The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer

Abstract

First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e., exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.

INTRODUCTION

Activating mutations in the kinase domain (exon 18 to 21) of the epidermal growth factor receptor (EGFR) gene result in the formation of ligand-independent EGFR proteins that activate downstream signaling pathways and are oncogenic drivers in a subset of non-small-cell lung cancers (NSCLCs). EGFR mutations account for approximately 10–15% of NSCLC cases in North America/Europe and 30–40% of NSCLCs in Asian countries [1–4]. The presence of an EGFR mutation in advanced NSCLC is predictive of disease responsiveness to EGFR tyrosine kinase inhibitors (TKIs) in preclinical models and patients [5–17]. The most common EGFR mutations are in-frame deletions around the LREA motif of amino-acids 747–750 in exon 19 and the L858R point mutation in exon 21, together accounting for approximately 85–90% of all EGFR mutations [18]. Multiple randomized trials have shown that the first-generation (gefitinib and erlotinib) and second-generation (afatinib) EGFR TKIs confer excellent radiographic overall response rates (ORRs) ranging from 50–75%, improved progression-free survival (PFS) as compared to standard platinum-doublet chemotherapy in patients with advanced NSCLC with EGFR mutations, and a trend towards improved overall survival [8–14]. As a result, gefitinib, erlotinib, and afatinib are approved first-line treatments by the United States (U.S.) Food and Drug Administration (FDA) for patients with advanced NSCLCs with EGFR exon 19 deletions or the L858R mutation.

Unfortunately, acquired resistance to first- and second-generation EGFR TKIs invariably develops within a median period of 9–13 months. Multiple mechanisms of acquired resistance have been identified, including secondary mutations in EGFR (e.g., EGFR-T790M), amplification of the MET oncogene, ERBB2 amplification, MAPK1 amplification, PIK3CA mutation, BRAF mutations, AXL activation, and small cell transformation among others [19–24]. The most common mechanism of acquired resistance involves development of the EGFR T790M mutation in exon 20 and is seen in approximately 50–60% of patients who experience disease progression on EGFR TKIs [19–21]. The EGFR T790M mutation was initially thought to develop only as an acquired mutation after EGFR TKI treatment, but subsequent studies have also reported existence of pre-treatment de novo EGFR T790M mutations as a minor clone concomitantly with other EGFR activating mutations [25–29]. Tyrosine kinase inhibitors in general compete with ATP to bind to the kinase domain of EGFR, and EGFR T790M significantly increases the affinity of EGFR for ATP, thereby reducing the efficacy of first-generation EGFR TKIs [30]. Second-generation EGFR TKIs were therefore originally developed to be irreversible EGFR inhibitors with the hope of achieving higher potency against EGFR T790M-mediated resistance, but the drugs that moved forward in confirmatory clinical trials (afatinib, dacomitinib, and neratinib) have failed to produce meaningful disease response after resistance to gefitinib or erlotinib [31–33]. The failure of second-generation EGFR TKIs to overcome T790M resistance is likely related to their potent non-mutant EGFR selectivity, resulting in dose-limiting skin and gastro-intestinal toxicities that limit maximum tolerated doses, and the absence of a therapeutic window between inhibition of EGFR T790M and wild-type EGFR [34,35].

The focus therefore shifted toward identification of novel EGFR TKIs with selectivity toward mutant forms of EGFR [36,37]. WZ4002, a preclinical covalent EGFR pyrimidine TKI, was the first such compound to be described in 2009 [36,37]. Osimertinib (previously AZD9291; AstraZeneca), rociletinib (CO-1686; Clovis Oncology), BI-1482694/HM61713 (Boehringer Ingelheim/Hanmi) and ASP8273 (Astellas) are newer third-generation EGFR TKIs with selectivity against EGFR T790M - as well as other commonly mutated forms of EGFR - that have progressed to clinical trials [36,38,39]. Here we review the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of osimertinib for treatment of NSCLCs harboring the EGFR T790M mutation.

OVERVIEW OF THE MARKET

Multiple third-generation EGFR TKIs – osimertinib, rociletinib, BI-1482694/HM61713, and ASP8273 among others – are currently in clinical trials and mid-to-late development. Rociletinib was evaluated in a phase I/II study of patients with EGFR mutated NSCLC who had disease progression during prior EGFR TKI treatment [40]. Rociletinib was originally reported to have an objective response rate of 59% in the 46 patients with EGFR T790M-positive disease and had an overall tolerable but worrisome safety profile, with clinically-relevant hyperglycemia as the common dose-limiting adverse event and cardiac abnormalities not uncommonly reported [41]. The U.S. FDA granted rociletinib breakthrough therapy designation based on these promising early efficacy results. However, more mature data in late 2015 has subsequently shown lower ORRs (below 35% in updated press releases) at the doses moving forward in clinical development for NSCLCs with EGFR T790M-positive disease [42]. In the intent to treat analysis of the 79 patients in the rociletinib 500 mg dose group, the current confirmed ORR is 28%, and of the 170 patients in the 625 mg dose group the ORR is only 34% [42]. Rociletinib is currently undergoing extended review by the U.S. FDA, but the aforementioned severe toxicities coupled with the suboptimal ORR lead most thoracic oncologists to believe the drug approval process will be difficult for rociletinib [43].

BI-1482694/HM61713 and ASP8273 are currently under evaluation in phase I/II trials in patients with advanced EGFR mutated NSCLCs who progressed on prior EGFR TKI and/or have confirmed EGFR T790M [38]. Final results of the ORR and toxicities of these drugs have not been published in peer-review periodicals.

Osimertinib is the first and only third-generation EGFR TKI to date to have gained approval by major regulatory agencies for treatment of EGFR T790M mutated NSCLC.

INTRODUCTION TO OSIMERTINIB

Chemistry and mechanism of action

Osimertinib is a mono-anilino-pyrimidine small molecule that acts as a covalent EGFR TKI. The molecular formula for osimertinib mesylate is C₂₈H₃₃N₇O₂•CH₄O₃S, and the compound possesses a molecular weight of 596 g/mol. Osimertinib was part of a novel series of small-molecule inhibitors developed by AstraZeneca to target double-mutant (i.e., activating mutation + T790M) forms of EGFR that are resistant to first- and second-generation EGFR TKIs [44]. Osimertinib is distinct in both structure and pharmacology from other approved EGFR TKIs [45]. The structural formula of osimertinib and other selected preclinical/clinical third-generation EGFR TKIs are shown in Figure 1.

Figure 1.

Chemical structures and basic information on selected preclinical and clinical third-generation EGFR inhibitors based on data deposited on the PubChem Compound and Substance databases [62]. Clinical responses reflect data from references [42] and [46]. Activity is grade from minimum (+) to maximum (+++++).

Osimertinib binds irreversibly, via the C797 amino-acid covalent bond, to certain mutant forms of EGFR (L858R, exon 19 deletion and double mutants containing T790M) at approximately 9-fold lower concentrations than to wild-type EGFR [45,46]. In preclinical models (e.g., NSCLC cell lines and tumor implantation models), osimertinib exhibited potent activity against cancers harboring EGFR-mutations (L858R, L858R+T790M, exon 19 deletion, and exon 19 deletion+T790M). Two pharmacologically-active metabolites AZ7550 and AZ5104, circulating at approximately 10% of the parent, have similar inhibitory profiles to osimertinib. AZ7550 maintains a similar potency as osimertinib. AZ5104 possesses a greater potency against EGFR exon 19 deletion and T790M mutation (approximately 8-fold) as well as EGFR wild-type (approximately 15-fold). Osimertinib, AZ7550, and AZ5104 each have half-lives of greater than 50 hours [45]. Osimertinib also inhibits the activity of ERBB2, ERBB3, ERBBR4, ACK1, and BLK at clinically relevant concentrations in vitro [46].

The commercially available form of osimertinib is distributed by AstraZeneca under the brand name Tagrisso™. Osimertinib is available in tablets of 40 mg or 80 mg, equivalent to 47.7 mg and 95.4 mg of osimertinib mesylate, respectively.

Pharmacodynamics

The pharmacodynamics of the drug has been studied in humans in cardiac electrophysiology studies. The heart rate-corrected QT (QTc) interval prolongation potential of osimertinib was assessed in 210 patients who received osimertinib 80 mg daily, and a pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec [46]. Pharmacodynamics in other organ systems have not been reported.

Pharmacokinetics and metabolism

Pharmacokinetics

The area under the plasma concentration-time curve (AUC), maximal plasma concentration (C_max), and minimal concentration (C_min) of osimertinib have been shown to increase over the 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) with linear pharmacokinetics. Oral osimertinib results in 3-fold accumulation and achieves steady state exposure after 15 days. At the steady state, the Cmax/Cmin ratio is greater than 1.5-fold. The AUC of osimertinib metabolites AZ5104 and AZ7550 was approximately 10% of the exposure of osimertinib. Pharmacokinetic exposure was not significantly different between Asian versus non-Asian patients [47].

Absorption

The median time to C_max was reported at 6 hours. Compared to fasting conditions, administration with a high-fat or high-calorie meal increased osimertinib concentrations by 14% and 19%, respectively [46].

Distribution

The mean volume of distribution of osimertinib was 986 L at steady-state, and plasma protein binding was based on its chemical assets [46].

Elimination

The drug’s plasma concentrations decrease with time, with a mean half-life of 48 hours [46].

Metabolism

The main metabolic pathways of osimertinib were oxidation and dealkylation in vitro [46].

Excretion

Osimertinib is primarily eliminated in the feces (>65%) and urine (<15%), with unchanged drug accounting for ~2% of total elimination [46].

Specific Populations

No clinically significant differences in the pharmacokinetics of osimertinib have been identified based on age, sex, ethnicity, body weight, smoking status, mild to moderate renal impairment, or mild hepatic dysfunction [46]. Data is unavailable regarding the pharmacokinetics of osimertinib in patients with severe renal impairment or with moderate to severe hepatic impairment.

Drug Interactions

Osimertinib is a competitive inhibitor of CYP3A. It does not inhibit CYP2C8, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 2E1. The drug can induce CYP3A4 and CYP1A2 enzymes. Osimertinib is a substrate of P-glycoprotein and ATP-binding cassette sub-family G member 2, but it is not a substrate of organic anion-transporting polypeptide proteins [46]. The exposure of osimertinib was not affected by concurrent administration of omeprazole in humans [46].

Carcinogenesis, mutagenesis, and fertility

Detailed carcinogenicity studies have not been conducted with osimertinib. The drug did not cause genetic damage in in vitro and in vivo assays [46]. Animal male fertility may be impaired by treatment with osimertinib. Nonclinical female fertility studies showed the drug may affect the ovaries, uterus, and vagina [46].

CLINICAL EFFICACY

Phase I studies

Osimertinib has been shown to carry significant activity in vitro and in mouse models against EGFR L858R or exon 19 deletion and compound EGFR L858R+T790M or exon 19 deletion+T790M tumors while having significantly reduced activity against wild-type EGFR [45]. Based on the promising preclinical data, the phase I AURA trial (ClinicalTrials.gov identifier NCT01802632) was initiated to assess the safety and efficacy of osimertinib in patients with locally advanced or metastatic EGFR mutated NSCLC who had documented disease progression while receiving a first- or second-generation EGFR TKI [47]. The study included a total of 253 patients from 33 sites in Japan, South Korea, Taiwan, France, Spain, Germany, Australia, the United Kingdom, and the U.S.

The study included two cohorts. The dose-escalation cohort included 31 patients, and the dose-expansion cohort included 222 patients who received osimertinib at five dosages ranging from 20 mg to 240 mg daily. Osimertinib demonstrated promising efficacy with an ORR of 51%. Of the 239 patients evaluated for disease response, 1 patient demonstrated a complete response, 122 (51%) had partial response, 78 (33%) had stable disease, 34 (14%) had disease progression, and 4 (2%) could not be assessed. The ORR was similar between Asian and non-Asian patients (50% vs 54%). Response rate was also similar at each of the dose levels examined. Based on the data that response rates were similar across all osimertinib dose levels and increasing toxicities at the 160 mg and 240 mg daily doses, a dose of 80 mg daily was adopted for future studies, including registration trials.

Osimertinib exhibited improved efficacy in patients whose tumor harbored the EGFR T790M mutation. Of the 127 patients with confirmed EGFR T790M on central testing by the sponsor and who were evaluated for disease response, the ORR was 61%. Patients without detectable EGFR T790M mutation on central testing showed an ORR of only 21%. Overall, the median PFS was 8.2 months. Patients with EGFR T790M mutation-positive tumors had a median PFS of 9.6 months, while those without the mutation had a median PFS of 2.8 months.

Phase II studies

Additional efficacy data from both the phase II extension cohort of the AURA trial and the phase II AURA2 trial (NCT02094261) were presented at the 2015 World Conference on Lung Cancer and revealed similarly promising results. The AURA trial extension showed previously treated patients with EGFR T790M mutation (n=201) had an ORR of 61% to osimertinib 80 mg daily [40]. Median duration of response and median PFS were not yet reached. Similarly, the AURA2 trial found that patients with EGFR T790M mutation-positive tumors previously treated with first- or second-generation EGFR TKIs (n=210) had an ORR of 71% and a disease control rate (i.e., complete response, partial response, or stable disease) of 92% when treated with osimertinib [48]. Median PFS was reported to be 8.6 months with a median duration of response of 7.8 months. The efficacy data for osimertinib in phase I and II trials are compared to those for rociletinib and summarized in Table 1. The ORR according to RECIST v1.1 as evaluated by a Blinded Independent Central Review in the FDA submission package for osimertinib disclosed an ORR of 57% for AURA and of 61% for AURA2, which formed the basis for the U.S. FDA efficacy approval of the drug [46].

Table 1.

Efficacy of osimertinib vs rociletinib in EGFR T790M mutated non-small-cell lung cancer.

Trial	Phase	Treatment	Patients with EGFR T790M positive tumors	ORR EGFR T790M positive tumors (independent central review and/or confirmed responses)
AURA extension	II	osimertinib 80 mg/day	201	57%
AURA2	II	osimertinib 80 mg/day	210	61%
TIGER-X and TIGER-2	I/II	rociletinib 500 mg/twice day	79	28%
		rociletinib 650 mg/twice day	170	34%

ORR, overall response rate.

Ongoing Phase III studies

Additional phase III trials involving osimertinib are ongoing. The AURA3 trial (NCT02151981) is an open label, randomized study of osimertinib versus platinum-based doublet chemotherapy as second-line therapy for locally advanced or metastatic NSCLC with EGFR T790M mutation.

The FLAURA trial (NCT02296125) is a double-blind, randomized study investigating osimertinib versus gefitinib or erlotinib as first-line therapy in patients with EGFR mutated locally advanced or metastatic NSCLC. Preliminary data from the first-line expansion cohort of the AURA trial investigating the efficacy and safety of osimertinib in treatment-naïve EGFR mutant advanced NSCLC patients showed an ORR of 70% and 6-month progression-free survival of 87% [49].

Finally, the ADAURA trial (NCT02511106) is a double-blind, randomized placebo-controlled trial assessing the efficacy and safety of osimertinib versus placebo as adjuvant therapy in patients with EGFR mutated stage IB-IIIA NSCLC following complete tumor resection.

SAFETY AND TOLERABILITY

Osimertinib was relatively well-tolerated in the phase I AURA trial. There were no dose-limiting toxicities observed at any dose level ranging from 20 mg to 240 mg daily during a 28-day evaluation period. Among the combined cohort of 253 patients in the trial, the most common adverse events included diarrhea (47%), rash (40%), nausea (22%), and decreased appetite (21%). Diarrhea and rash increased with escalating doses of osimertinib. Overall, however, osimertinib was associated with fewer dermatologic and gastro-intestinal toxicities compared to historical data and clinical experience with other approved EGFR TKIs. Any adverse event of grade 3 or higher occurred in 32% of patients, although only 13% of patients experienced a grade 3 or higher adverse event that was thought to be drug-related. Serious adverse events were seen in 22% of patients, with 6% of patients experiencing a serious adverse event that was considered to be drug-related. Adverse events prompted drug reduction in 7% of patients and drug discontinuation in 6% of patients. The frequency and severity of adverse events were similar between Asian and non-Asian patients. The major grade 3 or higher adverse events of osimertinib and rociletinib are summarized in Table 2.

Table 2.

CTCAE grade 3 or higher adverse events of osimertinib and rociletinib in the AURA and TIGER trials.

Trial	Treatment	CTCAE name	Percentage with grade 3 or higher adverse event
AURA	osimertinib	Dyspnea	2%
		Diarrhea	2%
		Anemia	2%
		Rash/Acne	1%
		Decreased appetite	1%
		Fatigue	1%
		Paronychia	<0.5%
		Nausea	<0.5%
TIGER-X	rociletinib	Hyperglycemia	22%
		QTc prolongation	5%
		Fatigue	4%
		Nausea	2%
		Vomiting	2%
		Decreased appetite	1%
		Muscle spasms	1%

CTCAE, Common Terminology Criteria for Adverse Events

The phase II AURA extension study and the AURA2 trial showed similar results regarding adverse events. Diarrhea and rash were the most common adverse events. Grade 3 or higher adverse events were seen in 21% of patients in the AURA extension study and 18% of patients in AURA2. Interstitial lung disease was reported in 5 (2.5%) patients in AURA extension and 4 (1.9%) patients in AURA2. Both trials had one case each of fatal interstitial lung disease that was considered possibly causally related to osimertinib by the investigator. In both studies, only 4% of patients discontinued treatment due to an adverse event.

REGULATORY AFFAIRS

Based on the results from the phase I AURA trial, the phase II AURA extension study, and the phase II AURA2 trial, the U.S. FDA granted accelerated approval in November 2015 for the use of osimertinib in patients with advanced NSCLC with EGFR T790M mutation. U.S. FDA approval of the drug was accompanied by approval of a companion diagnostic test (cobas EGFR Mutation Test v2; Roche) to detect the EGFR T790M mutation. The newer version (v2) of the cobas EGFR Mutation Test adds T790M mutation to other known activating mutations in EGFR.

The United Kingdom has also approved osimertinib in December 2015 under the Early Access to Medicines Scheme to meet the urgent unmet need of patients with advanced EGFR T790M mutated NSCLC. In December 2015, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the marketing authorization of osimertinib for the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC. The Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has granted priority review for osimertinib.

CONCLUSION

Osimertinib is a covalent third-generation EGFR TKI with significant activity against the EGFR T790M resistance mutation and common EGFR-activating mutations, and low activity against wild-type EGFR at clinical dosing schemes. Osimertinib is a novel compound with distinct structure and pharmacology from other TKIs, including other covalent third-generation EGFR TKIs. Phase I and II studies of osimertinib have shown ORRs ranging from 57–71% with a favorable cutaneous and gastro-intestinal side effect profile. Several phase III trials are ongoing in evaluating osimertinib as second-line treatment in EGFR T790M mutated NSCLC as well as first-line treatment for NSCLC with any EGFR activating mutation.

Osimertinib is the first EGFR TKI approved in the U.S. and Europe for the treatment of NSCLC with EGFR T790M mutation.

EXPERT COMMENTARY

The EGFR T790M mutation accounts for the majority of acquired resistance to first- and second-generation EGFR TKIs and represents a significant obstacle in the treatment of EGFR mutant advanced NSCLCs. Osimertinib has demonstrated efficacy and safety parameters in phase I and II studies, and has become the first EGFR inhibitor approved for the treatment of NSCLC with the EGFR T790 mutation. Patients with advanced NSCLC with EGFR activating mutations who progress on a first-line EGFR inhibitor have traditionally been offered platinum-doublet chemotherapy as second-line treatment [50,51]. Platinum-doublet chemotherapy yields a modest ORR of approximately 30%, significantly lower than the 51–71% ORR reported in the phase I and II studies on osimertinib. Whether osimertinib is truly superior to standard platinum-doublet chemotherapy as second-line treatment in patients with T790M acquired resistance is currently being evaluated in the phase III study AURA3. Nevertheless, given the overall favorable side effect profile of osimertinib and the promising phase I and II efficacy data, the majority of oncology providers, including the authors, will likely favor osimertinib and reserve chemotherapy as a third-line therapy. Another option of care for EGFR T790M-positive NSCLC is the use of dual EGFR inhibition with afatinib plus cetuximab [52], a scheme fraught with severe cutaneous adverse events and an ORR of only 29%. The latter strategy will likely no longer be used in the setting of acquired resistance to EGFR TKIs mediated by EGFR T790M. Figure 2 illustrates one potential treatment algorithm for EGFR-mutated advanced NSCLC.

Figure 2.

Treatment algorithm for patients with EGFR-mutated advanced NSCLC.

Additional indications for osimertinib are also being explored in the phase III FLAURA trial comparing osimertinib to gefitinib or erlotinib as first-line therapy for metastatic EGFR-mutated NSCLC, as well as the phase III ADAURA trial comparing osimertinib to placebo as adjuvant therapy following resection of EGFR-mutated NSCLC. These studies have the potential to significantly expand the role of osimertinib in the treatment algorithm for EGFR mutated NSCLC. Specifically, the FLAURA trial has the potential to catapult osimertinib into the first-line setting for treatment of EGFR mutated advanced NSCLC, particularly since pre-existing clones with EGFR-T790M have been identified in treatment-naïve tumors with sensitizing EGFR-activating mutations [29].

The cost for a one-month supply of osimertinib will reportedly be $12,750 [53], approximately 50% more than the cost of first- and second-generation EGFR TKIs. The cost-effectiveness of a strategy of rebiopsying tumors at the point of resistance to first-line EGFR TKIs and switching to osimertinib remains unclear. However, multiple cost-effectiveness studies conducted in the U.S. and in Asian countries have shown that a strategy of upfront molecular testing of NSCLCs and treatment with first-generation EGFR TKIs is generally more favorable than use of non-targeted chemotherapy, and a similar advantage with targeted therapy may extend to osimertinib [54–57].

Despite the apparent success of osimertinib in EGFR T790M-mutated NSCLC, disease progression invariably develops, with preliminary PFS of approximately 10 months. Just as the EGFR T790M acquired resistance develops after an initial period of response to first- and second-generation EGFR TKIs, tumor heterogeneity and adaptation drives additional resistance mechanisms in patients treated with osimertinib and other third-generation EGFR TKIs. The most common mechanism of acquired resistance in patients with the EGFR T790 mutation treated with osimertinib appears to be via acquisition of yet another mutation – C797S in exon 20 at the site of covalent bonding of third-generation EGFR TKIs. Cell-free plasma DNA analysis of 15 patients with acquired resistance who were treated with osimertinib in the AURA study identified 6 (40%) with the EGFR C797 mutation [58], which prevents binding of all third-generation EGFR TKIs [23,59,60]. Additional resistance mechanisms that bypass EGFR signaling are also likely involved, including MET amplification, ERBB2 amplification, MAPK1 amplification, NRAS mutation or amplification, and neuroendocrine transformation to small cell lung cancer [61].

FIVE-YEAR VIEW

Osimertinib is poised to be the de facto evidence-based palliative monotherapy for EGFR mutated advanced NSCLCs that acquired resistance to first- and second-generation EGFR TKIs mediated by EGFR T790M for the foreseeable near future. All other drugs within the same class of third-generation EGFR TKIs are either poised to have difficulties during regulatory approval (as is the case detailed above for rociletinib due to low ORR and significant adverse events) or are considerably behind in clinical development plans (as is the case of BI-1482694/HM61713 that only received U.S. FDA breakthrough therapy designation for review in December 2015). Although we expect that either BI-1482694/HM61713 or ASP8273 may receive regulatory approval within the next few years for the same current indication as osimertinib, it is likely that osimertinib will have cemented its status as the go-to EGFR TKI for EGFR T790M resistance by that time. The clinical development of osimertinib for the first line therapy of TKI-naïve EGFR mutated NSCLCs will be more convoluted and require larger phase III trials comparing it to the current evidence-based standards (gefitinib, erlotinib and afatinib).

The main focus of academic research moving forward for osimertinib will hinge on preventing acquired resistance to monotherapy and attempting to combine osimertinib with other anti-cancer therapies. To the latter end, a phase Ib clinical trial called TATTON (NCT02143466) was launched to evaluate osimertinib when given together with one of either durvalumab (immune check point inhibitor), savolitinib (MET inhibitor) or selumetinib (MEK inhibitor).

KEY ISSUES.

• Osimertinib is a small molecule third-generation covalent inhibitor of both EGFR-sensitizing and T790M resistance mutations with lesser activity against wild-type EGFR.

• Osimertinib has shown significant activity as second-line therapy in patients with advanced EGFR T790M mutated NSCLC with ORRs that exceed 50% in clinical trials.

• Osimertinib has a tolerable side effect profile. The most common adverse events include diarrhea, nausea, and decreased appetite.

• Osimertinib was granted accelerated approval by the U.S. FDA in November 2015 for the treatment of advanced NSCLC with EGFR T790 mutation.

INFORMATION RESOURCES.

• Cross DA, Ashton SE, Ghiorghiu S et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov, 4(9), 1046–1061 (2014).

• Jänne PA, Yang JC, Kim DW et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med, 372(18), 1689–1699 (2015).