (median of 10.5 pulses/min) and blood pressure (median of 10.0 mmHg for systolic blood pressure and median of 10.0 mmHg for diastolic blood pressure) were also observed. Whether these changes in vital signs are clinically relevant is currently unclear. In light of the fact that electrolyte imbalances and cardiac SAEs (atrial fibrillation, cardiac chest pain, global heart insufficiency, heart failure left ventricular systolic dysfunction, myocardial infarction and restrictive cardiomyopathy) were observed in patients treated with vismodegib in the pivotal and supportive study and the QT prolongation study was found to be inconclusive, the potential for cardiotoxicity should be further explored. As it was not currently possible to rule out a causal role for Erivedge therapy, the Erivedge Product Monograph was revised to include a cardiovascular section in the Warnings and Precautions section. The methodological concerns regarding the conduct of the QT prolongation study were satisfactorily addressed in the Erivedge Product Monograph,
• Gastrointestinal AEs including cases of gastrointestinal bleeding and intestinal obstruction were reported in different studies of vismodegib in patients with different cancers. A safety study report was provided. In summary, while gastrointestinal disorder events have occurred very commonly in vismodegib-treated patients, the majority of the events were Grade 1 or 2 in severity. Patients with gastrointestinal hemorrhage and small bowel obstruction had confounding factors; these events were considered not related by both the investigators and the sponsor. The sponsor included the relevant gastrointestinal AEs in the Product Monograph and created a Gastrointestinal section in the Warnings and Precautions section to include the cases of gastrointestinal hemorrhage and small intestinal obstruction.

Erivedge may cause embryo-fetal death or severe birth defects when administered to a female who is pregnant. Hedgehog pathway inhibitors, such as vismodegib, have been demonstrated to be embryotoxic, fetotoxic and/or teratogenic in multiple animal species at exposures lower than the human exposures at the recommended dose of 150 mg/day. Although typically silenced in adults, the hedgehog signaling pathway plays an important role in embryonic development, and spontaneous mutations that affect its normal functioning can result in serious birth defects such as midline defects, craniofacial anomalies or limb defects. Based on the mechanism of action of vismodegib and the results from the non-clinical studies showing teratogenicity, concerns were raised about the serious teratogenic potential of vismodegib.

Health Canada recommended that a number of elements be added to the proposed Pregnancy Prevention Program to rigorously mitigate the serious risk of teratogenicity associated with Erivedge. Health Canada recommended a restricted distribution program requiring patient-physician-pharmacist registration. The sponsor has agreed to dispense Erivedge through a controlled distribution program called the Erivedge Pregnancy Prevention program (EPPP) to prevent fetal exposure. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Erivedge can only be dispensed to patients who are registered and meet all the conditions of the EPPP. Health Canada has been extensively involved in the review of this issue and considers the EPPP and its associated material adequate to mitigate the risk of teratogenicity.

In summary, the data provided in this submission demonstrated that Erivedge can provide clinical benefit with a manageable level of toxicity. Furthermore, all issues raised in the Notice of Non-Compliance (NON) have been sufficiently addressed by the sponsor to Health Canada's satisfaction.

A Box Warning describing serious warnings and precautions has been included in the Product Monograph for Erivedge.

For more information, refer to the Erivedge Product Monograph, approved by Health Canada and available through the Drug Product Database.