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- Publisher
- Hindawi Publishing Corporation
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- Copyright © 2019 Nicholas Gravbrot and Srinath Sundararajan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 2090-6706
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- 2090-6714
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- 10.1155/2019/3051945
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Abstract
Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3051945, 4 pages https://doi.org/10.1155/2019/3051945 Case Report Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib Nicholas Gravbrot and Srinath Sundararajan Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA Correspondence should be addressed to Srinath Sundararajan; ssundararajan@email.arizona.edu Received 14 May 2019; Accepted 12 September 2019; Published 7 October 2019 Academic Editor: Raffaele Palmirotta Copyright © 2019 Nicholas Gravbrot and Srinath Sundararajan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600- mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range. 1. Introduction phase I and II studies evaluating MEK inhibition monother- apy, predominate [4–7]. These include acneiform rash, retinal Encorafenib (Braftovi™, LGX818; Array BioPharma, Boulder, toxicity, gastrointestinal (GI) symptoms (nausea, diarrhea), CO, USA) and binimetinib (Mektovi®, MEK162; Array Bio- and elevated creatine kinase [5–7]. Other common AEs consist Pharma) are novel therapies employed in the treatment of of arthralgia, pruritis, hyperkeratosis, and anorexia [3, 4]. metastatic melanoma. Both selectively inhibit distinct steps While rare (3-6% of patients), increased aspartate amino- in the MAP kinase pathway (RAS/RAF/MEK/ERK), pre- transferase (AST) and alanine aminotransferases (ALT) venting tumor cell proliferation [1, 2]. Specifically, encora- levels have been reported, of which 2-5% represent grade fenib is an ATP-competitive BRAF inhibitor (BRAFi) with 3 toxicity. longer dissociation half-life, whereas binimetinib is a non- Herein, we describe the case of a 58-year-old male who ATP-competitive MEK1 and MEK2 inhibitor (MEKi). In a developed grade 4 AST/ALT elevations with associated acute recent phase III trial (COLUMBUS) comparing combina- kidney injury shortly after initiating encorafenib/binimetinib tion encorafenib/binimetinib to encorafenib monotherapy therapy. To our knowledge, no other cases of grade 4 liver and vemurafenib monotherapy, combination encorafenib/- toxicity related to encorafenib/binimetinib have been reported binimetinib was shown to be superior to both monotherapies in the literature. in the treatment of BRAF-mutant metastatic melanoma, with improved progression-free survival (PFS), overall survival 2. Case Presentation (OS), and adverse effect (AE) profile [3]. In response, combi- nation encorafenib/binimetinib received approval from the A 58-year-old gentleman with history of BRAF-mutant meta- Food and Drug Administration in June 2018 for the treat- static melanoma that had initially progressed after 20 months ment of advanced, unresectable, or metastatic melanoma of combination dabrafenib/trametinib (BRAFi/MEKi) and with BRAFV600 mutations. again after palliative radiotherapy and three months of nivolu- Though typically well tolerated, encorafenib/binimetinib mab (PD1 inhibitor) was started on combination encorafe- is associated with several potential side effects. When present, nib/binimetinib in January 2019. Pertinent medical history AEs related to MEK inhibition, as determined by previous included hypercholesterolemia (on simvastatin 40 mg/day) 2 Case Reports in Oncological Medicine and hypertension (on hydrochlorothiazide 25 mg/day and to follow up with oncology and hepatology in the outpa- lisinopril 40 mg/day). He had no history of liver or kid- tient setting. ney disease. The patient was seen in the outpatient oncology clinic When encorafenib/binimetinib was initiated, the patient three days after discharge, and updated labs were obtained. was essentially asymptomatic. Comprehensive metabolic ALT was markedly elevated at 2,007 IU/L; AST was 825 IU/L. Total bilirubin and alkaline phosphatase were nor- panel (CMP) was unremarkable; baseline AST and ALT were 22 and 25 IU/L, respectively; creatinine was 1.23 mg/dL; and mal. Treatment was not reinitiated at this time, and serial CMPs were obtained every two to three days following. blood urea nitrogen (BUN) was 21 mg/dL. Repeat labs after AST and ALT slowly returned to normal over the course of the first month of treatment were similar. At a routine office the next several weeks. No complications were noted during visit following his second month of treatment, he reported a this timeframe. Figure 1 summarizes the patient’s AST/ALT three-day history of fatigue, fever, and chills. AST and ALT trends from his baseline prior to the liver injury to his gradual were found to be markedly elevated, measured at 671 and return to normal limits a few weeks later. From a treatment 1,251 IU/L, respectively. Total bilirubin and alkaline phos- standpoint, a subsequent positron emission tomography phatase were within normal limits. Creatine was 2.32 mg/dL; (PET)/computed tomography (CT) scan from April 2019 BUN was 55 mg/dL; and glomerular filtration rate (GFR) was demonstrated tumoral response with decreased fluorodeoxy- 49 mL/min/1.73 m . Treatment was withheld, and the patient glucose (FDG) uptake in several previously noted soft tissue was later admitted for workup of his abnormal laboratory and bony metastases. values due to persistent worsening of his liver function tests (LFTs) over the next two days. On admission, hepatology was consulted to assist with 3. Discussion the diagnostic workup. Evaluation consisted of serial CMPs, complete blood counts (CBCs), hepatitis panel, human her- For advanced melanoma, BRAFi and MEKi therapies are pesvirus panel (HSV-1, HSV-2, and VZV), autoimmune novel treatment options, which are rapidly becoming main- markers (antismooth muscle antibody, antimitochondrial stays of treatment in select cases due to their rapid and robust antibody), ceruloplasmin, coagulation studies, and magnetic tumoral response and generally well-tolerated AE profile [3, resonance imaging (MRI) of the abdomen with and without 4, 8, 9]. Nonetheless, as in our patient, severe AEs may be contrast. CMPs revealed persistent elevation of AST and possible, necessitating hospital admission for workup and ALT despite discontinuing treatment, reaching peaks of 950 treatment [3, 4, 10]. Drug-induced liver injury (DILI) is one and 1,638 IU/L during the course of the hospital stay. Total such complication. bilirubin and alkaline phosphatase remained within normal Diagnosis of DILI is often difficult to confirm and may limits. Creatinine, BUN, and GFR gradually returned to nor- therefore be a diagnosis of exclusion, ruling out other causes mal with hydration after two days (0.99 mg/dL, 17 mg/dL, such as liver metastases, viral infection, autoimmune disease, and 84 mL/min/1.73 m , respectively). CBCs revealed nor- and ischemia [11]. Multiple assessment tools have been mocytic anemia (hemoglobin 11.8 g/dL, MCV 86 fL, and nor- developed and validated in previous studies, but there is no mal iron studies) but was otherwise unremarkable. Viral consensus regarding their use in diagnosis of DILI [12]. As panels were negative for hepatitis A, B, and C, HSV-1, such, diagnosis often does not require the use of these scales HSV-2, and VZV. Antismooth muscle antibody and antimi- for confirmation. In general, a clear temporal relationship tochondrial antibody were negative. Ceruloplasmin was between drug administration and liver injury, as well as mildly elevated (35 mg/dL). Coagulation studies revealed an exclusion of other causes, is the key finding to diagnose DILI elevated prothrombin time (PT) of 14.5 seconds (interna- [12]. Resolution following cessation of the drug further sup- tional normalized ratio (INR) of 1.3), consistent with the ports the conclusion. Biopsy is sometimes necessary if evalu- known hepatic insult. Abdomen MRI revealed periportal ations are equivocal. In our case, the patient’s clinical picture and reactive gallbladder edema, consistent with acute hepatic was initially suggestive of DILI, and improvement of LFTs inflammation, but there was no evidence of chronic liver dis- following drug discontinuation further substantiated this the- ease or portal hypertension. Clinical evaluation focused on ory. Several alternative explanations were explored but were new symptoms suggestive of progressive liver injury, includ- excluded after workup was found to be negative. ing jaundice, scleral icterus, nausea, vomiting, and abdomi- The manifestations of DILI can vary greatly, ranging nal pain, as well as complications from impaired liver from asymptomatic enzyme elevations to fulminant liver fail- function including edema, bleeding, and encephalopathy. ure; consequently, several grading schemes have been devel- By the time of admission, the patient’s fever, fatigue, and oped to categorize DILI based on severity. Grades are chills had resolved. He remained asymptomatic throughout assigned on a 5-point scale, with grade 1 representing mild his hospital stay. disease and grade 5 representing fatal disease or need for Based on the unremarkable workup, it was felt that the transplant. Most assessments are stratified based on the liver injury was primarily related to encorafenib/binimeti- degree of elevation noted in serum AST, ALT, alkaline phos- nib, though simvastatin may have played a minor role. phatase, gamma-glutamyl transferase, and total bilirubin The concurrent kidney injury was thought to be multifac- levels [13, 14]. Abnormalities in PT/INR are also frequently torial, with encorafenib/binimetinib, hydrochlorothiazide, employed in classification. Clinical findings involved in grad- and lisinopril all contributing to its development. The ing include length and severity of symptoms, including jaun- patient was discharged after four days with instructions dice, pruritis, fatigue, weakness, nausea, anorexia, and weight Case Reports in Oncological Medicine 3 Aminotransferase measurements drugs’ long-term utility was limited by the grade 4 DILI. We speculate that this outcome in our BRAFi-pretreated patient was due, in part, to a number of factors, such as BRAFi resen- sitization, immunotherapy exposure, and the pharmacologic profile of encorafenib. Rechallenge with a different BRAFi and/or MEKi has been described previously as a possible therapeutic option for patients with melanoma who progress on a first BRAFi and subsequent second therapy from another drug class (such as checkpoint inhibitors) [15–17]. Interestingly, BRAFi-resistant melanoma cells become dependent on the inhibition for their growth, and consequently, withdrawal of the BRAFi leads to regression of the resistant cells [18]. The presence of a BRAFi-free period is therefore integral to Dates of AST/ALT measurement the resensitization of the malignancy to BRAFi therapy. AST The relationship between duration of BRAFi holiday and ALT tumor response rates has been explored previously, but the data thus far is conflicting, with some studies showing Figure 1: Aminotransferase measurements preceding, during, and improved response rates with longer BRAFi-free intervals following drug-induced liver injury. Measurements are expressed in [17] and others showing no significant temporal correlation international units per liter. AST peak was 950 on 03/02/2019; ALT [15, 16]. The collective data is also unclear about whether peak was 2,007 on 03/07/2019. ALT: alanine aminotransferase; AST: aspartate aminotransferase; DILI: drug-induced liver injury. AE profiles are affected by duration of BRAFi holiday, though one could speculate that this may be implicated. For our patient, the presence of the BRAFi holiday likely loss [14]. Evidence of damage to another organ may also be helped facilitate the partial response seen upon initiation of used in classifying high grade DILI. encorafenib/binimetinib. As it pertains to encorafenib/binimetinib, mild to moder- There is suggestion that the therapy selected in the ate aminotransferase elevations were described in the BRAFi-free period also plays a role in increasing tumor sen- COLUMBUS trial, but no grade 4 toxicity was reported [3]. sitivity on BRAFi rechallenge. In a small sample of patients, The National Cancer Institute and Drug-Induced Liver Injury Roux et al. found improved responses to a second BRAFi if Network define grade 4 liver toxicity as aminotransferase patients were treated with an immune checkpoint inhibitor elevations > 20x upper limit of normal [13] or acute liver during the BRAFi-free period [15]. However, these findings injury resulting in other organ dysfunction (brain, kidney, were not reproduced by Tietze et al. [16] or Valpione et al. etc.), respectively [14]. Our patient met both criteria, and to [17]; therefore, it is unclear whether immunotherapy truly our knowledge, he represents the first reported case of grade enhances tumor response on BRAFi rechallenge. Prospec- 4 liver toxicity from combination encorafenib/binimetinib. tive data would be helpful to determine this relationship Regarding DILI management, the cornerstones of treat- moving forward. ment are withdrawal of the offending agent and supportive Encorafenib has a distinct pharmacologic profile com- care [12]. Close monitoring of AST, ALT, alkaline phos- pared to other BRAFi therapies, with a long dissociative phatase, gamma-glutamyl transferase, total bilirubin, and half-life (greater than 30 hours), greater potency, and a stron- PT/INR is necessary to monitor response. In most cases, ger BRAF inhibitory effect [19]. It is also more selective than DILI resolves without additional sequelae once the offend- other BRAFi therapies for cells expressing the BRAFV600 ing agent is removed, though it may take many weeks mutation [20]. Underscoring this in the COLUMBUS study, before laboratory studies normalize [14]. In our case, the encorafenib/binimetinib combination was noted to have encorafenib/binimetinib was withdrawn the same day that the longest PFS and OS among the available BRAFi and the patient’s AST/ALT levels were found to be first ele- MEKi (with the caveat that this is an indirect comparison of vated. After several weeks, his laboratory studies normal- different trials done at different times) [3]. These superior ized and no additional complications were noted. Given pharmacologic properties may help to explain the response the severity of liver injury, we decided to permanently dis- to rechallenge in our patient. continue encorafenib/binimetinib. Unrelated to the liver toxicity, an additional interesting aspect of this case is that even though the patient had eventu- 4. Conclusion ally progressed on dabrafenib/trametinib (despite an overall impressive PFS of 20 months with this combination), he later Encorafenib and binimetinib represent newly approved had partial response to a different class of BRAFi/MEKi BRAFi/MEKi therapies that have recently been employed (encorafenib/binimetinib). This is to say that despite failing in combination for the treatment of BRAFV600-mutant one line of BRAFi/MEKi therapies (along with radiation melanoma. The literature has shown that this combination therapy and a short course of immune checkpoint inhibi- offers a superior response and AE profile to other BRAFi tion), rechallenge with a different BRAFi/MEKi combination monotherapies. That being said, care must still be taken to shortly afterward was at least partially successful, though the monitor for serious AEs from combination therapy. This AST or ALT levels (IU/L) 01/03/2019 - baseline 1/24/2019 2/28/2019 - DILI 3/1/2019 3/2/2019 3/3/2019 3/4/2019 3/7/2019 - follow-up 3/11/2019 3/13/2019 3/15/2019 3/21/2019 4/3/2019 4 Case Reports in Oncological Medicine case illustrates that rare serious AEs can be seen with [5] P. Koelblinger, J. Dornbierer, and R. Dummer, “A review of binimetinib for the treatment of mutant cutaneous mela- novel cancer agents in the real-world setting. Discontinua- noma,” Future Oncology, vol. 13, no. 20, pp. 1755–1766, 2017. tion of the combination BRAFi/MEKi therapies led to suc- [6] J. C. Bendell, M. Javle, T. S. Bekaii-Saab et al., “A phase 1 dose- cessful reversal of liver injury. Regular clinical monitoring escalation and expansion study of binimetinib (MEK162), a and LFT evaluation was essential in assessing response to potent and selective oral MEK1/2 inhibitor,” British Journal management. 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Fontana, “Vemurafenib- INR: International normalized ratio induced granulomatous hepatitis,” Hepatology, vol. 65, no. 2, LFTs: Liver function tests pp. 745–748, 2016. MRI: Magnetic resonance imaging [12] C. Giordano, J. Rivas, and X. Zervos, “An update on treatment MEKi: MEK inhibitor of drug-induced liver injury,” Journal of Clinical and Transla- OS: Overall survival tional Hepatology, vol. 2, no. 2, pp. 74–79, 2014. PET: Positron emission tomography [13] A. Grigorian and C. B. O'Brien, “Hepatotoxicity secondary to PFS: Progression-free survival chemotherapy,” Journal of Clinical and Translational Hepatol- PT: Prothrombin time. ogy, vol. 2, no. 2, pp. 95–102, 2014. [14] R. J. Fontana, P. B. Watkins, H. L. Bonkovsky et al., “Drug- induced liver injury network (DILIN) prospective study: Conflicts of Interest rationale, design, and conduct,” Drug Safety, vol. 32, no. 1, pp. 55–68, 2009. There are no conflicts of interest or financial disclosures [15] J. Roux, C. Pages, D. 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Published: Oct 7, 2019