Vemurafenib, an inhibitor of b-Raf serine-threonine kinase with V600E mutation ( BRAF V600E), is an antineoplastic agent.1, 2
Vemurafenib is used for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.1 Vemurafenib is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.3 An FDA-approved diagnostic test (e.g., cobas® 4800 BRAF V600 Mutation Test) is required to confirm the presence of the BRAF V600E mutation prior to initiation of therapy.1, 6
The current indication for vemurafenib is based principally on the results of a randomized, open-label phase 3 study (BRIM-3) in patients with previously untreated, unresectable or metastatic melanoma.1, 2, 4 All patients in this study tested positive for the BRAF V600E mutation detected by the cobas® 4800 BRAF V600 Mutation Test.1, 2, 6 In this study, 675 patients were randomized in a 1:1 ratio to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1 g/m2 IV every 3 weeks).1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient withdrew from the study.1, 2 The primary endpoints of this study were overall survival and progression-free survival.1, 2 The median age of patients enrolled in the study was 54 years.1, 2 Most of the patients had metastatic disease (95%).1
A planned interim analysis for overall survival indicated a reduction in the risk of death by 63% and a higher rate of overall survival at 6 months of therapy in patients receiving vemurafenib than in those receiving dacarbazine (84 versus 64%).2, 4 The median follow-up period at the time of the interim analysis was 3.8 months for those receiving vemurafenib and 2.3 months for those receiving dacarbazine.2, 4 Because of the survival benefit observed at the interim analysis, study investigators permitted patients previously randomized to receive dacarbazine to cross over to open-label vemurafenib therapy.2 A final analysis for progression-free survival estimated a prolonged median progression-free survival (5.3 versus 1.6 months) and reduction in risk of either death or disease progression (74%) in patients receiving vemurafenib compared with those receiving dacarbazine.1, 2, 4 An updated overall survival analysis with a median follow-up of 13.4 months confirmed prolonged median overall survival (13.6 versus 10.3 months; hazard ratio for death: 0.47) in patients receiving vemurafenib compared with those receiving dacarbazine.1, 19 Patients receiving vemurafenib also had a higher objective response rate (48.4 versus 5.5%) compared with those receiving dacarbazine; complete response was achieved in 0.9% of patients treated with vemurafenib compared with none treated with dacarbazine.1, 2, 4 A shorter median time to response (1.45 versus 2.7 months) also was observed in patients receiving vemurafenib compared with those receiving dacarbazine.2, 4
In a single-arm, multicenter, multinational phase 2 study, treatment with vemurafenib (960 mg orally twice daily) in patients with BRAF V600E mutation-positive, metastatic melanoma previously treated with systemic therapy (including interleukin-2 or standard chemotherapy) produced an overall response rate of 53% with a complete response reported in 6% and a partial response reported in 47% of these patients.2, 5 At the time of the analysis, the median duration of response was 6.7 months and median overall survival was 15.9 months.2, 5
In a post-hoc analysis of the BRIM-3 study, median overall and progression-free survival were significantly longer in vemurafenib-treated patients compared with dacarbazine-treated patients in those whose melanoma harbored either the BRAF V600E or the less common BRAF V600K mutation.19 Vemurafenib currently is not indicated for the treatment of metastatic melanoma with BRAF V600K mutation.1
Use of vemurafenib also was investigated in a single-arm, multicenter, open-label phase 2 study in patients with BRAF V600E mutation-positive melanoma with symptomatic or asymptomatic brain metastases.1, 28 Patients in this study were enrolled in 2 cohorts: those with previously untreated brain metastases and those with previously treated brain metastases (i.e., resection, whole brain radiation therapy, stereotactic radiation therapy) and measurable disease progression.1, 28 Patients enrolled in this study must have had at least one brain lesion 0.5 cm or greater in size, were receiving a stable or decreasing corticosteroid dosage, and had no history of BRAF or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor therapy.1 In this study, 146 patients received vemurafenib 960 mg orally twice daily until disease progression or unacceptable toxicity occurred.1, 28 The primary measure of efficacy was overall intracranial response rate in the cohort of patients with previously untreated brain metastases (as evaluated by an independent review committee according to Response Evaluation Criteria in Solid Tumors [RECIST]).1 The median duration of follow-up was 9.6 months.28 In the cohort of patients with previously untreated brain metastases, the intracranial overall response rate was 18%; complete responses were achieved in 2% of patients.1 In the cohort of patients with previously treated brain metastases, the overall intracranial response rate was 18%; however, none of the patients in this cohort achieved a complete response.1 At the time of analysis, the median duration of response was 4.6 or 6.6 months in those with previously untreated or previously treated brain metastases, respectively.1
The safety and efficacy of vemurafenib in patients with wild-type BRAF melanoma have not been established; use of vemurafenib is not indicated for use in these patients.1, 2
The American Society of Clinical Oncology (ASCO) guideline for systemic therapy for melanoma published in 2020 states that patients with unresectable or metastatic BRAF wild-type cutaneous melanoma should be offered ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone.200 Ipilimumab plus nivolumab, nivolumab alone, pembrolizumab alone, or combination BRAF/MEK inhibitor therapy (e.g., dabrafenib-trametinib, encorafenib-binimetinib, vemurafenib-cobimetinib) may be offered to patients with BRAF V600 mutation-positive cutaneous melanoma.200 For patients who progress on first-line programmed-death receptor-1 (PD-1) inhibitor therapy, combination BRAF/MEK inhibitor therapy may be offered.200 For patients who progress on first-line combination BRAF/MEK inhibitor therapy, PD-1 inhibitor therapy may be offered.200 Patients with mucosal melanoma may be offered the same treatment regimens as those recommended for cutaneous melanoma.200
ASCO states that switching between BRAF/MEK inhibitor combination regimens may be reasonable if patients experience toxicity since toxicity profiles may differ for each combination; however, no data exist regarding the efficacy of switching to a different BRAF/MEK combination.200
For the treatment of melanoma, monotherapy with a BRAF inhibitor is no longer recommended by experts since combination BRAF/MEK inhibition has demonstrated superior outcomes with a similar safety profile.200
Vemurafenib is used for the treatment of Erdheim-Chester disease with BRAF V600 mutation.1, 27 Vemurafenib is designated an orphan drug by the FDA for the treatment of this condition.3
The current indication for vemurafenib in the treatment of Erdheim-Chester disease is based principally on the results of a single-arm, multicenter, open-label phase 2 study in a cohort of 22 patients with BRAF V600 mutation-positive Erdheim-Chester disease.1, 27 In this study, patients received vemurafenib 960 mg orally twice daily.1, 27 The primary measure of efficacy was overall response rate (as evaluated by the investigator according to RECIST).1, 27 The median age of patients enrolled in the cohort of patients with Erdheim-Chester disease was 59 years; 55% were male and 68.2% had previously received systemic therapy.1
The overall response rate for patients in the Erdheim-Chester disease cohort of this study was 54.5% with a median time to response of 11 months;1, 27 complete response was achieved in one patient.1 The median duration of follow-up for the Erdheim-Chester disease cohort was 26.6 months.1 At the time of analysis, median duration of response had not been reached.1 At a median follow-up of 28.8 months, median progression-free survival and overall survival had not been reached.27 The rates of 2-year progression-free survival and overall survival were 83 and 95%, respectively.27
Erdheim-Chester disease, which constitutes a rare form of histiocytosis, involves the infiltration of organ systems by myeloid cells with diverse macrophage or dendritic cell phenotypes.33 Incidence of the BRAF V600E mutation has been detected at rates of 50-60% in patients with Erdheim-Chester disease or Langerhans cell histiocytosis.33
The most frequent first-line systemic therapies for multiorgan or disseminated forms of Erdheim-Chester disease are interferon alfa-2a and pegylated interferon alfa.33 Other potential options include anakinra, infliximab, or sirolimus in combination with corticosteroids.33 BRAF or MEK inhibitors have been used in the first-line setting in patients with life-threatening cases (e.g., CNS or cardiac involvement) of Erdheim-Chester disease.33 The most frequent second-line systemic therapy or salvage therapy for Erdheim-Chester disease includes BRAF or MEK inhibitors.33
Hairy cell leukemia is a rarely occurring, indolent, low-grade, B-cell malignancy that has a remitting and relapsing response pattern to sequential treatments.10001, 10002 Watchful waiting is the preferred first-line approach for the estimated 10-20% of patients with hairy cell leukemia who present without clinically significant cytopenias, symptomatic organomegaly, recurrent infections, and constitutional symptoms.10001 For those patients requiring therapy, purine analogues (i.e., cladribine or pentostatin) are quite effective, resulting in complete remission in approximately 80-90% of patients; administration of rituximab concurrently with or after purine analogues may also be an option.10001 Despite the high initial response rates observed with purine analogue therapy for hairy cell leukemia, many patients experience relapse.10001, 10002 A variety of treatment options have been evaluated for the treatment of relapsed/refractory disease including the administration of vemurafenib, a BRAF inhibitor†.10001, 10002 The BRAF V600E kinase-activating mutation is the genetic cause of hairy cell leukemia in ≥95% of cases.10001
Two phase 2, single-group, multicenter clinical studies (one in Italy and the other in the United States[US]) evaluated the use of vemurafenib monotherapy in relapsed or refractory hairy cell leukemia.10003 In the Italian trial, patients with hairy cell leukemia refractory to a purine analogue, early relapse after purine analogue therapy, or severe adverse effects from prior purine analogue treatment were eligible for study enrollment.10003 Patients were eligible for study enrollment in the US trial if their disease was refractory to a purine analogue, early relapse occurred after the initial course of purine analogue therapy, or ≥2 relapses occurred more than 2 years after a third or later course of a purine analogue.10003 In addition, patients in both trials were required to meet certain cytopenic requirements (e.g., hemoglobin level, neutrophil count, or platelet count) and confirm presence of a BRAF V600E mutation.10003 In the Italian study, patients were administered vemurafenib 960 mg orally twice daily for a minimum of 8 weeks; therapy could be continued for a maximum of 16 weeks if a complete response was not achieved at 8 weeks.10003 In the US study, vemurafenib was administered at a dose of 960 mg orally twice daily on a continuous schedule for 12 weeks.10003 Up to an additional 12 weeks of vemurafenib therapy was allowed for patients with residual disease.10003
In the Italian trial, 28 patients were enrolled, while 26 patients were included in the US trial (at the time of study publication, enrollment in this trial was ongoing with a planned total enrollment of 36 patients).10003 The median patient age was 57 and 62 years in the Italian and US trials, respectively.10003 The median number of prior therapies was 3 in both trials; 56% of patients in the Italian trial had disease refractory to the immediate prior therapy compared to 41% of patients in the US trial.10003 The primary endpoint of the Italian trial was the rate of complete response.10003 In the US trial, the primary endpoint was the overall response rate after 12 weeks of vemurafenib therapy.10003 Secondary endpoints varied between the trials.10003
Overall, 26 of the 28 patients in the Italian trial completed planned vemurafenib therapy, with one patient discontinuing treatment due to an acute myocardial infarction unrelated to the study drug and another withdrawing consent after experiencing drug-related grade 3 reversible pancreatitis.10003 In the US trial, 24 of the 26 patients were administered vemurafenib therapy for a median of 18 weeks (range: 12 to 24 weeks).10003 Of the other 2 enrolled patients, one died from progressive pneumonia deemed unrelated to the study drug and the other withdrew consent due to drug-related grade 3 reversible photosensitivity.10003 Results revealed an overall response rate of 96% (25 of 26 patient) in the Italian study and 100% (24 of 24 patients) in the US study.10003 The rates of complete and partial responses were similar between the 2 trials.10003 At a median follow-up of 23 months in the Italian trial, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those experiencing a partial response.10003 In addition, the median treatment-free survival was 25 months among those patients with a complete response and 18 months among those experiencing a partial response.10003 The progression-free survival rate and overall survival rate were 73% and 91%, respectively, in the US trial at 1 year.10003 Commonly reported vemurafenib-related adverse events in both trials included skin-related toxicity (e.g., rash, photosensitivity), arthralgias or arthritis, pyrexia, and an increased bilirubin level; these events were primarily of grade 1 or 2.10003 Of note, cutaneous basal cell carcinomas occurred in 2 patients and cutaneous superficial melanoma developed in 1 patient in the Italian study.10003 In the US trial, 3 patients developed cutaneous squamous cell carcinomas and a single patient experienced a cutaneous basal cell carcinoma.10003 All tumors were managed via simple excision.10003 Dosage reduction of vemurafenib was required in 15 of 26 patients in the Italian trial and 13 of 26 patients in the US trial.10003 Adverse events leading to dose reductions included rash; increased AST/ALT, creatinine, or bilirubin; arthralgia; pancreatitis; photosensitivity; neutropenia; palmar and plantar dysesthesia.10003
The complete results of the full cohort of 36 patients in the US trial were subsequently published, with 32 patients completing at least 4 weeks of vemurafenib therapy.10004 The best overall response rate with vemurafenib in the entire cohort was 86%, with 33% experiencing a complete response and 53% a partial response.10004 After a median follow-up of 40 months, 21 (68%) of 31 responders experienced relapse with a median relapse-free survival of 19 months.10004 Of the 21 patients with relapse, 14 were retreated with vemurafenib and 86% achieved a complete hematologic response.10004 At 4 years, overall survival was 82%, with a significantly reduced overall survival in patients who relapsed within 1 year of initial vemurafenib therapy.10004
In another phase 2, single-group, single-center trial, the combination of vemurafenib plus rituximab was evaluated in patients with relapsed or refractory hairy cell leukemia.10005 Patients eligible for study enrollment had hairy cell leukemia with a confirmed BRAF V600E mutation, cytopenia, and any of the following: primary refractoriness to a purine analogue; early relapse after an initial purine analog course or at any time after a second or later course; severe adverse effects related to purine analogue therapy; ineligibility for chemotherapy; and prior BRAF inhibitor treatment.10005 Vemurafenib was administered at a dose of 960 mg orally twice daily for 8 weeks with rituximab 375 mg/m2 as an IV infusion given 8 times over a period of 18 weeks.10005 Patients underwent 2 induction cycles, each consisting of 4 weeks of vemurafenib and 2 rituximab infusions on days 1 and 15, followed by 2 weeks of rest and evaluation of response.10005 After the second induction cycle, the last 4 rituximab infusions were given as consolidation therapy 2 weeks apart from one another.10005
Thirty-one patients were enrolled in the study with one patient subsequently withdrawn due to having an unclassified B-cell neoplasm instead of hairy cell leukemia; a majority were male (n=28) with a median age of 61 years.10005 The median number of prior therapies was 3 (range: 1 to 14); all patients received prior therapy with a purine analogue.10005 The primary study endpoint was complete response at the end of planned treatment.10005 Time to response, minimal residual disease status, and survival were also evaluated.10005 Results revealed occurrence of a complete response in 26 (87%) of 30 patients in the intention-to-treat analysis.10005 A complete response was seen in all patients who were refractory to chemotherapy or rituximab and all patients who had previously received a BRAF inhibitor.10005 Of those who experienced a complete response, 17 patients were cleared of minimal residual disease.10005 For all 30 patients, progression-free survival was 78% at a median follow-up of 37 months.10005 At a median follow-up of 34 months, relapse-free survival was 85% among the 26 patients with a complete response.10005 Adverse effects were primarily grade 1 or 2, transient, and were reported previously in patients administered vemurafenib and rituximab as monotherapy.10005 Dosage reduction of vemurafenib occurred in 14 patients due to increases in amylase/lipase, rash, arthralgia, hyperbilirubinemia, potential interaction with an azole antifungal, and hemolytic anemia.10005
In addition to the above clinical data, there are several case reports/case series detailing the successful use of vemurafenib (often in a low-dose regimen of 240 mg twice daily) in relapsed/refractory hairy cell leukemia.10006, 10007, 10008, 10009, 10010, 10011, 10012, 10013, 10014, 10015
Based on current evidence, vemurafenib, either as monotherapy or in combination with rituximab, as a treatment for relapsed/refractory hairy cell leukemia in patients with a confirmed BRAF V600E kinase-activating mutation has Level 2 (moderate strength/quality) evidence supporting its use.10003, 10005 Vemurafenib therapy results in an improvement in response in these patients with a tolerable safety profile.10003, 10005
Vemurafenib is administered orally twice daily without regard to meals.1 Vemurafenib tablets should not be crushed or chewed.1
If a dose of vemurafenib is missed, the dose may be taken up to 4 hours prior to the next dose to maintain the twice-daily dosing regimen.1 However, 2 doses should not be taken at the same time.1
If vomiting occurs following administration of vemurafenib, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.1
Store at 20-25°C (excursions permitted between 15-30°C).1
The recommended adult dosage of vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation is 960 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
The recommended adult dosage of vemurafenib for the treatment of Erdheim-Chester disease with BRAF V600 mutation is 960 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
In the principal efficacy study, the initial dosage of vemurafenib was 960 mg twice daily; however, 64 or 36% of patients required dosage reductions to 480 or 720 mg twice daily, respectively.1 The manufacturer states that efficacy of vemurafenib was maintained in patients requiring dosage reduction.1 The median duration of exposure to vemurafenib following dosage reduction to 480 or 720 mg twice daily was 236 or 77 days, respectively.1
When vemurafenib is used for the treatment of relapsed/refractory hairy cell leukemia in patients with a confirmed BRAF V600E kinase-activating mutation†, the usual dosage administered is 960 mg orally twice daily for a minimum of 8 weeks, and if a complete response does not occur, a maximum of 24 weeks.10003, 10005 However, low-dose vemurafenib regimens have been successfully administered in case reports.10006, 10007, 10008, 10009, 10010, 10011, 10012, 10013, 10014, 10015
If intolerable grade 2 or any grade 3 toxicity occurs, vemurafenib therapy should be temporarily interrupted.1 When the toxicity resolves to grade 0 or 1, vemurafenib may be resumed at a reduced dosage of 720 mg twice daily.1 If the toxicity recurs at a dosage of 720 mg twice daily, therapy should be withheld again until the toxicity resolves to grade 0 or 1; therapy may then be resumed at a reduced dosage of 480 mg twice daily.1 If toxicity recurs at a dosage of 480 mg twice daily, treatment with vemurafenib should be permanently discontinued.1
If grade 4 toxicity occurs, vemurafenib therapy should be permanently discontinued or interrupted until the toxicity resolves to grade 0 or 1; if clinically appropriate, therapy may then be resumed at a reduced dosage of 480 mg twice daily.1 If toxicity recurs at a dosage of 480 mg twice daily, treatment with vemurafenib should be permanently discontinued.1
Dosages less than 480 mg twice daily are not recommended.1
Vemurafenib therapy should be temporarily interrupted if the corrected QT interval (QTc) exceeds 500 msec.1 When the QTc interval decreases to 500 msec or less, the drug may be resumed at a reduced dosage.1 Vemurafenib should be permanently discontinued if the QTc interval exceeds 500 msec and increases more than 60 msec from baseline despite correction of electrolyte abnormalities and other risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias).1
Development of New Primary Cutaneous Malignancies
No dosage adjustment is necessary in patients who develop new primary cutaneous malignancies.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of vemurafenib with drugs that are potent inducers of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided.1 If concomitant therapy with a potent CYP3A4 inducer cannot be avoided, the manufacturer recommends increasing the dosage of vemurafenib by 240 mg twice daily (e.g., from 960 mg twice daily to 1.2 g twice daily).1, 4 When concomitant use of the potent CYP3A4 inducer is discontinued, the vemurafenib dosage should be returned (2 weeks after discontinuance of the CYP3A4 inducer) to the dosage used prior to initiation of the potent CYP3A4 inducer.1
Concomitant use of vemurafenib with drugs that are potent inhibitors of CYP3A4 should be avoided.1 If concomitant use cannot be avoided, consider reducing vemurafenib dosage as clinically indicated.1
No initial dosage adjustment is necessary in patients with mild or moderate hepatic impairment.1 The manufacturer makes no specific dosage recommendations in patients with severe hepatic impairment because data are limited in this population.1
No initial dosage adjustment is necessary in patients with mild or moderate renal impairment.1 The manufacturer makes no specific dosage recommendations in patients with severe renal impairment because data are limited in this population.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious hypersensitivity reactions (e.g., anaphylaxis, generalized rash and erythema, hypotension, drug reaction with eosinophilia and systemic symptoms [DRESS syndrome]) may occur during and upon reinitiation of vemurafenib therapy.1 Vemurafenib should be permanently discontinued in patients who experience a severe hypersensitivity reaction.1
Photosensitivity reactions (mild to severe) have been reported in 33-49% of patients receiving vemurafenib in clinical trials.1 If intolerable grade 2 or greater reaction occurs, the dosage of vemurafenib should be reduced.1
Other Warnings and Precautions
Development of New Primary Malignancies
In the phase 3 clinical trial evaluating vemurafenib in patients with unresectable or metastatic melanoma, cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma were reported more frequently in patients receiving vemurafenib compared with those receiving dacarbazine.1, 2, 5, 10, 17, 18 In this study, cutaneous squamous cell carcinoma and keratoacanthoma occurred in 24% of patients receiving vemurafenib compared with less than 1% of those receiving dacarbazine.1 In a phase 2 clinical trial in patients receiving the drug for metastatic melanoma, cutaneous squamous cell carcinoma and keratoacanthoma occurred in 24% of patients.1 In clinical trials, the median time to first appearance of cutaneous squamous cell carcinoma was 7-8 weeks.1, 4, 5 Approximately 33% of patients in a phase 3 clinical trial who had previously experienced cutaneous squamous cell carcinoma during vemurafenib treatment had more than one subsequent occurrence with median time between occurrences of 6 weeks.1 In clinical trials, skin lesions were excised and vemurafenib therapy was continued without dosage adjustment.2, 5 In the phase 3 clinical trial, development of new primary malignant melanoma was reported in 2.1% of patients receiving vemurafenib compared with none of those receiving dacarbazine.1 In a clinical trial evaluating vemurafenib in patients with Erdheim-Chester disease, cutaneous squamous cell carcinoma and/or keratoacanthoma occurred in 40.9% of patients.1 In this trial, the median time to first appearance of cutaneous squamous cell carcinoma was 12.1 weeks.1
In clinical trials, non-cutaneous squamous cell carcinoma of the head and neck (e.g., oropharyngeal squamous cell carcinoma) has been reported in less than 10% of patients receiving vemurafenib therapy.1 Progression of a preexisting chronic myelomonocytic leukemia with NRAS mutation also has been reported during postmarketing experience with the drug.1
Although the mechanism for development of cutaneous squamous cell carcinoma has not been fully determined, it has been suggested that paradoxical activation of mitogen-activated protein kinase (MAPK) signaling may lead to accelerated growth of such skin lesions as well as development of other primary malignancies.1, 5, 9, 10, 11, 17, 18 MAPK-mediated events in wild-type BRAF cells have been observed in a study evaluating the pathology and immunohistochemistry of normal and proliferating skin lesions in patients receiving the weak b-Raf kinase inhibitor sorafenib.9, 10, 11 Another study performed a molecular analysis of DNA extracted from tumor specimens of patients receiving vemurafenib; results indicated that these patients have a secondary mutation (in addition to the BRAF V600E mutation) that appears to be activated by vemurafenib treatment.17 Some clinicians suggest that advanced age (i.e., 65 years of age or older), history of skin cancer, and chronic sun exposure may be risk factors for developing cutaneous squamous cell carcinoma.1, 5, 17 Some data suggest that mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors (i.e., binimetinib, cobimetinib, trametinib) block the paradoxical activation of the MAPK pathway induced by BRAF inhibitors (i.e., vemurafenib, dabrafenib, encorafenib); therefore, combination therapy with a BRAF inhibitor and an MEK inhibitor may reduce the risk of developing cutaneous squamous cell carcinoma.23, 24, 25 Findings from a meta-analysis of randomized controlled studies that assessed the relative risk of development of cutaneous squamous cell carcinoma in cancer patients receiving a BRAF inhibitor indicate that the risk of cutaneous squamous cell carcinoma is higher in patients receiving a BRAF inhibitor than in patients receiving combination therapy with a BRAF inhibitor and an MEK inhibitor.26
A dermatologic evaluation should be performed at baseline and every 2 months during therapy.1 Continued monitoring for 6 months following discontinuance of vemurafenib may be considered.1 Suspicious cutaneous lesions should be treated as appropriate and excised for pathologic evaluation.1 Close monitoring for signs and symptoms of development of new non-cutaneous squamous cell carcinoma or of other primary malignancies should be performed.1
In clinical trials, myeloid neoplasms have been reported in patients with Erdheim-Chester disease receiving vemurafenib therapy.1 The manufacturer recommends monitoring complete blood cell (CBC) counts in patients with Erdheim-Chester disease and coexisting myeloid malignancies.1
Tumor Promotion in BRAF Wild-Type Melanoma
In vitro, paradoxical activation of MAPK signaling and increased cell proliferation have been observed in wild-type BRAF cells exposed to BRAF inhibitors.1 Presence of the BRAF V600E mutation must be confirmed prior to initiation of therapy.1
Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with vemurafenib.1 If severe skin reactions occur, vemurafenib therapy should be permanently discontinued.1
Vemurafenib prolongs the QT interval in a concentration-dependent manner.1 In a multicenter, open-label, phase 2 study, QT interval prolongation was evaluated in patients with BRAF V600E mutation-positive, metastatic melanoma who were receiving vemurafenib (960 mg twice daily).1 A maximum mean corrected QT (QTc) interval change from baseline of 12.8 msec during the first month of treatment and 15.1 msec during the first 6 months of treatment was observed in these patients.1
Vemurafenib should not be initiated in patients with electrolyte abnormalities unresponsive to corrective measures, QTc intervals exceeding 500 msec, or congenital long QT syndrome.1, 4 In addition, concomitant use of vemurafenib with drugs known to prolong the QT interval (e.g., class Ia and III antiarrhythmic agents) should be avoided.1, 4, 13, 15, 16
ECGs and serum electrolyte concentrations, including concentrations of potassium, magnesium, and calcium, should be obtained prior to initiation of therapy or following dosage modification for QT interval prolongation, and monitored 15 days following initiation of therapy, then monthly for the first 3 months of treatment, and then every 3 months thereafter or more often as clinically indicated.1, 4
Interruption or discontinuance of vemurafenib may be necessary if increases in the QTc interval occur during therapy with the drug.4
Hepatic injury may occur during therapy with vemurafenib resulting in functional hepatic impairment, including coagulopathy or other organ dysfunction.1 In clinical trials, grade 3 and 4 elevations in aminotransferase (ALT or AST), bilirubin, and alkaline phosphatase concentrations have been reported in 0.9-2.9% of patients receiving vemurafenib.1 Serum aminotransferase, bilirubin, and alkaline phosphatase concentrations should be evaluated prior to initiation of therapy and monitored monthly during treatment or as clinically indicated.1 Laboratory abnormalities should be managed with dosage reduction, treatment interruption, or discontinuance.1
The safety and efficacy of vemurafenib used concomitantly with ipilimumab have not been established; however, grade 3 elevations in aminotransferase and bilirubin concentrations have occurred in the majority of patients receiving vemurafenib (720 or 960 mg twice daily) and ipilimumab (3 mg/kg) concurrently.1
Uveitis, blurry vision, and photophobia have been reported in patients receiving vemurafenib.1 In the phase 3 clinical trial evaluating vemurafenib in patients with previously untreated metastatic melanoma, uveitis, including iritis, occurred in 2.1% of patients receiving vemurafenib compared with none of those receiving dacarbazine.1 Monitoring for signs and symptoms of uveitis should be performed.1 In patients experiencing uveitis, therapy with ophthalmic corticosteroid and mydriatic preparations may be required.1 Retinal vein occlusion also has been reported in patients receiving the drug.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, vemurafenib may cause fetal harm.1 No evidence of developmental toxicity was observed in pregnant animals receiving vemurafenib at exposure levels equivalent to approximately 0.6-1.3 times the area under the concentration-time curve [AUC] at the recommended human dosa however, these exposure levels to vemurafenib were not sufficient to fully evaluate its potential toxicity in pregnant women.1 In animals, fetal plasma concentrations of vemurafenib were 3-5% of maternal plasma concentrations, indicating that vemurafenib has the potential to cross the placenta.1
Pregnancy should be avoided during vemurafenib therapy.1 Women of childbearing potential should be advised to use effective contraception during therapy and for 2 weeks after the last dose.1 If used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Radiation Sensitization and Recall
Radiation sensitization and recall, sometimes severe or fatal, involving cutaneous and visceral organs have been reported during postmarketing experience in patients receiving vemurafenib prior to, during, or subsequent to radiation therapy.1 Fatal cases have been reported in patients with radiation sensitization or recall involving visceral organs.1 Patients receiving vemurafenib concomitantly or sequentially with radiation therapy should be closely monitored for signs and symptoms of radiation sensitization or recall.1
Renal failure, including acute interstitial nephritis and acute tubular necrosis, has been reported in patients receiving vemurafenib.1
In the phase 3 clinical trial evaluating vemurafenib in patients with previously untreated metastatic melanoma, grade 1-2 elevations of serum creatinine (exceeding the upper limit of normal [ULN], but no more than 3 times the ULN) occurred in 26% of patients receiving vemurafenib compared with 5% of those receiving dacarbazine; grade 3-4 elevations of serum creatinine (exceeding 3 times the ULN) occurred in 1.2 or 1.1% of patients receiving vemurafenib or dacarbazine, respectively.1
In a clinical trial evaluating vemurafenib in patients with Erdheim-Chester disease, grade 1-2 or 3 elevations of serum creatinine occurred in 86 or 9.1% of patients, respectively.1
Serum creatinine concentrations should be evaluated at baseline and periodically during therapy.1
Dupuytren Contracture and Plantar Fascial Fibromatosis
Dupuytren contracture and plantar fascial fibromatosis have been reported during postmarketing experience in patients receiving vemurafenib.1 The majority of cases have been mild to moderate in severity, but severe, disabling cases of Dupuytren contracture also have been reported.1
Vemurafenib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
There are no data on the presence of vemurafenib in human milk, the effects on the breast-fed infant, or the effects on milk production.1 Because of the potential for serious adverse reactions to vemurafenib in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose.1
Safety and efficacy of vemurafenib in pediatric patients have not been established.1
Based on limited data in pediatric patients (range: 15-17 years of age) with unresectable or metastatic melanoma with BRAF V600 mutation, steady-state exposure of vemurafenib in pediatric patients was similar to that observed in adults.1 The maximum tolerated dosage of the drug has not been established in pediatric patients; however, no new adverse effects were observed in pediatric patients receiving vemurafenib dosages up to 960 mg twice daily.1
Clinical studies of vemurafenib did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1
In a population pharmacokinetic analysis, the clearance of vemurafenib was not affected in patients with mild or moderate hepatic impairment.1 Pharmacokinetic data in patients with severe hepatic impairment are limited; therefore, the drug should be used with caution in these patients.1
In a population pharmacokinetic analysis, the clearance of vemurafenib was not affected in patients with mild or moderate renal impairment.1 Pharmacokinetic data in patients with severe renal impairment are limited; therefore, the drug should be used with caution in these patients.1
Adverse effects reported in 10% or more of patients receiving vemurafenib for the treatment of unresectable or metastatic melanoma include arthralgia,1, 2, 5, 7 rash,1, 2, 5, 7 alopecia,1, 2, 5 fatigue,1, 2, 5, 7 photosensitivity reaction,1, 2, 5, 7 nausea,1, 2, 7 pruritus,1, 2, 5, 7 cutaneous squamous cell carcinoma,1, 2, 5, 7 and skin papilloma.1, 5
Adverse effects reported in 20% or more of patients receiving vemurafenib for the treatment of Erdheim-Chester disease include arthralgia,1 maculopapular rash,1 alopecia,1 fatigue,1 QT interval prolongation,1 skin papilloma,1 diarrhea,1 hyperkeratosis,1 dry skin,1 palmar-plantar erythrodysesthesia syndrome,1 photosensitivity reaction,1 seborrheic keratosis,1 cough,1 cutaneous squamous cell carcinoma,1 hypertension,1 pruritus,1 peripheral sensory neuropathy,1 actinic keratosis,1 keratosis pilaris,1 nausea,1 melanocytic nevus,1 sunburn,1 papular rash,1 and vomiting.1
In vivo studies indicate that vemurafenib is a moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 1A2 and a weak inhibitor of CYP isoenzyme 2D6.1 In vitro studies suggest that vemurafenib is an inhibitor of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5.1 Vemurafenib is an inhibitor and a substrate of CYP isoenzyme 3A4.1 In vitro studies indicate that vemurafenib is a substrate and an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of vemurafenib with potent inhibitors of CYP3A4 may result in increased plasma concentrations of vemurafenib and an increased incidence of adverse effects.1 When vemurafenib 960 mg twice daily was coadministered with itraconazole 200 mg once daily, systemic exposure to vemurafenib increased by approximately 40% at steady state; the magnitude of effect on peak plasma concentration was similar.1 Concomitant use with potent CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, voriconazole) should be avoided.1 If coadministration of a potent CYP3A4 inhibitor cannot be avoided, consider reducing the dosage of vemurafenib, if clinically indicated.1
Concomitant use of vemurafenib with potent inducers of CYP3A4 may result in decreased plasma concentrations of vemurafenib and reduced vemurafenib efficacy.1 When the potent CYP3A inducer rifampin (600 mg daily) was administered concomitantly with vemurafenib (single 960-mg dose), systemic exposure to vemurafenib was decreased by 40% and peak plasma concentrations were unchanged.1 Concomitant use with potent CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) should be avoided, and selection of an alternative drug with no or minimal CYP3A4 induction potential is recommended.1 If concomitant therapy with a potent CYP3A4 inducer cannot be avoided, the manufacturer recommends increasing the dosage of vemurafenib by 240 mg twice daily (e.g., from 960 mg twice daily to 1.2 g twice daily).1, 4 When concomitant use of the potent CYP3A4 inducer is discontinued, the vemurafenib dosage should be returned (2 weeks after discontinuance of the CYP3A4 inducer) to the dosage used prior to initiation of the potent CYP3A4 inducer.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of vemurafenib with CYP1A2 substrates may result in increased plasma concentrations of the CYP1A2 substrate and possible toxicity.1 When the CYP1A2 substrate caffeine was administered concomitantly with vemurafenib, the systemic exposure to caffeine increased by 2.6-fold.1 When the sensitive CYP1A2 substrate tizanidine (single 2-mg dose) was administered concomitantly with vemurafenib (960 mg twice daily), systemic exposure and peak plasma concentrations of tizanidine increased by 4.7- and 2.2-fold, respectively.1 Concomitant use of vemurafenib with CYP1A2 substrates that have a narrow therapeutic index should be avoided.1 If concomitant use cannot be avoided, dosage reduction of the CYP1A2 substrate should be considered, and patients should be closely monitored for adverse effects.1
When the CYP2D6 substrate dextromethorphan was administered concomitantly with vemurafenib, the systemic exposure of dextromethorphan increased by 47%.1
When the CYP3A4 substrate midazolam was administered concomitantly with vemurafenib, the systemic exposure of midazolam decreased by 39%.1
When the CYP2C9 substrate warfarin was administered concomitantly with vemurafenib, the systemic exposure of S -warfarin increased by 18%.1
When the CYP2C19 substrate omeprazole was administered concomitantly with vemurafenib, the systemic exposure of omeprazole was unchanged.1
Drugs Affected by Efflux Transport Systems
Concomitant use of vemurafenib with P-gp substrates may result in increased plasma concentrations of the P-gp substrate.1 When the sensitive P-gp substrate digoxin (single 0.25-mg dose) was administered concomitantly with vemurafenib (960 mg twice daily), systemic exposure and peak plasma concentrations of digoxin increased by 1.8- and 1.5-fold, respectively.1 Concomitant use of vemurafenib with P-gp substrates that have a narrow therapeutic index should be avoided.1 If concomitant use cannot be avoided, dosage reduction of the P-gp substrate should be considered.1
Drugs that Prolong the QT Interval
Concomitant use of vemurafenib with drugs known to prolong the QT interval, including class Ia (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol) antiarrhythmic agents, some antipsychotic agents (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone), some anti-infectives (e.g., gatifloxacin, moxifloxacin), and tetrabenazine, should be avoided.1, 4, 13, 14, 15, 16
Concomitant use of vemurafenib with ipilimumab resulted in increased aminotransferase and bilirubin concentrations in a majority of patients.1
Vemurafenib, a potent inhibitor of b-Raf serine-threonine kinase with V600E mutation ( BRAF V600E), is an antineoplastic agent.1, 2 Approximately 40-60% of cutaneous melanomas carry a BRAF mutation.2, 7 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 ( BRAF V600E);2, 8 a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 ( BRAF V600K).29, 30, 31, 32 The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular-signal regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).8, 9 In vitro studies indicate that vemurafenib also inhibits other kinases such as c-Raf, a-Raf, wild-type b-Raf, SRMS, ACK1, MAP4K5, and FGR at similar concentrations at which inhibition of BRAF V600E occurs.1
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway.20, 21, 22 Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib).20, 21, 22
The bioavailability of vemurafenib is 64% at steady state.1 Following administration of vemurafenib within the dosage range of 240-960 mg, the drug exhibits linear pharmacokinetics and achieves steady-state concentrations within approximately 15-22 days.1 The median terminal half-life of vemurafenib in patients with unresectable melanoma is 57 hours.1 Following oral administration of a radiolabeled dose of vemurafenib, about 94% of the dose is recovered in feces and 1% is recovered in urine.1
Systemic exposure to vemurafenib is increased when the drug is administered with a high-fat meal.1 Administration of a single dose of vemurafenib with a high-fat meal resulted in increases in systemic exposure or peak plasma concentrations of approximately fivefold or 2.5-fold, respectively.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Vemurafenib is available only from a designated specialty pharmacies.12 The manufacturer should be contacted for additional information.12
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