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Osimertinib in EGFR T790M Mutation–Positive Non–Small Cell Lung Cancer Ferdinandos Skoulidis and Vassiliki A

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Osimertinib in EGFR T790M Mutation–Positive Non–Small Cell Lung Cancer Ferdinandos Skoulidis and Vassiliki A Published OnlineFirst November 7, 2016; DOI: 10.1158/1078-0432.CCR-15-2815 CCR Drug Updates Clinical Cancer Research Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation–Positive Non–Small Cell Lung Cancer Ferdinandos Skoulidis and Vassiliki A. Papadimitrakopoulou Abstract In 2015, the FDA approved an unprecedented number of new patients with metastatic EGFR T790M mutation–positive NSCLC, therapies for non–small cell lung cancer (NSCLC), among them as detected by an FDA-approved test, who have progressed on or therapies addressing specific genomic tumor subsets in the setting after EGFR tyrosine kinase inhibitor therapy. It received break- of development of resistance to first-line targeted therapy. Osimer- through therapy designation, priority review status, and accelerated tinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for approval from the FDA. Clin Cancer Res; 23(3); 618–22. Ó2016 AACR. Introduction clinical doses required to effectively inhibit T790M in vivo. In a phase Ib clinical trial, afatinib in combination with the chimeric The treatment of non–small cell lung cancer (NSCLC) bearing monoclonal anti-EGFR antibody cetuximab in patients with activating mutations in EGFR with EGFR tyrosine kinase inhibi- acquired resistance to erlotinib or gefitinib resulted in a meaning- tors (TKI) represents a paradigm of science-driven personalized ful 32% objective response rate [ORR; 95% confidence interval cancer therapy. For patients bearing EGFR TKI–sensitizing muta- (CI), 21.8–44.5] and 4.6-month median progression-free survival tions, most commonly in-frame microdeletions in exon 19 (PFS) in EGFR T790-mutant patients, but it was associated with a (Ex19del) and point mutations in exon 21 (leading to L858R or 46% rate of grade 3/4 adverse events, mostly rash and diarrhea L861Q amino acid substitutions) or exon 18 (G719X), treatment (11). Thus, development of highly selective third-generation EGFR with the first-generation EGFR TKIs erlotinib (Tarceva; Genen- TKIs that potently inhibit mutant EGFR and T790M but spare the tech/Astellas Pharma) and gefitinib (Iressa; AstraZeneca) or the wild-type protein emerged as a major clinical need. second-generation inhibitor afatinib (Gilotrif; Boehringer Ingel- Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is an heim) has resulted in objective responses in 56% to 74% of oral, third-generation, pyrimidine-based, irreversible EGFR TKI patients and confers clinical benefit compared with first-line that received accelerated approval from the FDA in November platinum-based doublet chemotherapy (1–6). However, initial 2015 for the treatment of patients with metastatic, EGFR T790M disease control in the majority of treated patients is inexorably mutation–positive NSCLC (as detected by an FDA-approved test) followed by the development of clinical resistance, with median who have progressed during or after EGFR TKI therapy. This progression-free survival of 9.2 to 14.0 months (1–6). In 50% to approval was followed shortly thereafter by approvals in the 60% of cases, this is attributable to de novo acquisition or expan- European Union in February 2016 (for patients with EGFR sion of preexisting clones bearing the gatekeeper T790M mutation T790M mutation–positive NSCLC, as determined by a tissue- or in EGFR, which increases the affinity of the mutant oncoprotein blood-based test, irrespective of previous treatment with an EGFR for ATP to near wild-type levels. Accordingly, drug development TKI) and the United Kingdom and Japan in December 2015 and efforts have focused on strategies to tackle T790M (7–9). March 2016, respectively, for patients with EGFR T790M muta- The second-generation irreversible EGFR TKIs afatinib and tion–positive NSCLC resistant to EGFR TKI therapy. dacomitinib bind covalently to Cys797 at the edge of the ATP- binding cleft and are effective at inhibiting T790M-mutant EGFR in vitro and in preclinical models (10). However, their clinical utility Preclinical Data in this context is hampered by a lack of selectivity for T790M- Osimertinib is a mono-anilino-pyrimidine compound devel- mutant versus wild-type EGFR, which results in a narrow thera- oped by AstraZeneca as a mutant-selective, irreversible inhibitor peutic window with high rates of cutaneous and enteric toxicity at of EGFR. In keeping with the mode of action of other irreversible inhibitors, osimertinib binds covalently via its acrylamide group to Cys797 in the ATP-binding site, but it is structurally distinct Department of Thoracic/Head and Neck Medical Oncology, The University of from the other third-generation EGFR TKIs rociletinib (CO-1686) Texas MD Anderson Cancer Center, Houston, Texas. and WZ4002 (12). In EGFR recombinant enzyme assays, it Corresponding Author: Vassiliki A. Papadimitrakopoulou, The University of exhibited 184 times greater potency for L858R/T790M-mutant Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Hous- compared with wild-type EGFR. It further demonstrated limited ton, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: promiscuity when assayed across an extensive commercial bio- [email protected] chemical kinase panel with the exception of moderate inhibition doi: 10.1158/1078-0432.CCR-15-2815 of ERBB2/HER2 (erb-b2 receptor tyrosine kinase 2), ERBB4/HER4 Ó2016 American Association for Cancer Research. (erb-b2 receptor tyrosine kinase 4), and BLK (BLK proto- 618 Clin Cancer Res; 23(3) February 1, 2017 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 7, 2016; DOI: 10.1158/1078-0432.CCR-15-2815 Osimertinib in EGFR T790M Mutation–Positive NSCLC oncogene, Src family tyrosine kinase; ref.12). In vitro, osimertinib 2.1–4.3; 71% maturity) for T790M-negative patients. In the inhibited EGFR phosphorylation and reduced cell viability with overall population of 239 patients evaluable for response treated comparable potency with first-generation EGFR TKIs in NSCLC across all dose levels, the ORR was 51% (95% CI, 45–58; ref. 16). cell lines bearing typical EGFR-sensitizing mutations (Ex19del, Updated results with a January 4, 2016, data cutoff for 63 patients L858R), but not in those with wild-type EGFR, and exhibited with T790M treated in the 80 mg orally OD dose-expansion dramatically enhanced activity compared with first-generation cohort indicated investigator-assessed ORR of 71% (95% CI, TKIs in cell lines bearing the T790M resistance mutation (12). 57–82), with a median DoR of 9.6 months (95% CI, 7.7–15.6) In vivo antitumor activity was demonstrated across a wide spec- and median PFS of 9.7 months (95% CI, 8.3–13.6; ref. 15). trum of xenograft models representative of common sensitizing EGFR mutations, including PC-9 (Ex19del) and H3255 (L858R), Pharmacokinetics as well as the T790M gatekeeper mutation in H1975 (L858R/ Osimertinib can be taken with or without food and can be T790M) and PC-9VanR (Exon19del/T790M), and was further dispersed in noncarbonated water for patients unable to swallow confirmed in genetically engineered murine models of EgfrL858R tablets. Following single-dose administration of the capsule and EgfrL858R/T790M –driven NSCLC (12). formulation, Cmax is reached after a median of 6 hours, and dose-proportional exposure is observed over the 20- to 240-mg Clinical Data dose range with linear pharmacokinetics (17). Population-esti- mated mean half-life (t ) of osimertinib is 48 hours, and steady- The regulatory approval of osimertinib was based on efficacy 1/2 state accumulation following once daily dosing is reached after 15 results from two single-arm phase II clinical trials: the (or 22) days. The drug is metabolized by oxidation (mostly via the phase II extension of the pivotal AURA phase I/II clinical trial CYP3A pathway) and dealkylation to two active metabolites; (NCT01802632) and the confirmatory AURA2 trial therefore, strong CYP3A inducers or inhibitors should be avoided (NCT02094261). Both trials enrolled patients with locally (17). No dose adjustments are recommended for patients with advanced or metastatic NSCLC bearing sensitizing activating mild or moderate renal impairment (CLcr 30–89 mL/minute) or EGFR mutations that had progressed following prior EGFR TKI mild hepatic impairment [bilirubin < upper limit of normal therapy and were positive for the T790M gatekeeper mutation (ULN) and AST between 1 and 1.5Â ULN or total bilirubin on central testing, using the cobas EGFR Mutation Test (Roche between 1.0 and 1.5 ULN and any AST], but no data are available Molecular Systems). Patients with asymptomatic, stable central for patients with severe renal impairment or moderate/severe nervous system (CNS) metastases were eligible for both studies. hepatic impairment (17). At the data cutoff (May 1, 2015), the ORR (by RECIST 1.1) to osimertinib at the recommended dose of 80 mg orally once daily (tablet formulation) among 199 of 201 evaluable patients in the Drug Safety phase II extension cohort of AURA was 61% (95% CI, 54–68) by In the dose-escalation phase of AURA, no dose-limiting blinded independent central review (BICR), for an overall disease toxicities were identified at any of the prespecified osimertinib control rate [DCR: complete response (CR) þ partial response dose levels. Commensurate with the selectivity of osimertinib for (PR) þ stable disease 6 weeks] of 91% (95% CI, 85–94; ref. 13). mutant EGFR, the frequency and severity of reported "on-target" The median duration of response (DoR) and median PFS had not adverse events of the 80-mg dose in AURA and AURA2 were reached maturity (13). Comparable results were obtained in significantly reduced compared with historical data with first- and AURA2. At the same data cutoff, the BICR ORR to osimertinib second-generation EGFR TKIs. In the AURA phase II extension among 199 of 210 patients evaluable for response was 71% (95% (N ¼ 201), the most common adverse events were diarrhea (45% CI, 64–77), for a DCR of 92% (95% CI, 87–95; ref. 14).
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