Case Report
Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy
J Oncol Pharm Practice 2015, Vol. 21(4) 293–295 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214527859 opp.sagepub.com
Julian N Lindsay1 and Michael Barras2
Abstract With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/ chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case.
Keywords Melanoma, pyrexia, BRAF inhibitor, trametinib, dabrafenib
Introduction Metastatic melanoma is becoming increasingly prevalent, with an estimated 3.5 deaths in every 100,000 Australians per year and a median survival after diagnosis ranging from 8 to 18 months.1 Several new oral therapies for metastatic melanoma are now marketed, as well as numerous ongoing phase 2 and 3 trials being undertaken. Therefore, it is important to keep up to date with the side effect profiles of these medications, particularly the treatment options for associated side effects. This is essential to minimize discontinuation, as these medications are often the last line of options for metastatic melanoma patients. One potential treatment-limiting side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills, which in recent trials lead to dose modification of therapy in 58% of participants.2
rigors/chills, confusion and severe nausea. On admission to the emergency department, her temperature was recorded as 40.1 C (104.18 F). The patient’s medical history consisted of BRAF V600E mutation-positive metastatic melanoma, paroxysmal atrial fibrillation, hypertension, diet controlled type 2 diabetes mellitus and dyslipidaemia. On presentation, she was taking dabrafenib 150 mg twice daily, trametinib 2 mg daily (which were both initiated 59 days prior to presentation), digoxin 62.5 mg daily, telmisartan 40 mg daily, rosuvastatin 40 mg daily, omeprazole 20 mg daily and paracetamol 1 g six hourly. Routine investigations showed no source of infection with a clear chest x-ray and no visible sites of infection. Her pathology was unremarkable with electrolytes and C-reactive protein in the normal ranges and a white cell 1 2
Case report A 77-year-old Caucasian female patient was admitted to our hospital following complaints of debilitating
Royal North Shore Hospital, Sydney, Australia Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
Corresponding author: Julian N Lindsay, Royal North Shore Hospital, Reserve Rd, St Leonards, Sydney, NSW 2065, Australia. Email: [email protected]
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
294
Journal of Oncology Pharmacy Practice 21(4)
count of 3000 cells/mL (neutrophils 2360 cells/mL). Cultures for urine and blood returned negative. The patient was treated for non-neutropaenic fevers with cefepime 2 g eight hourly due to penicillin allergy. Within approximately 4 h from the initial presentation, the patient’s temperature had reduced to 36.8 C (98.24 F) and her nausea had resolved; however, intermittent rigors still persisted. The treating physician withheld her dabrafenib and trametinib, started IV fluids and admitted her for ongoing monitoring. On day 2, after a consultation between the oncologist and pharmacist, dabrafenib and trametinib were restarted, along with a trial of prednisolone 10 mg daily to treat the pyrexia. This decision was based on anecdotal evidence. Over the next three days, there were no further episodes of fever or chills/rigors, and the patient was discharged on the prednisolone 10 mg daily, in addition to her regular medications. For eight weeks, we made weekly phone calls to the patient to monitor her progress and during this time there were no further episodes of fevers or chills. Her dose of prednisolone remained at 10 mg daily for this period and was well tolerated.
Discussion It is a common misconception that newer oral-targeted therapy options are safer and more tolerable than intravenous chemotherapy. In the first phase 3 BRAF inhibitor trial using vemurafenib, there was a higher incidence of adverse effects in the oral vemurafenib arm compared to intravenous dacarbazine therapy, with 38% of patients requiring dose modification compared to 18%, respectively.1 The common adverse effects included cutaneous events, arthralgia, fatigue and photosensitivity skin reactions including Grade 3 reactions characterized by blistering that could often be prevented with sunblock. Most patients taking newer oral therapies will experience adverse effects at home and may not have had the full medicine counseling that a patient receiving intravenous chemotherapy in a hospital day therapy unit will receive. It is for this reason that pharmacists need to maintain a contemporary knowledge of new therapies and their prospective adverse effect profiles, as well as spending adequate time with the patient to provide a comprehensive medication education. Although associated with less side effects than its recent predecessor vemurafenib,3 approximately 30% of patients (n ¼ 187) taking dabrafenib alone in phase 3 trials had dose interruptions, reductions or discontinuations due to adverse effects, and 15% of patients experienced pyrexia.4,5 In a recent open-labelled trial,
when used in combination with trametinib 2 mg, a mitogen-activated protein kinase (MEK) inhibitor, 71% of patients (n ¼ 54) experienced pyrexia and 58% chills, with 5% and 2%, respectively, being Grade 3 or 4 reactions2 (defined as >40.0 C or 104.0 F for >24 h, with rigors not responsive to narcotic medication6). Of these patients, 25% required hospitalization. The cause of pyrexia in patients taking dabrafenib and trametinib is currently still unknown. Dabrafenib was registered by the (Australian) Therapeutic Goods Administration in August 2013 and is available in Australia through an access scheme by its manufacturer. The choice to treat the pyrexia with prednisolone follows the commonly used off label use for the treatment of fever secondary to malignancy. In the absence of a microbial infection, inflammation, trauma or antigen–antibody complexes induce the production of interleukin 1 (IL-1), tumour necrosis factor and interleukin 6 (IL-6), which trigger the hypothalamus to raise the set-point to febrile levels.7 This immune response is a possible mechanism of action for the pyrexia and rigors associated with BRAF inhibition. As corticosteroids are effective inhibitors of these cytokines, they produce a reduction in the inflammatory response elicited,8 thus providing a potential treatment for the dabrafenibassociated pyrexia. This case study demonstrates an important advancement in the treatment of metastatic melanoma with the combination of dabrafenib and trametinib, as it allowed the patient to continue the treatment at the full dose, giving the best possible advantage for progression-free survival.5 The use of prednisolone for the treatment and prevention of further adverse events is not published in any references to our knowledge; however, it is a low risk and low cost option that was very effective in this case. The case also demonstrates that the incidence of pyrexia and rigors can be delayed, with the patient taking dabrafenib and trametinib for two months before the onset of the severe adverse reaction. It is important to always consider the benefits and risks of treatment in this patient group. The most recent study in the treatment of metastatic melanoma showed that the median progression-free survival of a patient taking the combination of dabrafenib and trametinib was 9.4 months.2 Whilst this is still a poor prognosis, it is more than double the prior treatment of choice, dacarbazine, demonstrating a median progression-free survival of less than four months.9 By successfully treating severe adverse effects such as Grade 4 pyrexia, a patient can both remain on the most effective treatment, as well as maintain the best quality of life for this period.
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
Lindsay and Barras
295
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
5.
Conflict of interest None declared. 6.
References 1. Chapman PB, Hauschild A, Robert C, et al. BRIM-3 study group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–2516. 2. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367: 1694–1703. 3. Menzies AM, Long GV and Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther 2012; 6: 391–405. 4. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
7. 8.
9.
open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–365. Hauschild A, Grob JJ, Demidov LV, et al. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012; 30(suppl): abstract LBA8500. European Organisation for Research and Treatment of Cancer. Common Toxicity Criteria (CTC). EORTC, www.eortc.be (accessed 19 September 2013). Dinarello CA. Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am 1996; 10: 433. Schwiebert LA, Beck LA, Stellato C, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996; 97: 143–152. Patel PM, Suciu S, Mortier L, et al. EORTC Melanoma group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 2011; 47: 1476–1483.
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy
J Oncol Pharm Practice 2015, Vol. 21(4) 293–295 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214527859 opp.sagepub.com
Julian N Lindsay1 and Michael Barras2
Abstract With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/ chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case.
Keywords Melanoma, pyrexia, BRAF inhibitor, trametinib, dabrafenib
Introduction Metastatic melanoma is becoming increasingly prevalent, with an estimated 3.5 deaths in every 100,000 Australians per year and a median survival after diagnosis ranging from 8 to 18 months.1 Several new oral therapies for metastatic melanoma are now marketed, as well as numerous ongoing phase 2 and 3 trials being undertaken. Therefore, it is important to keep up to date with the side effect profiles of these medications, particularly the treatment options for associated side effects. This is essential to minimize discontinuation, as these medications are often the last line of options for metastatic melanoma patients. One potential treatment-limiting side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills, which in recent trials lead to dose modification of therapy in 58% of participants.2
rigors/chills, confusion and severe nausea. On admission to the emergency department, her temperature was recorded as 40.1 C (104.18 F). The patient’s medical history consisted of BRAF V600E mutation-positive metastatic melanoma, paroxysmal atrial fibrillation, hypertension, diet controlled type 2 diabetes mellitus and dyslipidaemia. On presentation, she was taking dabrafenib 150 mg twice daily, trametinib 2 mg daily (which were both initiated 59 days prior to presentation), digoxin 62.5 mg daily, telmisartan 40 mg daily, rosuvastatin 40 mg daily, omeprazole 20 mg daily and paracetamol 1 g six hourly. Routine investigations showed no source of infection with a clear chest x-ray and no visible sites of infection. Her pathology was unremarkable with electrolytes and C-reactive protein in the normal ranges and a white cell 1 2
Case report A 77-year-old Caucasian female patient was admitted to our hospital following complaints of debilitating
Royal North Shore Hospital, Sydney, Australia Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
Corresponding author: Julian N Lindsay, Royal North Shore Hospital, Reserve Rd, St Leonards, Sydney, NSW 2065, Australia. Email: [email protected]
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
294
Journal of Oncology Pharmacy Practice 21(4)
count of 3000 cells/mL (neutrophils 2360 cells/mL). Cultures for urine and blood returned negative. The patient was treated for non-neutropaenic fevers with cefepime 2 g eight hourly due to penicillin allergy. Within approximately 4 h from the initial presentation, the patient’s temperature had reduced to 36.8 C (98.24 F) and her nausea had resolved; however, intermittent rigors still persisted. The treating physician withheld her dabrafenib and trametinib, started IV fluids and admitted her for ongoing monitoring. On day 2, after a consultation between the oncologist and pharmacist, dabrafenib and trametinib were restarted, along with a trial of prednisolone 10 mg daily to treat the pyrexia. This decision was based on anecdotal evidence. Over the next three days, there were no further episodes of fever or chills/rigors, and the patient was discharged on the prednisolone 10 mg daily, in addition to her regular medications. For eight weeks, we made weekly phone calls to the patient to monitor her progress and during this time there were no further episodes of fevers or chills. Her dose of prednisolone remained at 10 mg daily for this period and was well tolerated.
Discussion It is a common misconception that newer oral-targeted therapy options are safer and more tolerable than intravenous chemotherapy. In the first phase 3 BRAF inhibitor trial using vemurafenib, there was a higher incidence of adverse effects in the oral vemurafenib arm compared to intravenous dacarbazine therapy, with 38% of patients requiring dose modification compared to 18%, respectively.1 The common adverse effects included cutaneous events, arthralgia, fatigue and photosensitivity skin reactions including Grade 3 reactions characterized by blistering that could often be prevented with sunblock. Most patients taking newer oral therapies will experience adverse effects at home and may not have had the full medicine counseling that a patient receiving intravenous chemotherapy in a hospital day therapy unit will receive. It is for this reason that pharmacists need to maintain a contemporary knowledge of new therapies and their prospective adverse effect profiles, as well as spending adequate time with the patient to provide a comprehensive medication education. Although associated with less side effects than its recent predecessor vemurafenib,3 approximately 30% of patients (n ¼ 187) taking dabrafenib alone in phase 3 trials had dose interruptions, reductions or discontinuations due to adverse effects, and 15% of patients experienced pyrexia.4,5 In a recent open-labelled trial,
when used in combination with trametinib 2 mg, a mitogen-activated protein kinase (MEK) inhibitor, 71% of patients (n ¼ 54) experienced pyrexia and 58% chills, with 5% and 2%, respectively, being Grade 3 or 4 reactions2 (defined as >40.0 C or 104.0 F for >24 h, with rigors not responsive to narcotic medication6). Of these patients, 25% required hospitalization. The cause of pyrexia in patients taking dabrafenib and trametinib is currently still unknown. Dabrafenib was registered by the (Australian) Therapeutic Goods Administration in August 2013 and is available in Australia through an access scheme by its manufacturer. The choice to treat the pyrexia with prednisolone follows the commonly used off label use for the treatment of fever secondary to malignancy. In the absence of a microbial infection, inflammation, trauma or antigen–antibody complexes induce the production of interleukin 1 (IL-1), tumour necrosis factor and interleukin 6 (IL-6), which trigger the hypothalamus to raise the set-point to febrile levels.7 This immune response is a possible mechanism of action for the pyrexia and rigors associated with BRAF inhibition. As corticosteroids are effective inhibitors of these cytokines, they produce a reduction in the inflammatory response elicited,8 thus providing a potential treatment for the dabrafenibassociated pyrexia. This case study demonstrates an important advancement in the treatment of metastatic melanoma with the combination of dabrafenib and trametinib, as it allowed the patient to continue the treatment at the full dose, giving the best possible advantage for progression-free survival.5 The use of prednisolone for the treatment and prevention of further adverse events is not published in any references to our knowledge; however, it is a low risk and low cost option that was very effective in this case. The case also demonstrates that the incidence of pyrexia and rigors can be delayed, with the patient taking dabrafenib and trametinib for two months before the onset of the severe adverse reaction. It is important to always consider the benefits and risks of treatment in this patient group. The most recent study in the treatment of metastatic melanoma showed that the median progression-free survival of a patient taking the combination of dabrafenib and trametinib was 9.4 months.2 Whilst this is still a poor prognosis, it is more than double the prior treatment of choice, dacarbazine, demonstrating a median progression-free survival of less than four months.9 By successfully treating severe adverse effects such as Grade 4 pyrexia, a patient can both remain on the most effective treatment, as well as maintain the best quality of life for this period.
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
Lindsay and Barras
295
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
5.
Conflict of interest None declared. 6.
References 1. Chapman PB, Hauschild A, Robert C, et al. BRIM-3 study group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–2516. 2. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367: 1694–1703. 3. Menzies AM, Long GV and Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther 2012; 6: 391–405. 4. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
7. 8.
9.
open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–365. Hauschild A, Grob JJ, Demidov LV, et al. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012; 30(suppl): abstract LBA8500. European Organisation for Research and Treatment of Cancer. Common Toxicity Criteria (CTC). EORTC, www.eortc.be (accessed 19 September 2013). Dinarello CA. Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am 1996; 10: 433. Schwiebert LA, Beck LA, Stellato C, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996; 97: 143–152. Patel PM, Suciu S, Mortier L, et al. EORTC Melanoma group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 2011; 47: 1476–1483.
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on November 10, 2015
