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Mechanisms of Resistance to Osimertinib 2858 Review Article on Mechanisms of Resistance to EGFR-targeted Therapy Mechanisms of resistance to osimertinib Chiara Lazzari1, Vanesa Gregorc1, Niki Karachaliou2, Rafael Rosell3, Mariacarmela Santarpia4 1Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Milan, Italy; 2Merck KGaA, Darmstadt, Germany; 3Germans Trias i Pujol Research Institute and Hospital (IGPT), Badalona, Spain; 4Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy Contributions: (I) Conception and design: C Lazzari, R Rosell, M Santarpia; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpre-tation: C Lazzari, M Santarpia; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Mariacarmela Santarpia, MD, PhD. Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University Of Messina, Messina, Italy. Email: [email protected]; Rafael Rosell, MD, PhD, Catalan Institute of Oncology, Germans Trias i Pujol Research Institute and Hospital (IGPT), Badalona, Spain. Email: [email protected]. Abstract: The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is represented by the secondary T790M mutation. Osimertinib, a third-generation TKI designed to target both EGFR sensitizing mutations and T790M, was first approved for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. The FLAURA study demonstrated that first-line treatment of EGFR mutant patients with osimertinib significantly improved progression free survival (PFS) over first-generation EGFR-TKIs, thus leading to its approval also in this setting. Moreover, osimertinib has shown significant central nervous system (CNS) activity and a favorable safety profile. The current review focuses on the clinical development of osimertinib, the mechanisms of acquired resistance identified in patients receiving osimertinib and the strategies currently under evaluation to overcome resistance. Keywords: Osimertinib; epidermal growth factor receptor (EGFR); mechanisms of resistance Submitted Jun 04, 2019. Accepted for publication Jul 31, 2019. doi: 10.21037/jtd.2019.08.30 View this article at: http://dx.doi.org/10.21037/jtd.2019.08.30 Introduction sequencing (NGS) panels is helping to better define the genomic complexity of EGFR mutated NSCLC patients. The discovery of activating mutations in the tyrosine kinase Currently, EGFR mutated NSCLC is not considered as (TK) domain of the epidermal growth factor receptor a homogenous tumor, driven by a common oncogenic (EGFR) gene (1,2) has opened the era of stratified medicine event, but as a heterogeneous disease, including subsets in the treatment of patients with non-small cell lung cancer of molecularly subcategorized patients. A higher somatic (NSCLC) (3). tumor mutation burden (TMB) was found in patients Despite the high percentage of objective response rate harboring EGFR L858R exon 21 mutation compared with (ORR) and the survival improvement observed in EGFR those carrying exon 19 deletion. These data suggest the mutated patients receiving EGFR tyrosine kinase inhibitors presence of heterogeneous preexisting subclones, that might (TKIs), complete responses are uncommon, and after a emerge under pressure of TKI therapy, thus explaining median of 8–18 months, acquired resistance mechanisms the poor prognosis observed in patients harboring EGFR emerge, determining the development of patients’ L858R mutation (5). In addition, concomitant molecular progression (4). The use of comprehensive next generation alterations that might influence patients’ prognosis and © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2020;12(5):2851-2858 | http://dx.doi.org/10.21037/jtd.2019.08.30 2852 Lazzari et al. Resistance to osimertinib Table 1 Clinical trials evaluating osimertinib Study ref Treatment No. of patients ORR PFS (months) AURA 1 (phase 1) (12) Osimertinib 127 T790M+ 61% (52–70%) 9.6 (8.3–NR) AURA2 (phase 2) (13) Osimertinib 210 T790M+ 70% (64–77%) 9.9 (8.5–12.3) AURA 3 (phase 3) (14) Osimertinib vs. platinum- 419 T790M+ 71 vs. 31, OR 5.39 (95% CI, 10.1 vs. 4.4, HR 0.30 (95% CI, pemetrexed 3.47–8.48), P<0.001 0.23–0.41), P<0.001 FLAURA (phase 3) (15) Osimertinib vs. gefitinib or 556 naive 80 vs. 76, OR 1.27 (95% CI, 18.9 vs. 10.2, HR 0.46 (95% CI, erlotinib 0.85–1.90), P=0.24 0.37–0.57), P<0.001 ORR, objective response rate; OR, odds ratio; CI, confidence interval; PFS, progression free survival; HR, hazard ratio; NR, not reached. the sensitivity to treatment have been identified. Recently, that represents the most common acquired resistance the NGS MSK-IMPACT assay was used to classify 200 mechanism to first and second-generation EGFR-TKIs (8). advanced EGFR mutated NSCLC patients with available Osimertinib irreversibly binds to the cysteine-797 located pretreatment tissue and define the impact of co-occurring in the adenosine triphosphate (ATP) binding site within genetic alterations on prognosis (6). Concomitant mutations the TK domain of the EGFR, while sparing the wild-type in TP53, phosphatidylinositol-4,5-bisphosphate 3-kinase form of the receptor (8,9). It inhibits proliferation of cell catalytic subunit alpha (PIK3CA), catenin beta-1 (CTNNB1) lines harboring EGFR sensitizing and T790M mutations, and retinoblastoma (RB1) were observed. The presence of and determines significant tumor regression in mutant TP53 mutations was associated with shorter overall survival xenograft models and transgenic tumor models carrying (OS) and progression free survival (PFS). Currently, the these alterations. functional role of all TP53 mutations identified in EGFR Moreover, osimertinib was designed to penetrate the mutated NSCLC has not been determined. However, blood brain barrier (BBB), since gefitinib, erlotinib and loss of function mutations in TP53 and RB1, observed in afatinib have unfavorable physicochemical properties to approximately nine percent of EGFR mutated patients, achieve an effective exposure in the central nervous system increases the risk of small cell lung cancer (SCLC) (CNS), due to the presence of two hydrogen bond donors transformation. Similarly, concomitant amplification in in the case of afatinib and multiple rotatable bonds (10 mesenchymal-epithelial transition factor (MET) or ERBB2 for gefitinib and 11 for erlotinib), that limit the CNS genes significantly reduces PFS in patients under EGFR- penetration (10). Despite the fact that osimertinib is a TKIs, thus suggesting the need to define customized substrate of P-glycoprotein and breast cancer resistance combinatorial treatment strategy (6). The recent approval protein (BCRP) efflux transporters, which remove drugs of osimertinib, an orally available, irreversible inhibitor from the CNS, its permeability is sufficient to overcome of EGFR-sensitizing and T790M-resistant mutations, the efflux, thus suggesting its potential efficacy on brain has improved the therapeutic armamentarium in EGFR metastases (11). Preclinical data indicate that osimertinib mutated NSCLC patients (7). Based on its favorable toxicity distribution at mouse brain is greater compared to gefitinib, profile, osimertinib is considered a particularly attractive erlotinib or afatinib, and determines brain tumor regression candidate for combinatorial approaches that may potentially in EGFR mouse brain metastases model (11). improve the clinical outcome of this subset of patients. Based on these preclinical data, osimertinib entered in The current review focuses on the clinical data leading to clinical development. The phase I AURA trial (Table 1) the approval of osimertinib and provides an overview of the evaluated the pharmacokinetic profile and efficacy of mechanisms of acquired resistance to osimertinib and the osimertinib in EGFR mutated patients with radiological ongoing therapeutic strategies to overcome resistance. documented progression to previous EGFR-TKIs (12). Osimertinib was well tolerated and no dose limiting toxicity was registered. The dose of 80 mg once daily was selected Clinical development of osimertinib for the further clinical development. Partial responses were Osimertinib was originally designed to target EGFR observed in 51% of the enrolled patients, with a disease sensitizing mutations and T790M resistant mutation, control rate of 84%. ORR increased to 61% when only © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2020;12(5):2851-2858 | http://dx.doi.org/10.21037/jtd.2019.08.30 Journal of Thoracic Disease, Vol 12, No 5 May 2020 2853 T790M positive patients were considered. These results osimertinib was allowed at disease progression in patients were confirmed in the phase II AURA2 study Table( 1), that receiving standard EGFR-TKI after documentation of enrolled patients progressing to prior EGFR-TKI therapy, T790M-positive mutation status on plasma or tissue. with centrally confirmedT790M resistance mutation (13). Results demonstrated prolonged PFS with osimertinib An ORR of 70% was registered, with a median PFS over standard EGFR-TKI, with a benefit observed across of approximately 10 months, leading to the accelerated all predefined
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