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. 2016 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 2016 American Association for Cancer Research. (erb-b2 receptor tyrosine kinase 4), and BLK (BLK proto-

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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 1.5 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). Among all grades, 1% grade 3/4), rash (40% all grades, 1% grade 3/4), dry responding patients, the median DoR was 7.8 months (27% skin (21% all grades, 0% grade 3/4), and paronychia (20% all maturity). Among evaluable patients, the median PFS was 8.6 grades, 0% grade 3/4). Similar rates of rash (42% all grades, 1% months (95% CI, 8.3–9.7; 38% maturity). Importantly, patients grade 3/4), diarrhea (39% all grades, 1% grade 3/4), dry skin with brain metastases exhibited an ORR of 68% (95% CI, 57–78), (25% all grades, 0% grade 3/4), and paronychia (15% all grades, thus indicating that the drug achieves clinically meaningful con- 0% grade 3/4) were reported in AURA2 (N ¼ 210; ref. 17). centrations in the CNS. Patients with Ex19del exhibited higher The incidence of interstitial lung disease/pneumonitis across ORR compared with patients bearing the L858R amino acid clinical trials of osimertinib (N ¼ 813) was 3.3%, with fatal outcome substitution (78%; 95% CI, 69–84 vs. 59%; 95% CI, 46–71; in 0.5% of treated patients. In the event of confirmed pneumonitis, ref. 14). Updated results from a preplanned pooled analysis of osimertinib should be permanently discontinued. Other label warn- the AURA extension and AURA2 (N ¼ 411) presented at the 2016 ings include prolongation of the corrected QT interval (QTc; 0.2% European Lung Cancer Conference (data cutoff on November 1, greater than 500 msec), cardiomyopathy (recorded in 1.4% of 2015) indicated a 66% ORR (95% CI, 61–71) by BICR, with a patients, with 0.2% of cases fatal), and fetal toxicity (17). median DoR of 12.5 months (95% CI, 11.1–NC) and median PFS of 11.0 months (95% CI, 9.6–12.4; ref. 15). Among 127 T790M-positive patients in the phase I component Mechanisms of Resistance to Osimertinib of AURA (NCT01802632) that were evaluable for response, the The landscape of clinical resistance pathways to third-genera- ORR was 61% (95% CI, 52–70) and the DCR 95% (95% CI, tion EGFR TKIs, including osimertinib, has recently began to 90–98; ref. 16). Among T790M-negative patients, the ORR was unfold. In view of the critical importance of the Cys-797 residue 21% (95% CI, 12–34) and DCR 61% (95% CI, 47–73). Median for covalent binding of all third-generation inhibitors (as well as PFS was 9.6 months [95% CI, 8.3–nonresponse (NR); 30% second-generation irreversible inhibitors), it is not surprising that maturity] for T790M-positive patients and 2.8 months (95% CI, acquisition of a C797S somatic mutation that disrupts irreversible

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drug binding was identified in cell-free plasma DNA in 22% (15/ been reported in EGFR T790M-positive patients at the time of 67) of T790M-positive patients from the phase I AURA trial at the progression on osimertinib, similar to what has been reported time of progression by digital droplet PCR (18, 19). In all cases previously for first-generation EGFR TKIs (18, 24, 25). with detectable C797S, the T790M mutation also persisted in Finally, it remains unclear whether acquired resistance to EGFR circulating cell-free DNA (cfDNA). Interestingly, the incidence of TKIs is a stochastic phenomenon or whether preexisting molec- C797S at the time of disease progression was more common in ular features of the primary tumor channel development of patients with Ex19del (30%, 13/43 patients) compared with those resistance toward a specific molecular trajectory. Indeed, a recent bearing L858R (8%, 2/24; ref. 18). Larger studies will be required provocative study highlighted that emergence of gefitinib-resis- to fully characterize the incidence of C797S; it is, however, clear tant, T790M-mutant clones of the PC9 EGFR Ex19del-mutant cell that this will represent a dominant mechanism of osimertinib line could either occur rapidly, as a result of the expansion of resistance. It is further important to note that the C797S mutation preexisting drug-resistant T790M-positive clones, or, alternative- can be present on the same allele as T790M (in cis) or on a different ly, emerge with a proscribed latency from dormant drug-resistant allele (trans configuration; ref. 20). The allelic context of second- cells following de novo acquisition of secondary T790M mutations ary resistance mutations may be clinically relevant, because in vitro (26). Importantly, latent T790M-positive clones exhibited dimin- EGFR-mutant cell lines bearing T790M and C797S on different ished apoptotic response to osimertinib compared with early alleles were reported to retain sensitivity to the combination of resistant clones that could be restored with navitoclax (ABT- osimertinib with first-generation EGFR TKIs. In contrast, coexis- 263), a potent BCL2 (BCL2, apoptosis regulator)/BCL2L1 tence of T790M and C797S on the same allele confers resistance to (BCL2-like 1)/BCL2L2 (BCL2-like 2) inhibitor, which led to a all currently available EGFR TKIs, although partial sensitivity to phase IB clinical trial (NCT02520778) of combined therapy with cetuximab may be retained in this setting. osimertinib and navitoclax in EGFR T790M mutation–positive Perhaps less anticipated was the observation that at the time NSCLC. of disease progression, the T790M allele was no longer detectable in 48% of initially T790M-positive patients (32/67) in AURA, despite increased abundance of the primary EGFR- Comparison with Alternative Therapies sensitizing mutation (18). This suggests that under the negative Rociletinib (also known as CO-1686; Clovis) is a third-gener- selective pressure applied by osimertinib, resistance can develop ation, mutant-selective, pyrimidine-based, irreversible EGFR TKI from T790M-negative clones, thus highlighting intratumoral that followed an analogous clinical development path to osimer- heterogeneity as a potent barrier to the clinical efficacy of tinib. The rate of confirmed responses with rociletinib was 22.8% osimertinib monotherapy and indicating a need for upfront (95% CI, 14.1–33.6) at the 500-mg twice a day dose level, with a combination regimens that simultaneously target more than median DoR of 9.1 months (95% CI, 6.8–12.9) among patients one resistance mechanism. treated in TIGER-X and TIGER-2. Hyperglycemia (54% all grades, Emulating previous findings with first-generation EGFR TKIs 31% grade 3/4 at the 500-mg twice a day dose) and QTc pro- (21), reactivation of downstream signal transduction pathways in longation (33% all grades, 8% grade 3/4) represent two major, the context of persistence of the T790M mutation and ongoing clinically significant adverse events of rociletinib. QTc prolonga- potent inhibition of EGFR signaling has also been reported at the tion resulted in Torsade de Pointes in one patient. One further time of clinical osimertinib progression. Signaling bypass important point in the comparison between the two compounds mechanisms that have so far been validated in patient samples relates to the inferior CNS penetration of rociletinib compared include high-level amplification of ERBB2/HER2 or MET (MET with osimertinib. It is also notable that among nine patients who proto-oncogene, receptor tyrosine kinase) and emergence of BRAF developed resistance to rociletinib in TIGER-X who were subse- (B-Raf proto-oncogene serine/threonine kinase) V600E-mutant quently enrolled in AURA2, seven derived clinical benefit, includ- clones (18). In cell line models of acquired resistance to third- ing three patients who developed brain metastases on rociletinib generation EGFR TKIs, several additional mechanisms have been (8). This suggests incomplete target inhibition at clinical doses of reported, including mutations in NRAS and amplification of wild- rociletinib and is in keeping with patterns of acquired resistance type NRAS (neuroblastoma RAS viral oncogene homologue) or that are characterized by loss of the EGFR T790M in approximately KRAS (KRAS proto-oncogene GTPase; ref. 22). Enhanced sensi- 31% of cases (4/13), small-cell transformation with associated tivity to the MAP2K1 (mitogen-activated protein kinase kinase loss of T790M (15%, 2/13 cases), EGFR amplification (23%, 1-MEK1)/MAP2K2 (mitogen-activated protein kinase kinase 2- 3/13), and retention of T790M without other identified mechan- MEK2) inhibitor selumetinib (AZD6244), when used in conjunc- isms in 31% (4/13; ref. 8). Importantly, the typical C797S mutation with the initial EGFR TKI, was observed in some of these tion that prevents irreversible binding of third-generation EGFR cellular resistance models. Importantly, concomitant administra- TKIs was not observed in this cohort. In May 2016, Clovis tion of the potent MEK1/2 inhibitor trametinib with the third- announced that further clinical development of rociletinib was generation EGFR TKI WZ4002 tool compound was demonstrated stopped. to prevent the development of acquired resistance by both Other mutant-selective third-generation EGFR TKIs include BI T790M-dependent and T790M-independent mechanisms in pre- 1482694 (olmutinib, formerly HM61713; Boehringer Ingelheim), clinical models, although treatment of resistant tumors was EGF816 (Novartis), ASP8273 (Astellas), and PF-06747775 (Pfizer). effective only in the context of T790M (23). Among T790M mutation–positive patients from South Korea who Phenotypic transformation to small-cell carcinoma coupled were treated with BI 1482694 at the recommended phase II dose of with the acquisition of its genetic hallmarks, mutational inacti- 800 mg once daily in the phase I/II HM-EMSI-101 clinical trial vation or deletion of TP53 (tumor protein p53) and RB1 (RB (NCT01588145), a 54% rate of confirmed objective responses was transcriptional corepressor 1), with downregulation of EGFR reported, with a median DoR of 8.3 months (27). BI 1482694 was expression and loss of dependence on EGFR signaling has also granted breakthrough therapy designation by the FDA in December

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2015 and was approved in South Korea in May 2016 for the uated in the randomized, double-blind phase III ADAURA clinical treatment of patients with T790M-positive disease following the trial (NCT02511106) of osimertinib versus placebo following failure of a first-generation EGFR TKI. Enrollment in the pivotal surgical resection of stages IB to IIIA EGFR-mutant NSCLC with or phase II ELUXA 1/HM-EMSI-202 (NCT02485652) was completed, without adjuvant chemotherapy (N ¼ 700). Two additional and ELUXA 2, a phase III clinical trial comparing the clinical efficacy open-label phase II clinical trials are assessing the efficacy of olmutinib with that of standard platinum-based doublet che- of osimertinib for locally advanced/metastatic, EGFR T790M motherapy in patients with a T790M resistance mutation following mutation–positive NSCLC in different ethnic populations failure of prior EGFR TKI therapy, was scheduled to commence in (NCT02442349 and NCT02504346), whereas the large multina- 2016. EGF816 is being evaluated in the ongoing CEGF816X2101 tional open-label phase III ASTRIS trial (NCT02474355) is asses- (NCT02108964) multicenter phase I/II trial. As of the January 29, sing the efficacy and safety of osimertinib in T790M mutation– 2016, data cutoff among 127 patients evaluable for response in positive advanced NSCLC following failure of EGFR TKI in a real- the phase I dose-escalation part of the study, a 46.9% (95% CI, world setting (N ¼ 1,500), with overall survival representing the 38.7–55.3) rate of confirmed objective response was reported with primary efficacy outcome. The combination of osimertinib at a a median DoR of 9.5 months (95% CI, 9.2–14.7) and median PFS dose of 80 mg daily with promising additional targeted therapies, of 9.7 months (95% CI, 7.3–11.1; ref. 28). Updated data from the including the MEK1/2 inhibitor selumetinib (two different dos- phase I trial of ASP8273 (NCT02113813) were presented at the ing schedules), the MET inhibitor savolitinib, and the PD-L1 2016 ASCO Annual Meeting; among T790M-positive patients inhibitor durvalumab (MEDI4736), is evaluated in the multiarm treated at the recommended phase II dose of 300 mg orally once phase Ib TATTON trial in patients with EGFR-mutant, locally daily, the ORR was 31%, with a DCR of 57% and median PFS of 6.0 advanced or metastatic NSCLC that progressed during or follow- months (95% CI, 5.3–9.8; ref. 29). The clinical efficacy and safety of ing a prior EGFR TKI. The efficacy of the combination of osimer- ASP8273 are further being evaluated in a head-to-head comparison tinib with durvalumab (MEDI4736) versus osimertinib mono- with erlotinib or gefitinib for the first-line treatment of patients with therapy is further evaluated in the randomized phase III CAURAL advanced EGFR-mutant NSCLC in the randomized phase III trial (NCT02454933) in patients with advanced, EGFR T790M SOLAR clinical trial (NCT02588261). Finally, PF-06747775 is mutation–positive NSCLC patients who progressed during or currently undergoing evaluation in the NCT02349633 phase I/II following prior EGFR TKI therapy. However, this trial was tem- clinical trial. porarily suspended following reports of elevated rate of pneumonitis (3/23 patients) in the combination arm. Future Directions and Ongoing Clinical Trials Disclosure of Potential Conflicts of Interest V.A. Papadimitrakopoulou reports receiving commercial research grants The impressive clinical activity and favorable toxicity profile from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis Oncology, of osimertinib for EGFR-mutant NSCLC bearing the T790M Genentech, Janssen, Merck, Novartis, and Pfizer and is a consultant/advisory secondary resistance mutation, culminating in its regulatory board member for ARAD, AstraZeneca, Genentech, Janssen, and Merck. No fl approval in the United States, the European Union, and Japan, potential con icts of interest were disclosed by the other author. spearheaded an extensive clinical development program, with several phase I to III clinical trials currently open or planned. The Authors' Contributions randomized, double-blind, multinational phase III FLAURA trial Conception and design: F. Skoulidis, V.A. Papadimitrakopoulou Development of methodology: F. Skoulidis (NCT02296125) compares osimertinib with erlotinib/gefitinib fi Acquisition of data (provided animals, acquired and managed patients, for the rst-line treatment of locally advanced or metastatic, provided facilities, etc.): V.A. Papadimitrakopoulou EGFR-mutant NSCLC (N ¼ 530). This trial is designed to address Analysis and interpretation of data (e.g., statistical analysis, biostatistics, the key unanswered question regarding the optimal sequencing of computational analysis): V.A. Papadimitrakopoulou EGFR TKIs in EGFR-mutant NSCLC. The primary efficacy end- Writing, review, and/or revision of the manuscript: F. Skoulidis, point is PFS. Crossover to osimertinib at the time of disease V.A. Papadimitrakopoulou progression in the standard-of-care arm (erlotinib or gefitinib) is allowed. AURA 3 (NCT02151981) is a randomized, open-label Grant Support phase III clinical trial of osimertinib versus pemetrexed/platinum F. Skoulidis is supported by the Andrew Sabin Family Foundation, the Lung Cancer Research Foundation, a Sheikh Khalifa Bin Zayed Al Nahyan Scholar (cisplatin or carboplatin) doublet chemotherapy in T790M muta- – Award, and generous philanthropic contributions to the University of Texas tion positive patients who progressed during or after EGFR TKI Lung Moon Shot Program. therapy (N ¼ 410). PFS is the primary endpoint, and crossover to the osimertinib arm is allowed following progression on chemo- Received June 2, 2016; revised September 9, 2016; accepted September 9, therapy. The role of osimertinib in the adjuvant setting is eval- 2016; published OnlineFirst November 7, 2016.

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622 Clin Cancer Res; 23(3) February 1, 2017 Clinical Cancer Research

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation − Positive Non−Small Cell Lung Cancer

Ferdinandos Skoulidis and Vassiliki A. Papadimitrakopoulou

Clin Cancer Res 2017;23:618-622. Published OnlineFirst November 7, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-15-2815

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