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Management of Hyperglycemia from Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (Tkis) Targeting T790M- Mediated Resistance

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Management of Hyperglycemia from Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (Tkis) Targeting T790M- Mediated Resistance Review Article on Lung Cancer Diagnostics and Treatments 2015: A Renaissance of Patient Care Management of hyperglycemia from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) targeting T790M- mediated resistance Jeryl Villadolid1, Jennifer L. Ersek2, Mei Ka Fong1, Lindsey Sirianno3, Ellen S. Story4 1Department of Pharmacy, 2Department of Solid Tumor Oncology and Investigational Therapeutics, 3Department of Solid Tumor Oncology, 4Endocrine Center, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC 28204, USA Contributions: (I) Conception and design: J Villadolid, ES Story; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Jeryl Villadolid, PhD, BCPS, BCOP. Department of Pharmacy, Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA. Email: [email protected]. Abstract: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. Although studies show an increased progression free survival (PFS) with use of EGFR TKIs in the first-line setting, most patients will develop resistance to therapy after the first 8-16 months. T790M is an acquired resistance mutation reported in 60-70% of patients who initially responded to a prior EGFR TKI. Recently, EGFR TKIs targeting T790M have been developed to overcome resistance with positive results in PFS and objective response rate in patients who have had disease progression on at least one TKI. Two EGFR TKIs targeting T790M, AZD9291 and rociletinib, are new active treatment options for NSCLC but differ in adverse effect profiles. Dose-limiting hyperglycemia has been reported with rociletinib and has required dose reduction, an oral antihyperglycemic, or both, without discontinuation of therapy. This suggests that patients may be effectively treated chronically for hyperglycemia associated with EGFR TKIs targeting T790M, however, guidelines for treatment of hyperglycemia in this setting have not been published. We discuss mechanisms of hyperglycemia associated with TKIs and initial management of hyperglycemia, including benefits and limitations of oral antihyperglycemic options, adjustment of therapy based on grade of hyperglycemia, and recommendations for follow-up glucose monitoring. Keywords: Hyperglycemia; epidermal growth factor receptor (EGFR); T790M Submitted Sep 22, 2015. Accepted for publication Sep 25, 2015. doi: 10.3978/j.issn.2218-6751.2015.10.01 View this article at: http://dx.doi.org/10.3978/j.issn.2218-6751.2015.10.01 Background line systemic therapy (1,2). Approximately 45% and 40% of NSCLC patients with a positive EGFR mutation have The treatment approach to non-small cell lung cancer exon 19 deletion or exon 21 L858R mutations, respectively, (NSCLC) has become more individualized based on several biomarkers that have emerged as predictive and prognostic which are predictive of treatment benefit to small molecule markers for NSCLC. Data show that progression free TKIs such as erlotinib, gefitinib, and afatinib. These survival (PFS) is improved with the use of targeted sensitizing EGFR mutations are found in approximately epidermal growth factor receptor (EGFR) tyrosine kinase 10% of Caucasian patients and up to 50% of Asian patients inhibitors (TKIs) in patients with sensitizing EGFR with NSCLC (3). mutations when compared to standard therapy as first- Although patients with sensitizing EGFR mutations © Translational lung cancer research. All rights reserved. www.tlcr.org Transl Lung Cancer Res 2015;4(5):576-583 Translational lung cancer research, Vol 4, No 5 October 2015 577 have positive initial responses of 56-74% and a median to 70). The median PFS was 9.6 months (95% CI: 8.3 to PFS of 10-14 months, most will become resistant to first- not reached) in EGFR T790M mutation-positive patients generation TKI therapy (e.g., erlotinib and gefitinib) after compared to 2.8 months (95% CI: 2.1 to 4.3) in patients about 8-16 months (4). Acquired resistance due to an who did not have an EGFR T790M mutation. The most EGFR T790M mutation occurs in 60-70% of patients with common all-cause adverse events were diarrhea (47%), rash disease progression after an initial response to erlotinib (4). (40%), nausea (22%), and decreased appetite (21%). Six The mutation is due to a replacement of threonine with patients (2.4%) reported hyperglycemia, however, there methionine that interferes with TKI binding by altering were no dose-limiting adverse effects observed. AZD9291 the conformation of the tyrosine kinase domain of EGFR, was effective in the T790M mutation-positive setting with restoring the affinity of the receptor for adenosine limited skin and gastrointestinal adverse effects (13). triphosphate (ATP), and reducing the ability of TKIs to Rociletinib is a covalent inhibitor of mutated forms of compete with ATP (4-9). Second generation irreversible EGFR including exon 19 deletions, L858R, and T790M EGFR inhibitors such as afatinib inhibit EGFR T790M in mutations, but not exon 20 insertions. In a dose-escalation vitro but are associated with response rates of less than 10% and expansion study, 130 patients with NSCLC who and a PFS of 4 months in patients with NSCLC who have progressed following treatment with a first- or second- received previous treatment with a first-generation TKI. generation EGFR TKI were enrolled to receive two The clinical activity of afatinib monotherapy is impacted by formulations of rociletinib, the first 57 patients receiving a the inability to achieve the dose required to inhibit T790M free-base and the remaining patients receiving a hydrogen due to wild type activity. Vertical pathway suppression with bromide salt formulation. The objective response rate afatinib and cetuximab appears more effective (10). Studies among the patients with T790M mutation-positive disease have also shown that the T790M mutation may also occur who could be evaluated was 59% (95% CI: 45 to 73) in patients who have not previously received a TKI (11). compared to 29% (95% CI: 98 to 51) in 17 patients with Recently, two newer third-generation EGFR TKIs T790M mutation-negative disease. Patients received a targeting T790M have been developed to attempt to range of 500 milligrams twice daily to 1,000 milligrams overcome EGFR TKI resistance. AZD9291 and rociletinib twice daily of the hydrogen bromide formulation being used (CO-1686) received breakthrough designation by the U.S. in all ongoing and future development. Based on the dose Food and Drug Administration (FDA) in 2014 for the relationship with toxicity, it appears that 500 milligrams treatment of patients with EGFR T790M mutation-positive twice daily has decreased rates of toxicity and preserved NSCLC whose disease has progressed during treatment response rate. Grade 3 toxicities included QT prolongation with a prior TKI. Both agents were active in preclinical and hyperglycemia. Hyperglycemia occurred in 20 of the models of EGFR-mutated NSCLC with or without T790M, 92 patients (22%) who received therapeutic doses and 25 of but the clinical adverse effect profiles for the two agents the 92 patients (38%) received glucose-lowering therapy. were different. Diarrhea, rash and nausea were the most Hyperglycemia generally occurred within the first 3 weeks common for AZD9291, whereas hyperglycemia, nausea and of therapy (14). fatigue were the most common for rociletinib. The only While the two TKIs targeting T790M are both new dose-limiting toxicity for either agent was hyperglycemia active treatment options for EGFR-mutated NSCLC, the reported with rociletinib, however, a maximum tolerated adverse effect profile differences may distinguish place in dose was not identified for either agent (12-14). therapy. Patients who had hyperglycemia with rociletinib AZD9291 is an irreversible inhibitor of EGFR and were most often managed with dose reduction, an oral T790M mutations with a reduced affinity for wild-type hypoglycemic agent, or both. No patients in the study EGFR and more antitumor activity in EGFR L858R discontinued therapy (14), suggesting that hyperglycemia tumors with a concurrent T790M mutation than afatinib. can be managed while on long-term TKI therapy to In a dose-escalation and expansion study, 253 patients maintain treatment response and tolerability. Because with NSCLC who progressed on at least one prior EGFR there have not been published recommendations regarding TKI received at least one dose of AZD9291. The overall hyperglycemia induced by EGFR TKIs targeting T790M, objective tumor response rate was 51% (95% CI: 45 to this review aims to highlight hyperglycemia management 58) and among 127 patients with centrally confirmed based on previous study protocols, related hyperglycemia EGFR T790M, the response rate was 61% (95% CI: 52 guidelines, and reviews in other patient populations and © Translational lung cancer research. All rights reserved. www.tlcr.org Transl Lung Cancer Res 2015;4(5):576-583 578 Villadolid et al. Hyperglycemia from EGFR TKIs targeting T790M anticancer pathways. induction of beta cell apoptosis and insulin resistance in peripheral tissues (15). Imatinib and dasatinib have also been shown
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