Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients

Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients Abstract Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC. osimertinib, EGFR TKI, acquired resistance, NSCLC Introduction Activating epidermal growth factor receptor (EGFR) mutations predict sensitivity to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, icotinib and afatinib with higher overall response rate (ORR) and progression-free survival (PFS) compared with upfront platinum doublet chemotherapy, making them the standard of care [1, 2]. However, tumours invariably develop acquired resistance (AR) ∼9–12 months after treatment initiation [1]. Several mechanisms of AR have been reported, such as secondary EGFR mutations, bypass track signalling pathways and histologic transformation [3]. The substitution of threonine to methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene reduces first-generation EGFR TKIs binding by enhancing the ATP binding affinity of the kinase domain of the EGFR-mutant receptor [4]. This mutation accounts for AR in ∼50%–60% of the patients [3, 5]. MET amplification is the second most common mechanism of AR to EGFR TKIs in up to 20% of cases [6] irrespective of the T790M mutational status [7]. Histologic transformation to small-cell lung cancer (SCLC) accounts for 5%–10% of EGFR-mutant tumours with AR. Those EGFR mutant tumours harbouring completely inactivated Rb and p53 have a 43 times greater risk of small-cell transformation [8]. These transformed SCLC tumours express neuroendocrine markers, maintain the original EGFR-sensitizing mutation and respond to standard SCLC chemotherapy [3]. Knowledge of AR mechanisms to EGFR TKIs was one of the triggers behind the development of third-generation EGFR-TKIs, which are active against exon 19 and 21 mutations as well as the T790M mutation. Among them, osimertinib (AZD9291) was the first to receive FDA and EMA approval in November 2015 and February 2016, respectively, for metastatic EGFR-mutant and acquired EGFR T790M mutation–positive non-small-cell lung cancer (NSCLC) patients [9, 10] progressing on or after EGFR TKI therapy. This article provides an overview of preclinical and clinical data on osimertinib and other third-generation EGFR TKIs currently in development. The potential use of osimertinib in the adjuvant setting and the combination of EGFR TKIs with immune checkpoint inhibitors in resistant EGFR-mutation NSCLC patients will be also reviewed. Osimertinib Osimertinib is a mono-anilino-pyrimidine compound that specifically binds to the EGFR kinase domain irreversibly by targeting the cysteine-797 residue in the ATP binding site via covalent bond formation. In cell lines, osimertinib potently inhibited phosphorylation of EGFR in PC-9 (Del19) and H3255 (L858R) cell lines with mean IC50 values ranging from 13 to 54 nmol/l. In H1975 (L858R/T790M) and PC-9 VanR (Del19/T790M) resistant cell lines, activity of osimertinib was reported with mean IC50 potency of <15 nmol/l (Table 1) [11]. Osimertinib is more selective to the mutated receptor as evidenced by a high IC50 (range from 480 to 1865 nmol/l) in inhibiting phosphorylation of EGFR in wild-type cell lines. Interestingly, osimertinib was not potent against lines harbouring non-T790M resistance mechanisms, such as MET amplification or NRAS [11]. Table 1. IC50 values in different EGFR mutant T790M resistant cancer cell lines treated with reversible (gefitinib, erlotinib) and irreversible (afatinib, dacomitinib, osimertinib) tyrosine kinase inhibitors (adapted from Cross [9])   H1975  PC-9VanR  PC-9  H3255  EGFR  (L858R/T790M)  (Del19/T790M)  (Del19)  (L858R)a  WT  Osimertinib  15  6  17  49–60  480  Dacomitinib  40  6  0.7  1.2–1.3  12  Afatinib  22  3  0.6  0.8–1  15  Gefitinib  3102  741  7  11–12  59  Erlotinib  6073  1262  6  8–11  91    H1975  PC-9VanR  PC-9  H3255  EGFR  (L858R/T790M)  (Del19/T790M)  (Del19)  (L858R)a  WT  Osimertinib  15  6  17  49–60  480  Dacomitinib  40  6  0.7  1.2–1.3  12  Afatinib  22  3  0.6  0.8–1  15  Gefitinib  3102  741  7  11–12  59  Erlotinib  6073  1262  6  8–11  91  a 95% confidence interval. WT, wild type. Osimertinib is metabolized to produce at least two circulating metabolites, AZD5104 and AZD7550. In biochemical assays, AZD7550 had a comparable potency and selectivity profile to osimertinib, although AZD5104 showed greater potency against EGFR Del19, T790M mutations (both ∼8-fold) and wild-type EGFR (∼15-fold) [11]. In tumour xenograft and transgenic mouse models harbouring sensitizing and resistance EGFR mutations, osimertinib exposure resulted in a profound and sustained tumour regression [11]. Due to the higher selectivity to the mutated receptor, osimertinib is associated with less severe gastrointestinal and skin toxicity compared with first- or second-generation EGFR TKIs [12]. Mean half-life of osimertinib is 48.3 h with minimal food effect on exposure and no differences according to ethnicity (Asian and Non-Asian), body weight, sex or age [13]. Additionally, data from a pharmacokinetic study (NCT02163733) showed that administration of omeprazole does not have an effect on osimertinib exposure [14]. Clinical activity with osimertinib Phase I experience A phase I/II dose escalation study of osimertinib (AURA, NCT01802632) was carried out in patients with locally advanced or metastatic EGFR-mutant NSCLC patients who had disease progression on previous treatment with an EGFR TKI [15]. The study included dose-escalation and dose-expansion cohorts. Patients were only preselected according to T790M status in the expansion cohort. Sequential cohorts of patients (N = 253) received five dose levels of osimertinib ranging from 20 to 240 mg daily. Among 31 patients in the dose-escalation cohort, no dose-limiting toxicity was observed and the maximum tolerated dose was not reached. An additional 222 patients were treated in five dose-expansion cohorts. The T790M was detected in 138 patients (62%), not detected in 62 patients (28%), and of unknown status in 22 patients (10%) [15]. Of the 253 patients treated across all dose levels, 239 were assessable for response. The ORR and disease control rate (DCR) in the whole population were 51% [95% confidence interval (CI), 45–58] and 84% (95% CI, 79–88), respectively, without differences according to ethnicity. The median PFS was 8.2 months. Among the 138 patients with centrally confirmed T790M mutations, 127 patients were assessable for response. Outcomes were substantiality better in T790M-positive tumours compared with T790M-negative tumours, with an ORR of 61% (95% CI, 52–70) versus 21% (95% CI, 12–34), a DCR of 95% (95% CI, 90–98) versus 61% (95% CI, 47–73) and median PFS of 9.6 months (95% CI, 8.3 to not reached) versus 2.8 months (95% CI, 2.1–4.3), respectively [15]. The most common adverse events (AEs) were diarrhoea (47%), skin toxicity (rash/acne 40%), nausea (22%) and decreased appetite (21%), and the majority of these were grade 1 or 2 in severity. The 80 mg daily dose was selected as the recommended dose for further clinical trials based on its optimal therapeutic index [15] (Table 2). Table 2. Efficacy of osimertinib in phase I, phase II and phase III clinical trials as second-line treatment in EGFR-mutant NSCLC patients   AURA ph I [15]  AURA extension (T790M+) [17]  AURA2 (T790M+) [18]  AURA3 (T790M+) Osimertinib versus CT [19]  FL-AURA (EGFR+) Osimertinib versus gefitinib [30]  N  253  201  210  419  556  T790M+: 138  (279 osimertinib and 140 to CT).  (279 osimertinib and 277 gefitinib or erlotinib)  ORR  51%  62%  70%  71% versus 31%, P<0.001  80% versus 76%  T790M+: 61%  T790M−: 21%  PFS  8.2 mo.  12.3 months  9.9  10.1 versus 4.4 months  18.9 versus 10.2 months  T790M+: 9.6 months  Brain M1: 7.1 months  HR 0.30; 95% CI 0.23–0.41  HR 0.46; 95% CI 0.37–0.57  T790M−: 2.8 months  {C4}  P < 0.0001  P < 0.0001    AURA ph I [15]  AURA extension (T790M+) [17]  AURA2 (T790M+) [18]  AURA3 (T790M+) Osimertinib versus CT [19]  FL-AURA (EGFR+) Osimertinib versus gefitinib [30]  N  253  201  210  419  556  T790M+: 138  (279 osimertinib and 140 to CT).  (279 osimertinib and 277 gefitinib or erlotinib)  ORR  51%  62%  70%  71% versus 31%, P<0.001  80% versus 76%  T790M+: 61%  T790M−: 21%  PFS  8.2 mo.  12.3 months  9.9  10.1 versus 4.4 months  18.9 versus 10.2 months  T790M+: 9.6 months  Brain M1: 7.1 months  HR 0.30; 95% CI 0.23–0.41  HR 0.46; 95% CI 0.37–0.57  T790M−: 2.8 months  {C4}  P < 0.0001  P < 0.0001  CT, chemotherapy; ORR, overall response rate; PFS, progression-free survival; HR, hazard ratio; 95% CI, 95% confidence interval. In an updated report of the dose expansion cohort in the AURA trial (NCT01802632) with osimertinib 80 mg daily in patients with centrally confirmed T790M-positive NSCLC, 61 of 63 patients were assessable for response. The ORR was 71% (95% CI, 57–82) and median PFS was 9.7 months (95% CI, 8.3–13.6) [16]. Phase I extension and phase II studies with osimertinib Further confirmation of the efficacy and safety of osimertinib 80 mg daily was provided by the extension part of the AURA study in 201 T790M-positive advanced NSCLC patients [17]. The ORR and DCR was 62% (95% CI, 54–68) and 90% (95% CI, 85–94), respectively. Median PFS was 12.3 months (95% CI, 9.5–15.5), with 12-month PFS and OS of 52% and 79%, respectively (Table 2). Subset PFS analysis did not report differences according to line of therapy, EGFR-mutation subtype, ethnicity or previous exposure to EGFR TKIs. The most common casually related AEs were diarrhoea (43%; grade ≥ 3, <1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (ILD) was reported in 4% of patients (n = 8, grade 3–5 in six patients). Among those patients with asymptomatic and stable brain metastases (n = 74), median PFS was shorter compared with those patients without brain metastases (7.1 versus 13.7 months). In the CNS response analysis set, the ORR was 64% [17], suggesting encouraging results with osimertinib in EGFR-mutant NSCLC patients with brain metastases. The phase II AURA2 trial (NCT02094261) demonstrated similar results [18] (Table 2). The study enrolled 210 T790M-positive metastatic NSCLC patients who had progressed after previous therapy with an approved EGFR TKI. The ORR and DCR were 70% (95% CI 64–77) and 92% (95% CI 87–95), respectively, including patients with CNS metastases. Overall, median PFS was 9.9 months (95% CI, 8.5–12.3), with 6- and 12-month PFS of 71% and 44%, respectively. The most common all-causality grade 3 and 4 AEs were pulmonary embolism (3%), prolonged electrocardiogram QT (2%), decreased neutrophil count (2%), anaemia, dyspnoea, hyponatremia, increased alanine aminotransferase, and thrombocytopenia (1%, each) [18]. A pre-planned pooled analysis of AURA extension [17] and AURA2 trial [18] was carried out and included 411 patients (129 patients at second-line and 282 as third-line or beyond). The ORR was 66% (95% CI, 67–71), with median duration of response of 12.3 months (95% CI, 11.1–13.8). Pooled median PFS and OS were 9.9 and 26.8 months, respectively. At 12 and 24 months, 80% and 56% of patients were alive, respectively. The most common (investigator assessed) possibly causally related AEs were rash [grouped term 42%, (grade 3, 1%)] and diarrhoea [39% (<1%)]. Four patients died due to possibly causally related toxicity [19]. Comparison of osimertinib to chemotherapy The robust efficacy of osimertinib in patients with T790M-mediated AR resulted in accelerated approval by the FDA in November 2015. Recently, the results of the confirmatory phase III study of osimertinib versus platinum-based chemotherapy were reported. The AURA3 (NCT02151981) was an open-label randomized phase III trial in second-line setting [20], comparing osimertinib to platinum plus pemetrexed (up to six cycles and followed by optional pemetrexed maintenance) for patients with centrally confirmed T790M-positive advanced NSCLC after first-line EGFR TKI. The trial enrolled 419 patients with 60% of patients in the chemotherapy arm crossing over to receive osimertinib at progression. Osimertinib significantly improved PFS compared with chemotherapy [10.1 versus 4.4 months, hazard ratio (HR) 0.30; 95% CI, 0.23–0.41, P < 0.0001], and ORR (71% versus 31%, P < 0.001, Table 2). Grade 3 AEs were lower with osimertinib (23% versus 47%). In the osimertinib group, the most common AEs reported were diarrhoea (41%), rash (34%), dry skin (23%) and paronychia (22%). ILD-like AEs were reported in 4% of patients. Data on OS are not yet available [20]. These results clearly demonstrate the efficacy of osimertinib as standard treatment in T790M-positive NSCLC patients after disease progression on a first- or second-generation EGFR TKI. Osimertinib as first-line therapy In EGFR TKI-naive patients, de novo T790M mutations were described with variable frequency, ranging from <1% to 80%, depending on detection method [21–23], and predict for less benefit to reversible EGFR TKIs [24, 25]. Unlike gefitinib or afatinib, chronic treatment with osimertinib did not cause AR in PC-9 cells in vitro through gain of T790M [26]. Therefore, upfront osimertinib therapy for patients with an activating EGFR mutation could avoid this mechanism of resistance, given its superior potency against T790M. In the phase I AURA trial, 60 treatment-naive patients with metastatic EGFR-mutant NSCLC (77% T790M-negative) received upfront osimertinib at 80 mg/day (N = 30) or 160 mg/day (N = 30). According to treatment dose group, 80 and 160 mg, the ORR was 67% and 87% (77% across doses) and PFS was 22.1 and 19.3 months (20.5 months across doses), respectively [27]. These results are encouraging relative to the efficacy of gefitinib or afatinib in the first-line setting [28, 29] and suggest osimertinib as a potential option in the first-line setting, independent of T790M-status. The phase III FLAURA trial (NCT02296125) compared osimertinib to erlotinib or gefitinib (standard of care) as first-line treatment in patients with advanced NSCLC and common EGFR mutations. Patients with stable CNS metastases were allowed. In the control arm, cross-over to osimertinib was allowed in case of disease progression and confirmation of T790M mutation–based resistance. The primary end point of the trial was PFS. Among 556 patients enrolled (∼20% with brain metastases), a significant improvement in PFS (18.9 versus 10.2 months, HR 0.46, P < 0.0001) was reported with osimertinib irrespective of race or EGFR mutation subtype compared with standard of care. Osimertinib also improved the systemic PFS in patients with brain metastases compared with standard of care (15.2 versus 9.6 months, HR 0.47, P = 0.0009). There were no differences in ORR (80% versus 76%), but osimertinib resulted in a two-fold increase in the median duration of response (17.2 versus 8.5 months). OS data were immature but preliminary results showed promising results (HR 0.63, P = 0.00068) in favour of osimertinib, despite the fact that cross-over was allowed. Lower grade ≥3 AEs (34% versus 45%) and a lower discontinuation rate were reported with osimertinib compared with standard of care treatment [30]. These results suggest osimertinib as a new standard in first-line treatment of patients with EGFR-mutant advanced NSCLC. Recently, mechanisms of AR to osimertinib as first-line treatment have been described in cell-free DNA samples from 19 patients included in the phase I AURA trial cohort. Putative genomic resistance mutations were identified in 9 of 19 patients with detectable circulating tumour DNA (ctDNA). There was no evidence of acquired T790M mutation in any plasma ctDNA sample analysed. Two cases of acquired EGFR C797S resistance mutations were detected: one in a patient with a de novo T790M mutation, and one in the absence of T790M. Also, an acquired MEK1 G128V variant, HER2 exon 20 insertion, JAK2 V617F and MET copy number gains have been described as mechanisms of AR with upfront osimertinib [27]. However, no specific treatment strategies have been established at osimertinib resistance. In preclinical models, if the C797S mutation develops in cells wild-type for T790M (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs [31]. Efficacy, toxicity and treatment options after osimertinib resistance may help to define the best strategy for sequencing upfront EGFR TKI in this population. Osimertinib efficacy in central nervous system metastases Globally, the incidence of brain and leptomeningeal metastases among EGFR-mutant NSCLC patients is 31% [32] and ∼9% [33–35], respectively. Erlotinib [36], gefitinib [37] and afatinib [38] have a modest degree of intracranial activity. However, preclinical data demonstrated greater penetration and brain exposure with osimertinib than with gefitinib, rociletinib or afatinib [39]. CNS activity of osimertinib had been reported in the AURA study phase II extension component [17], the phase II AURA2 trial [18], and was recently confirmed in the phase III AURA3 trial. In the phase III AURA3 trial, among 144 patients with stable and asymptomatic brain metastases, PFS was also longer with osimertinib compared with chemotherapy (8.5 versus 4.2 months, HR 0.32; 95% CI, 0.21–0.49) [20]. Among those patients with CNS disease assessable for response (n = 46), CNS ORR was 70% with osimertinib compared with 31% with chemotherapy with a median duration of response of 8.9 versus 5.7 months, respectively. Also, the cumulative incidence of CNS progression at 6 months was lower with osimertinib compared with chemotherapy (11.5% versus 28.2%) [40]. AURA3 confirmed the CNS efficacy of osimertinib, with higher and more durable responses while also delaying the onset of brain metastases in this population. A phase II trial (NCT 02971501) assessed the PFS of osimertinib with or without bevacizumab. Indeed, preliminary results from the phase I (BLOOM) trial have reported long-lasting clinical and radiological activity of osimertinib at 160 mg among 21 EGFR TKI pre-treated EGFR-mutant NSCLC patients with leptomeningeal metastases (cytologically confirmed) and controlled extracranial disease. Baseline T790M mutation was detected in cerebrospinal fluid in two patients and in plasma in six [41]. The ongoing phase II (BLOOM) study (NCT02228369) is enrolling T790M-positive (tested in plasma or tissue) NSCLC patients with leptomeningeal disease. Globally, these results endorse the efficacy of osimertinib in cerebral nervous system metastases among T790M-positive NSCLC patients. T790M detection in plasma ctDNA in osimertinib studies Liquid biopsies based on ctDNA analysis have been described as surrogate samples for molecular analysis replacing molecular analysis of tumour tissue [42] and may allow real-time sampling of multifocal clonal evolution [43, 44]. Also, ctDNA analysis can be used to monitor clonal evolution [45] and identify mechanisms of AR to treatment [44]. Retrospective exploratory analyses have reported that acquired T790M mutations (tested by cobas EGFR Mutation Testv2) among EGFR-mutant NSCLC patients was detected in 50% of patients, in concordance with tumour biopsy–derived genotyping which was 61% [46]. Among patients with sufficient material for concurrent ctDNA and tumour-derived genotyping, ctDNA identified the T790M mutation in 5 of 25 (20%) patients in whom the concurrent tissue biopsy was negative [46]. Recently, the cobas plasma EGFR Mutation Testv2 detected the T790M mutation in 61% of tumour tissue T790M mutation–positive patients from AURA extension and AURA phase II trials [47]. New techniques are being developed to increase the sensitivity of detecting EGFR sensitizing and resistance EGFR-mutations [48]. A retrospective analysis from the AURA I trial demonstrated that patients who were T790M positive in plasma had outcomes with osimertinib that were equivalent in RR and PFS to patients found to be positive by a tissue-based assay. Indeed, T790M was detected in plasma in 31% of T790M-negative tumours [49]. In the AURA3 trial, patients with T790M-positive status on both tumour and plasma analysis (n = 172) had an RR of 77% with osimertinib, and median PFS with osimertinib was 8.2 months compared with 4.2 with chemotherapy (HR 0.42, 95% CI, 0.29–0.61), an outcome improvement similar to that in the intent-to-treat population [20]. However, all these data are retrospective and in a population with a known T790M status in the tumour. Prospective validation of liquid biopsy as a surrogate marker for making treatment decisions has started to emerge. Recently, in a cohort of heavily pretreated EGFR-mutant NSCLC patients with progression and unknown T790M status in the tumour were prospectively treated on the basis of the ctDNA analysis. Those patients with T790M positivity in plasma achieved an ORR of 62.5% and 6-month PFS of 66.7%, similar to those patients treated on the basis of tissue analysis [50]. Interestingly, responses were also seen in patients with very low allele fractions of T790M mutation in plasma (<0.5%) [50]. Liquid biopsies also have the potential to function as dynamic surrogate markers of treatment efficacy. Clearance of plasma EGFR mutations after 6 weeks of osimertinib therapy was found to be associated with improved RR (70% versus 35%) and median PFS (10.9 versus 5.5 months) among 143 patients with T790M-positive NSCLC included in the phase I AURA trial (NCT01802632) [51]. These results support the feasibility of detecting T790M from plasma ctDNA samples for making treatment decisions and evaluating efficacy. Additionally, a recent algorithm for plasma and tissue T790M testing in patients with AR has been proposed, suggesting that those patients with a negative plasma result should undergo a tissue test [49, 52]. At the present time, EMA and FDA have accepted the use of information from ctDNA analysis to help to select EGFR-mutant NSCLC patients for osimertinib [9, 10]. Future directions Optimal sequence of TKIs As therapeutic options for this patient population, the issue of optimal sequencing of available agents is still an important question. Moreover, it is unknown whether switching treatment according to molecular progression (i.e. ctDNA T790M mutation positivity without RECIST progression) instead of RECIST progression could have an impact on treatment outcomes. Based on the predictive value of liquid biopsies, the three-arm phase II APPLE trial (NCT02856893) [53] in treatment-naive and common EGFR mutation NSCLC patients will explore upfront osimertinib, upfront gefitinib switching to osimertinib in case of T790M-positivity in plasma and upfront gefitinib and switching to osimertinib according to RECIST criteria regardless of T790M status. The primary end point of the trial is 18-month PFS on osimertinib for assessing whether liquid biopsies could become the new standard procedure for defining disease progression versus RECIST progression in this population and also assessing whether a sequenced strategy is more appropriate than upfront osimertinib. Dual vascular endothelial growth factor receptor and EGFR blockade inhibit tumour growth in EGFR TKI resistance xenograft models [54]. Two phase II clinical trials have reported improvement in outcome with erlotinib plus bevacizumab combination as first-line treatment in EGFR-mutant NSCLC patients [55, 56]. Combination of osimertinib and bevacizumab as first-line strategy is being tested in a phase I/II clinical trial (NCT02803203) and osimertinib and ramucirumab as a second-line strategy among T790M-positive tumours in a phase I clinical trial (NCT02789345). Osimertinib in the adjuvant setting The role of EGFR TKIs in patients with early NSCLC has not been defined [57, 58]. Following surgical resection, adjuvant platinum-based chemotherapy remains the standard of care, even for patients with an activating EGFR mutation. The ADAURA trial (NCT02511106) is a double-blind, randomized, placebo-controlled trial that will study the efficacy of osimertinib in 700 completely resected EGFR-mutant stage IB–IIIA NSCLC patients after adjuvant chemotherapy. The primary end point of the study is disease-free survival. The study is presently accruing patients. Osimertinib and immune checkpoint inhibitors Immune checkpoint inhibitors are considered the standard second-line treatment in advanced NSCLC patients based on survival improvement reported in four randomized phase III clinical trials [59–62]. Recently, another phase III trial has reported significant improvement in PFS and ORR with pembrolizumab as first-line treatment compared with standard platinum-based chemotherapy among tumours with high PD-L1 expression (≥ 50%) [63]. However, a recent meta-analysis has reported lack of survival benefit with these agents among EGFR-mutant tumours [64] and a retrospective study has reported lower RR with immune checkpoint inhibitors in EGFR-mutant versus EGFR-wild-type NSCLC patients [65]. The lack of association with smoking and the limited mutational tumour burden of EGFR-mutant tumours [66, 67] may explain the lack of efficacy among this population. Preclinical data have reported T790M-positive tumours as immunogenic [68], and tumours with AR to EGFR TKIs express higher levels of PD-L1 than sensitive tumours [69]. However, in the clinic, T790M mutation correlates with lower PD-L1 expression and PD-L1 expression was a negative prognostic factor [70]. EGFR-mutant NSCLC patients and T790M-negative tumours were more likely to benefit from nivolumab after EGFR-TKI treatment, probably as a result of higher PD-L1 expression than is present in T790M-positive patients [71]. Other trials testing the combination of osimertinib and immune checkpoint inhibitors, such as the phase III CAURAL trial (NCT02454933) and the multi-arm phase IB TATTON trial (NCT02143466) investigating osimertinib (80 mg/d) in combination with durvalumab (anti-PD-L1 monoclonal antibody), were stopped for safety concerns regarding increased incidence of ILD. Exploratory analysis from the TATTON trial (n = 34) reported encouraging clinical activity with RR of 67% in 9 patients with T790M-positive tumours compared with 21% in 14 T790M-negative NSCLC. ILD was reported in 38% of patients, which is higher than would be expected with either drug alone, including five patients (15%) with grade 3–4 events [72]. Results from the other two arms in the TATTON trial (osimertinib plus selumetinib and osimertinib plus AZD6094) are awaited. Other third-generation EGFR TKIs Rociletinib and olmutinib are other third-generation TKIs in development. Rociletinib has demonstrated promising results with a 59% ORR for patients with an activating EGFR mutation and the T790M mutation. However, updated data decreased the observed ORR to 28–34% [73]. This decrease, along with toxicity issues such as hyperglycaemia, led to halting of the clinical development of rociletinib. Olmutinib also demonstrated initial successes with ORR of 56% and median PFS of 8.3 months in T790M-positive NSCLC patients [74]. While it was initially approved in South Korea, its clinical development is currently uncertain, as two cases of toxic epidermal necrolysis and one case of Stevens–Johnson syndrome have been reported. However, there are several other third-generation EGFR TKIs currently in clinical development. Avitinib is a third-generation irreversible EGFR TKI that targets both EGFR activating mutations as well as the T790M mutations. Enrolment is currently ongoing in a phase I trial for patients who progress on a first-generation EGFR TKI, with or without the T790M mutation. Overall, the drug has been well tolerated and ORR for 48 assessable patients was 41.7% with a DCR of 87.9% [75]. The drug ASP8273 is also an irreversible EGFR TKI that targets the T790M mutation. Preliminary results from the phase I study have been reported; 60 patients have been enrolled and no dose-limiting toxicities were noted. ORR is 36% and the median PFS is 6.7 months [76]. However, the phase III SOLAR trial (NCT02588261) comparing ASP8273 with erlotinib or gefitinib as first-line treatment in EGFR-mutant NSCLC patients has been discontinued and no further development programs for ASP8273 have been announced. The phase I with the EGFR TKI EGF816 enrolled 127 patients with a T790M mutation that could be evaluated for response, with an ORR of 44% and estimated PFS of 9.2 months [77]. Finally, the EGFR TKIs PF-06747775 and AZD3759 are at an early stage in clinical development. Interestingly, AZD3739 was specifically designed to penetrate the blood–brain barrier, as CNS metastasis is a common location of progression for EGFR patients. The early data are promising for this patient population, with 40% of patients demonstrating CNS tumour shrinkage [78]. Further studies are ongoing for these drugs and will potentially increase the therapeutic options. Discussion Conclusion Osimertinib is the first FDA and EMA approved third-generation EGFR TKI and has proven to be both well-tolerated and effective in patients with the acquired T790M resistance mutation, significantly improving the treatment options for this disease. The results of the FLAURA study support the use of osimertinib as first-line therapy and represent a new standard for this patient population. Further research into how to improve on these findings are currently under way, including combining osimertinib with other drugs, examining its use in adjuvant settings and furthering research into resistance mechanisms. The development of osimertinib has clearly improved the therapeutic landscape for EGFR-mutant NSCLC and presents exciting opportunities for clinicians and patients. Funding AstraZeneca has provided a sponsorship grant towards this independent publication. Disclosure Professor Vansteenkiste has acted as a consultant for Merck-Serono, GSK-Bio, and Lilly Oncology. key message Osimertinib was the first third-generation EGFR TKI to receive FDA and EMA approval for metastatic EGFR-mutant NSCLC patients that have acquired the EGFR T790M resistance mutation. Additional clinically relevant questions in this patient population, such as the efficacy of osimertinib in patients with brain metastases, role of liquid biopsies, and combination with immune checkpoint inhibitors are being studied. References 1 Reguart N, Remon J. Common EGFR-mutated subgroups (Del19/L858R) in advanced non-small-cell lung cancer: chasing better outcomes with tyrosine-kinase inhibitors. Future Oncol  2015; 1– 13. 2 Shi YK, Wang L, Han BH et al.   First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol  2017; 28( 10): 2443– 2450. Google Scholar CrossRef Search ADS PubMed  3 Sequist LV, Waltman BA, Dias-Santagata D et al.   Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med  2011; 3( 75): 75ra26. Google Scholar CrossRef Search ADS PubMed  4 Yun C-H, Mengwasser KE, Toms AV et al.   The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A  2008; 105( 6): 2070– 2075. Google Scholar CrossRef Search ADS PubMed  5 Yu HA, Arcila ME, Rekhtman N et al.   Analysis of tumour specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res  2013; 19( 8): 2240– 2247. Google Scholar CrossRef Search ADS PubMed  6 Engelman JA, Zejnullahu K, Mitsudomi T et al.   MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science  2007; 316( 5827): 1039– 1043. Google Scholar CrossRef Search ADS PubMed  7 Bean J, Brennan C, Shih J-Y et al.   MET amplification occurs with or without T790M mutations in EGFR mutant lung tumours with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A  2007; 104( 52): 20932– 20937. Google Scholar CrossRef Search ADS PubMed  8 Lee J-K, Lee J, Kim S et al.   Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol  2017; 35( 26): 3065– 3074. Google Scholar CrossRef Search ADS PubMed  9 http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. 10 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004124/WC500202022.pdf. 11 Cross DAE, Ashton SE, Ghiorghiu S et al.   AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov  2014; 4( 9): 1046– 1061. Google Scholar CrossRef Search ADS PubMed  12 Finlay MRV, Anderton M, Ashton S et al.   Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem  2014; 57( 20): 8249– 8267. Google Scholar CrossRef Search ADS PubMed  13 Planchard D, Brown KH, Kim D-W et al.   Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother Pharmacol  2016; 77( 4): 767– 776. Google Scholar CrossRef Search ADS PubMed  14 Vishwanathan K, Dickinson P, Bui K et al.   Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291. Mole Cancer Ther  2015; 14(12 Suppl 2): B153. doi: 10.1158/1535-7163.TARG-15-B153. Google Scholar CrossRef Search ADS   15 Jänne PA, Yang JC-H, Kim D-W et al.   AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med  2015; 372( 18): 1689– 1699. Google Scholar CrossRef Search ADS PubMed  16 Yang J, Ramalingam SS, Jänne PA et al.   LBA2_PR: osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results. J Thorac Oncol  2016; 11( 4): S152– S153. Google Scholar CrossRef Search ADS   17 Yang JC-H, Ahn M-J, Kim D-W et al.   Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA Study Phase II Extension Component. J Clin Oncol  2017; 35( 12): 1288– 1296. Google Scholar CrossRef Search ADS PubMed  18 Goss G, Tsai C-M, Shepherd FA et al.   Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol  2016; 17( 12): 1643– 1652. Google Scholar CrossRef Search ADS PubMed  19 Mitsudomi T, Ahn MJ, Bazhenova L et al.   Overall survival (OS) in patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) treated with osimertinib: Results from two phase II studies. AnnOncol  2017; 28(Suppl 5). https://doi.org/10.1093/annonc/mdx380.050. 20 Mok TS, Wu Y-L, Ahn M-J et al.   Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med  2017; 376( 7): 629– 640. Google Scholar CrossRef Search ADS PubMed  21 Rosell R, Molina MA, Costa C et al.   Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res  2011; 17( 5): 1160– 1168. Google Scholar CrossRef Search ADS PubMed  22 Watanabe M, Kawaguchi T, Isa S-I et al.   Ultra-sensitive detection of the pretreatment EGFR t790m mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res  2015; 21( 15): 3552– 3560. Google Scholar CrossRef Search ADS PubMed  23 Yu HA, Arcila ME, Hellmann MD et al.   Poor response to erlotinib in patients with tumours containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol  2014; 25( 2): 423– 428. Google Scholar CrossRef Search ADS PubMed  24 Ding D, Yu Y, Li Z et al.   The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Onco Targets Ther  2014; 7: 387– 393. Google Scholar PubMed  25 Costa C, Molina MA, Drozdowskyj A et al.   The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res  2014; 20( 7): 2001– 2010. Google Scholar CrossRef Search ADS PubMed  26 Eberlein CA, Stetson D, Markovets AA et al.   Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res  2015; 75( 12): 2489– 2500. Google Scholar CrossRef Search ADS PubMed  27 Ramalingam SS, Yang JC-H, Lee CK et al.   Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol  2017; JCO2017747576. 28 Mok TS, Wu Y-L, Thongprasert S et al.   Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med  2009; 361( 10): 947– 957. Google Scholar CrossRef Search ADS PubMed  29 Sequist LV, Yang JC-H, Yamamoto N et al.   Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol  2013; 31( 27): 3327– 3334. Google Scholar CrossRef Search ADS PubMed  30 Ramalingam S, Reungwetwattana T, Chewaskulyong B et al.   Osimertinib versus standard of care EGFT KI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA. Ann Oncol  2017; 28(Suppl_5): LBA2_PR. 31 Niederst MJ, Hu H, Mulvey HE et al.   The allelic context of the C797S mutation acquired upon treatment with third generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res  2015; 21( 17): 3924– 3933. Google Scholar CrossRef Search ADS PubMed  32 Iuchi T, Shingyoji M, Itakura M et al.   Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol  2015; 20( 4): 674– 679. Google Scholar CrossRef Search ADS PubMed  33 Liao B-C, Lee J-H, Lin C-C et al.   Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol  2015; 10( 12): 1754– 1761. Google Scholar CrossRef Search ADS PubMed  34 Kuiper JL, Hendriks LE, van der Wekken AJ et al.   Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer  2015; 89( 3): 255– 261. Google Scholar CrossRef Search ADS PubMed  35 Li Y-S, Jiang B-Y, Yang J-J et al.   Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol  2016; 11( 11): 1962– 1969. Google Scholar CrossRef Search ADS PubMed  36 Porta R, Sánchez-Torres JM, Paz-Ares L et al.   Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J  2011; 37( 3): 624– 631. Google Scholar CrossRef Search ADS PubMed  37 Park K, Tan E-H, O'Byrne K et al.   Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol  2016; 17( 5): 577– 589. Google Scholar CrossRef Search ADS PubMed  38 Schuler M, Wu Y-L, Hirsh V et al.   First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol  2016; 11( 3): 380– 390. Google Scholar CrossRef Search ADS PubMed  39 Ballard P, Yates JW, Yang Z et al.   Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res  2016; 22( 20): 5130– 5140. Google Scholar CrossRef Search ADS PubMed  40 Mok T, Ahn M-J, Han J-Y et al.   CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: data from a randomized phase III trial (AURA3). Jco  2017; 35(15_Suppl): 9005– 9005. 41 Yang JC-H, Kim D-W, Kim S-W et al.   Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a phase I study. ASCO Meeting Abstracts  2016; 34(15_Suppl): 9002. 42 Jovelet C, Ileana E, Le Deley M-C et al.   Circulating cell-free tumour DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO trial. Clin Cancer Res  2016; 22( 12): 2960– 2968. Google Scholar CrossRef Search ADS PubMed  43 Murtaza M, Dawson S-J, Pogrebniak K et al.   Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Comms  2015; 6: 8760. Google Scholar CrossRef Search ADS   44 Wan JCM, Massie C, Garcia-Corbacho J et al.   Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer  2017; 17( 4): 223. doi: 10.1038/nrc.2017.7. Google Scholar CrossRef Search ADS PubMed  45 Iwama E, Sakai K, Azuma K et al.   Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations. Ann Oncol  2017; 28( 1): 136– 141. Google Scholar PubMed  46 Sundaresan TK, Sequist LV, Heymach JV et al.   Detection of T790M, the acquired resistance EGFR mutation, by tumour biopsy versus noninvasive blood-based analyses. Clin Cancer Res  2016; 22( 5): 1103– 1110. Google Scholar CrossRef Search ADS PubMed  47 Jenkins S, Yang JC-H, Ramalingam SS et al.   Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol  2017; 12( 7): 1061– 1070. Google Scholar CrossRef Search ADS PubMed  48 Jovelet C, Madic J, Remon J et al.   Crystal digital droplet PCR for detection and quantification of circulating EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer. PLoS One  2017; 12( 8): e0183319. Google Scholar CrossRef Search ADS PubMed  49 Oxnard GR, Thress KS, Alden RS et al.   Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol  2016; 34( 28): 3375– 3382. Google Scholar CrossRef Search ADS PubMed  50 Remon J, Caramella C, Jovelet C et al.   Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol  2017; doi: 10.1093/annonc/mdx017. 51 Thress KS, Markovets A, Barrett JC et al.   Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial. Jco  2017; 35(15_Suppl): 9018– 9018. 52 Jenkins S, Yang C-H, Ramalingam SS et al.   Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol  2017; doi: 10.1016/j.jtho.2017.04.003. 53 Remon J, Menis J, Hasan B et al.   The APPLE trial: feasibility and activity of AZD9291 (Osimertinib) treatment on positive PLASMA T790M in EGFR-mutant NSCLC patients. EORTC 1613. Clin Lung Cancer  2017; 28( 4): 784– 790. 54 Naumov GN, Nilsson MB, Cascone T et al.   Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumour growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res  2009; 15( 10): 3484– 3494. Google Scholar CrossRef Search ADS PubMed  55 Seto T, Kato T, Nishio M et al.   Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol  2014; 15( 11): 1236– 1244. Google Scholar CrossRef Search ADS PubMed  56 Rosell R, Dafni U, Felip E et al.   Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med  2017; 5( 5): 435– 444. Google Scholar CrossRef Search ADS PubMed  57 Goss GD, O'Callaghan C, Lorimer I et al.   Gefitinib versus placebo in completely resected non–small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol  2013; 31( 27): 3320– 3326. Google Scholar CrossRef Search ADS PubMed  58 Kelly K, Altorki NK, Eberhardt WEE et al.   Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol  2015; 33( 34): 4007– 4014. Google Scholar CrossRef Search ADS PubMed  59 Brahmer J, Reckamp KL, Baas P et al.   Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med  2015; 373( 2): 123– 135. Google Scholar CrossRef Search ADS PubMed  60 Borghaei H, Paz-Ares L, Horn L et al.   Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med  2015; 373( 17): 1627– 1639. Google Scholar CrossRef Search ADS PubMed  61 Herbst RS, Baas P, Kim D-W et al.   Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet  2016; 387( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  62 Rittmeyer A, Barlesi F, Waterkamp D et al.   Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet  2017; 389( 10066): 255– 265. Google Scholar CrossRef Search ADS PubMed  63 Reck M, Rodríguez-Abreu D, Robinson AG et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  64 Lee CK, Man J, Lord S et al.   Checkpoint inhibitors in metastatic egfr-mutated non-small cell lung cancer—a meta-analysis. J Thorac Oncol  2017; 12( 2): 403– 407. Google Scholar CrossRef Search ADS PubMed  65 Gainor JF, Shaw AT, Sequist LV et al.   EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res  2016; 22( 18): 4585– 4593. Google Scholar CrossRef Search ADS PubMed  66 Rizvi NA, Hellmann MD, Snyder A et al.   Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science  2015; 348( 6230): 124– 128. Google Scholar CrossRef Search ADS PubMed  67 Spigel D, Schrock A, Fabrizio D et al.   Total mutation burden (TMB) in lung cancer and relationship with response to PD-1/PD-L1 targeted therapies. J Clin Oncol  2016; 34(Suppl): abstr 9017. 68 Ofuji K, Tada Y, Yoshikawa T et al.   A peptide antigen derived from EGFR T790M is immunogenic in non-small cell lung cancer. Int J Oncol  2015; 46( 2): 497– 504. Google Scholar CrossRef Search ADS PubMed  69 Lin K, Cheng J, Yang T et al.   EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB. Biochem Biophys Res Commun  2015; 463( 1–2): 95– 101. Google Scholar CrossRef Search ADS PubMed  70 Hata A, Katakami N, Nanjo S et al.   Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer. Lung Cancer  2017; 111: 182– 189. Google Scholar CrossRef Search ADS PubMed  71 Haratani K, Hayashi H, Tanaka T et al.   Tumour immune microenvironment and nivolumab efficacy in egfr mutation-positive non-small cell lung cancer based on T790m status after disease progression during EGFR-TKI treatment. Ann Oncol  2017; 28( 7): 1532– 1539. Google Scholar CrossRef Search ADS PubMed  72 Ahn M, Yang J, Yu H, et al.   Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. Elcc  2016; Abstract 136O. 73 Sequist LV, Soria J-C, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med  2016; 374( 23): 2296– 2297. Google Scholar CrossRef Search ADS PubMed  74 Park K, Lee J-S, Lee KH et al.   BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: efficacy and safety at the RP2D. ASCO Meeting Abstracts  2016; 34(15_Suppl): 9055. 75 Zhang L, Zhao H, Hu B et al.   First-in-human study of AC0010, a novel irreversible, mutant-selective EGFR inhibitor in patients with 1st generation EGFR TKI-resistant non-small cell lung cancer (NSCLC). Ann Oncol  2016; 27(Suppl_6): 3590. 76 Yu HA, Spira AI, Horn L et al.   Antitumour activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: Interim results from an ongoing phase 1 study. J Clin Oncol  2016; 34( Suppl 15): 9050– 9050. 77 Tan DS-W, Yang JC-H, Leighl NB et al.   Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M. J Clin Oncol  2016. 78 Ahn M-J, Kim D-W, Kim TM et al.   Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). ASCO Meeting Abstracts  2016; 34(15_Suppl): 9003. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients

Loading next page...
 
/lp/ou_press/osimertinib-and-other-third-generation-egfr-tki-in-egfr-mutant-nsclc-P5NdwqChMi
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx704
Publisher site
See Article on Publisher Site

Abstract

Abstract Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC. osimertinib, EGFR TKI, acquired resistance, NSCLC Introduction Activating epidermal growth factor receptor (EGFR) mutations predict sensitivity to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, icotinib and afatinib with higher overall response rate (ORR) and progression-free survival (PFS) compared with upfront platinum doublet chemotherapy, making them the standard of care [1, 2]. However, tumours invariably develop acquired resistance (AR) ∼9–12 months after treatment initiation [1]. Several mechanisms of AR have been reported, such as secondary EGFR mutations, bypass track signalling pathways and histologic transformation [3]. The substitution of threonine to methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene reduces first-generation EGFR TKIs binding by enhancing the ATP binding affinity of the kinase domain of the EGFR-mutant receptor [4]. This mutation accounts for AR in ∼50%–60% of the patients [3, 5]. MET amplification is the second most common mechanism of AR to EGFR TKIs in up to 20% of cases [6] irrespective of the T790M mutational status [7]. Histologic transformation to small-cell lung cancer (SCLC) accounts for 5%–10% of EGFR-mutant tumours with AR. Those EGFR mutant tumours harbouring completely inactivated Rb and p53 have a 43 times greater risk of small-cell transformation [8]. These transformed SCLC tumours express neuroendocrine markers, maintain the original EGFR-sensitizing mutation and respond to standard SCLC chemotherapy [3]. Knowledge of AR mechanisms to EGFR TKIs was one of the triggers behind the development of third-generation EGFR-TKIs, which are active against exon 19 and 21 mutations as well as the T790M mutation. Among them, osimertinib (AZD9291) was the first to receive FDA and EMA approval in November 2015 and February 2016, respectively, for metastatic EGFR-mutant and acquired EGFR T790M mutation–positive non-small-cell lung cancer (NSCLC) patients [9, 10] progressing on or after EGFR TKI therapy. This article provides an overview of preclinical and clinical data on osimertinib and other third-generation EGFR TKIs currently in development. The potential use of osimertinib in the adjuvant setting and the combination of EGFR TKIs with immune checkpoint inhibitors in resistant EGFR-mutation NSCLC patients will be also reviewed. Osimertinib Osimertinib is a mono-anilino-pyrimidine compound that specifically binds to the EGFR kinase domain irreversibly by targeting the cysteine-797 residue in the ATP binding site via covalent bond formation. In cell lines, osimertinib potently inhibited phosphorylation of EGFR in PC-9 (Del19) and H3255 (L858R) cell lines with mean IC50 values ranging from 13 to 54 nmol/l. In H1975 (L858R/T790M) and PC-9 VanR (Del19/T790M) resistant cell lines, activity of osimertinib was reported with mean IC50 potency of <15 nmol/l (Table 1) [11]. Osimertinib is more selective to the mutated receptor as evidenced by a high IC50 (range from 480 to 1865 nmol/l) in inhibiting phosphorylation of EGFR in wild-type cell lines. Interestingly, osimertinib was not potent against lines harbouring non-T790M resistance mechanisms, such as MET amplification or NRAS [11]. Table 1. IC50 values in different EGFR mutant T790M resistant cancer cell lines treated with reversible (gefitinib, erlotinib) and irreversible (afatinib, dacomitinib, osimertinib) tyrosine kinase inhibitors (adapted from Cross [9])   H1975  PC-9VanR  PC-9  H3255  EGFR  (L858R/T790M)  (Del19/T790M)  (Del19)  (L858R)a  WT  Osimertinib  15  6  17  49–60  480  Dacomitinib  40  6  0.7  1.2–1.3  12  Afatinib  22  3  0.6  0.8–1  15  Gefitinib  3102  741  7  11–12  59  Erlotinib  6073  1262  6  8–11  91    H1975  PC-9VanR  PC-9  H3255  EGFR  (L858R/T790M)  (Del19/T790M)  (Del19)  (L858R)a  WT  Osimertinib  15  6  17  49–60  480  Dacomitinib  40  6  0.7  1.2–1.3  12  Afatinib  22  3  0.6  0.8–1  15  Gefitinib  3102  741  7  11–12  59  Erlotinib  6073  1262  6  8–11  91  a 95% confidence interval. WT, wild type. Osimertinib is metabolized to produce at least two circulating metabolites, AZD5104 and AZD7550. In biochemical assays, AZD7550 had a comparable potency and selectivity profile to osimertinib, although AZD5104 showed greater potency against EGFR Del19, T790M mutations (both ∼8-fold) and wild-type EGFR (∼15-fold) [11]. In tumour xenograft and transgenic mouse models harbouring sensitizing and resistance EGFR mutations, osimertinib exposure resulted in a profound and sustained tumour regression [11]. Due to the higher selectivity to the mutated receptor, osimertinib is associated with less severe gastrointestinal and skin toxicity compared with first- or second-generation EGFR TKIs [12]. Mean half-life of osimertinib is 48.3 h with minimal food effect on exposure and no differences according to ethnicity (Asian and Non-Asian), body weight, sex or age [13]. Additionally, data from a pharmacokinetic study (NCT02163733) showed that administration of omeprazole does not have an effect on osimertinib exposure [14]. Clinical activity with osimertinib Phase I experience A phase I/II dose escalation study of osimertinib (AURA, NCT01802632) was carried out in patients with locally advanced or metastatic EGFR-mutant NSCLC patients who had disease progression on previous treatment with an EGFR TKI [15]. The study included dose-escalation and dose-expansion cohorts. Patients were only preselected according to T790M status in the expansion cohort. Sequential cohorts of patients (N = 253) received five dose levels of osimertinib ranging from 20 to 240 mg daily. Among 31 patients in the dose-escalation cohort, no dose-limiting toxicity was observed and the maximum tolerated dose was not reached. An additional 222 patients were treated in five dose-expansion cohorts. The T790M was detected in 138 patients (62%), not detected in 62 patients (28%), and of unknown status in 22 patients (10%) [15]. Of the 253 patients treated across all dose levels, 239 were assessable for response. The ORR and disease control rate (DCR) in the whole population were 51% [95% confidence interval (CI), 45–58] and 84% (95% CI, 79–88), respectively, without differences according to ethnicity. The median PFS was 8.2 months. Among the 138 patients with centrally confirmed T790M mutations, 127 patients were assessable for response. Outcomes were substantiality better in T790M-positive tumours compared with T790M-negative tumours, with an ORR of 61% (95% CI, 52–70) versus 21% (95% CI, 12–34), a DCR of 95% (95% CI, 90–98) versus 61% (95% CI, 47–73) and median PFS of 9.6 months (95% CI, 8.3 to not reached) versus 2.8 months (95% CI, 2.1–4.3), respectively [15]. The most common adverse events (AEs) were diarrhoea (47%), skin toxicity (rash/acne 40%), nausea (22%) and decreased appetite (21%), and the majority of these were grade 1 or 2 in severity. The 80 mg daily dose was selected as the recommended dose for further clinical trials based on its optimal therapeutic index [15] (Table 2). Table 2. Efficacy of osimertinib in phase I, phase II and phase III clinical trials as second-line treatment in EGFR-mutant NSCLC patients   AURA ph I [15]  AURA extension (T790M+) [17]  AURA2 (T790M+) [18]  AURA3 (T790M+) Osimertinib versus CT [19]  FL-AURA (EGFR+) Osimertinib versus gefitinib [30]  N  253  201  210  419  556  T790M+: 138  (279 osimertinib and 140 to CT).  (279 osimertinib and 277 gefitinib or erlotinib)  ORR  51%  62%  70%  71% versus 31%, P<0.001  80% versus 76%  T790M+: 61%  T790M−: 21%  PFS  8.2 mo.  12.3 months  9.9  10.1 versus 4.4 months  18.9 versus 10.2 months  T790M+: 9.6 months  Brain M1: 7.1 months  HR 0.30; 95% CI 0.23–0.41  HR 0.46; 95% CI 0.37–0.57  T790M−: 2.8 months  {C4}  P < 0.0001  P < 0.0001    AURA ph I [15]  AURA extension (T790M+) [17]  AURA2 (T790M+) [18]  AURA3 (T790M+) Osimertinib versus CT [19]  FL-AURA (EGFR+) Osimertinib versus gefitinib [30]  N  253  201  210  419  556  T790M+: 138  (279 osimertinib and 140 to CT).  (279 osimertinib and 277 gefitinib or erlotinib)  ORR  51%  62%  70%  71% versus 31%, P<0.001  80% versus 76%  T790M+: 61%  T790M−: 21%  PFS  8.2 mo.  12.3 months  9.9  10.1 versus 4.4 months  18.9 versus 10.2 months  T790M+: 9.6 months  Brain M1: 7.1 months  HR 0.30; 95% CI 0.23–0.41  HR 0.46; 95% CI 0.37–0.57  T790M−: 2.8 months  {C4}  P < 0.0001  P < 0.0001  CT, chemotherapy; ORR, overall response rate; PFS, progression-free survival; HR, hazard ratio; 95% CI, 95% confidence interval. In an updated report of the dose expansion cohort in the AURA trial (NCT01802632) with osimertinib 80 mg daily in patients with centrally confirmed T790M-positive NSCLC, 61 of 63 patients were assessable for response. The ORR was 71% (95% CI, 57–82) and median PFS was 9.7 months (95% CI, 8.3–13.6) [16]. Phase I extension and phase II studies with osimertinib Further confirmation of the efficacy and safety of osimertinib 80 mg daily was provided by the extension part of the AURA study in 201 T790M-positive advanced NSCLC patients [17]. The ORR and DCR was 62% (95% CI, 54–68) and 90% (95% CI, 85–94), respectively. Median PFS was 12.3 months (95% CI, 9.5–15.5), with 12-month PFS and OS of 52% and 79%, respectively (Table 2). Subset PFS analysis did not report differences according to line of therapy, EGFR-mutation subtype, ethnicity or previous exposure to EGFR TKIs. The most common casually related AEs were diarrhoea (43%; grade ≥ 3, <1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (ILD) was reported in 4% of patients (n = 8, grade 3–5 in six patients). Among those patients with asymptomatic and stable brain metastases (n = 74), median PFS was shorter compared with those patients without brain metastases (7.1 versus 13.7 months). In the CNS response analysis set, the ORR was 64% [17], suggesting encouraging results with osimertinib in EGFR-mutant NSCLC patients with brain metastases. The phase II AURA2 trial (NCT02094261) demonstrated similar results [18] (Table 2). The study enrolled 210 T790M-positive metastatic NSCLC patients who had progressed after previous therapy with an approved EGFR TKI. The ORR and DCR were 70% (95% CI 64–77) and 92% (95% CI 87–95), respectively, including patients with CNS metastases. Overall, median PFS was 9.9 months (95% CI, 8.5–12.3), with 6- and 12-month PFS of 71% and 44%, respectively. The most common all-causality grade 3 and 4 AEs were pulmonary embolism (3%), prolonged electrocardiogram QT (2%), decreased neutrophil count (2%), anaemia, dyspnoea, hyponatremia, increased alanine aminotransferase, and thrombocytopenia (1%, each) [18]. A pre-planned pooled analysis of AURA extension [17] and AURA2 trial [18] was carried out and included 411 patients (129 patients at second-line and 282 as third-line or beyond). The ORR was 66% (95% CI, 67–71), with median duration of response of 12.3 months (95% CI, 11.1–13.8). Pooled median PFS and OS were 9.9 and 26.8 months, respectively. At 12 and 24 months, 80% and 56% of patients were alive, respectively. The most common (investigator assessed) possibly causally related AEs were rash [grouped term 42%, (grade 3, 1%)] and diarrhoea [39% (<1%)]. Four patients died due to possibly causally related toxicity [19]. Comparison of osimertinib to chemotherapy The robust efficacy of osimertinib in patients with T790M-mediated AR resulted in accelerated approval by the FDA in November 2015. Recently, the results of the confirmatory phase III study of osimertinib versus platinum-based chemotherapy were reported. The AURA3 (NCT02151981) was an open-label randomized phase III trial in second-line setting [20], comparing osimertinib to platinum plus pemetrexed (up to six cycles and followed by optional pemetrexed maintenance) for patients with centrally confirmed T790M-positive advanced NSCLC after first-line EGFR TKI. The trial enrolled 419 patients with 60% of patients in the chemotherapy arm crossing over to receive osimertinib at progression. Osimertinib significantly improved PFS compared with chemotherapy [10.1 versus 4.4 months, hazard ratio (HR) 0.30; 95% CI, 0.23–0.41, P < 0.0001], and ORR (71% versus 31%, P < 0.001, Table 2). Grade 3 AEs were lower with osimertinib (23% versus 47%). In the osimertinib group, the most common AEs reported were diarrhoea (41%), rash (34%), dry skin (23%) and paronychia (22%). ILD-like AEs were reported in 4% of patients. Data on OS are not yet available [20]. These results clearly demonstrate the efficacy of osimertinib as standard treatment in T790M-positive NSCLC patients after disease progression on a first- or second-generation EGFR TKI. Osimertinib as first-line therapy In EGFR TKI-naive patients, de novo T790M mutations were described with variable frequency, ranging from <1% to 80%, depending on detection method [21–23], and predict for less benefit to reversible EGFR TKIs [24, 25]. Unlike gefitinib or afatinib, chronic treatment with osimertinib did not cause AR in PC-9 cells in vitro through gain of T790M [26]. Therefore, upfront osimertinib therapy for patients with an activating EGFR mutation could avoid this mechanism of resistance, given its superior potency against T790M. In the phase I AURA trial, 60 treatment-naive patients with metastatic EGFR-mutant NSCLC (77% T790M-negative) received upfront osimertinib at 80 mg/day (N = 30) or 160 mg/day (N = 30). According to treatment dose group, 80 and 160 mg, the ORR was 67% and 87% (77% across doses) and PFS was 22.1 and 19.3 months (20.5 months across doses), respectively [27]. These results are encouraging relative to the efficacy of gefitinib or afatinib in the first-line setting [28, 29] and suggest osimertinib as a potential option in the first-line setting, independent of T790M-status. The phase III FLAURA trial (NCT02296125) compared osimertinib to erlotinib or gefitinib (standard of care) as first-line treatment in patients with advanced NSCLC and common EGFR mutations. Patients with stable CNS metastases were allowed. In the control arm, cross-over to osimertinib was allowed in case of disease progression and confirmation of T790M mutation–based resistance. The primary end point of the trial was PFS. Among 556 patients enrolled (∼20% with brain metastases), a significant improvement in PFS (18.9 versus 10.2 months, HR 0.46, P < 0.0001) was reported with osimertinib irrespective of race or EGFR mutation subtype compared with standard of care. Osimertinib also improved the systemic PFS in patients with brain metastases compared with standard of care (15.2 versus 9.6 months, HR 0.47, P = 0.0009). There were no differences in ORR (80% versus 76%), but osimertinib resulted in a two-fold increase in the median duration of response (17.2 versus 8.5 months). OS data were immature but preliminary results showed promising results (HR 0.63, P = 0.00068) in favour of osimertinib, despite the fact that cross-over was allowed. Lower grade ≥3 AEs (34% versus 45%) and a lower discontinuation rate were reported with osimertinib compared with standard of care treatment [30]. These results suggest osimertinib as a new standard in first-line treatment of patients with EGFR-mutant advanced NSCLC. Recently, mechanisms of AR to osimertinib as first-line treatment have been described in cell-free DNA samples from 19 patients included in the phase I AURA trial cohort. Putative genomic resistance mutations were identified in 9 of 19 patients with detectable circulating tumour DNA (ctDNA). There was no evidence of acquired T790M mutation in any plasma ctDNA sample analysed. Two cases of acquired EGFR C797S resistance mutations were detected: one in a patient with a de novo T790M mutation, and one in the absence of T790M. Also, an acquired MEK1 G128V variant, HER2 exon 20 insertion, JAK2 V617F and MET copy number gains have been described as mechanisms of AR with upfront osimertinib [27]. However, no specific treatment strategies have been established at osimertinib resistance. In preclinical models, if the C797S mutation develops in cells wild-type for T790M (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs [31]. Efficacy, toxicity and treatment options after osimertinib resistance may help to define the best strategy for sequencing upfront EGFR TKI in this population. Osimertinib efficacy in central nervous system metastases Globally, the incidence of brain and leptomeningeal metastases among EGFR-mutant NSCLC patients is 31% [32] and ∼9% [33–35], respectively. Erlotinib [36], gefitinib [37] and afatinib [38] have a modest degree of intracranial activity. However, preclinical data demonstrated greater penetration and brain exposure with osimertinib than with gefitinib, rociletinib or afatinib [39]. CNS activity of osimertinib had been reported in the AURA study phase II extension component [17], the phase II AURA2 trial [18], and was recently confirmed in the phase III AURA3 trial. In the phase III AURA3 trial, among 144 patients with stable and asymptomatic brain metastases, PFS was also longer with osimertinib compared with chemotherapy (8.5 versus 4.2 months, HR 0.32; 95% CI, 0.21–0.49) [20]. Among those patients with CNS disease assessable for response (n = 46), CNS ORR was 70% with osimertinib compared with 31% with chemotherapy with a median duration of response of 8.9 versus 5.7 months, respectively. Also, the cumulative incidence of CNS progression at 6 months was lower with osimertinib compared with chemotherapy (11.5% versus 28.2%) [40]. AURA3 confirmed the CNS efficacy of osimertinib, with higher and more durable responses while also delaying the onset of brain metastases in this population. A phase II trial (NCT 02971501) assessed the PFS of osimertinib with or without bevacizumab. Indeed, preliminary results from the phase I (BLOOM) trial have reported long-lasting clinical and radiological activity of osimertinib at 160 mg among 21 EGFR TKI pre-treated EGFR-mutant NSCLC patients with leptomeningeal metastases (cytologically confirmed) and controlled extracranial disease. Baseline T790M mutation was detected in cerebrospinal fluid in two patients and in plasma in six [41]. The ongoing phase II (BLOOM) study (NCT02228369) is enrolling T790M-positive (tested in plasma or tissue) NSCLC patients with leptomeningeal disease. Globally, these results endorse the efficacy of osimertinib in cerebral nervous system metastases among T790M-positive NSCLC patients. T790M detection in plasma ctDNA in osimertinib studies Liquid biopsies based on ctDNA analysis have been described as surrogate samples for molecular analysis replacing molecular analysis of tumour tissue [42] and may allow real-time sampling of multifocal clonal evolution [43, 44]. Also, ctDNA analysis can be used to monitor clonal evolution [45] and identify mechanisms of AR to treatment [44]. Retrospective exploratory analyses have reported that acquired T790M mutations (tested by cobas EGFR Mutation Testv2) among EGFR-mutant NSCLC patients was detected in 50% of patients, in concordance with tumour biopsy–derived genotyping which was 61% [46]. Among patients with sufficient material for concurrent ctDNA and tumour-derived genotyping, ctDNA identified the T790M mutation in 5 of 25 (20%) patients in whom the concurrent tissue biopsy was negative [46]. Recently, the cobas plasma EGFR Mutation Testv2 detected the T790M mutation in 61% of tumour tissue T790M mutation–positive patients from AURA extension and AURA phase II trials [47]. New techniques are being developed to increase the sensitivity of detecting EGFR sensitizing and resistance EGFR-mutations [48]. A retrospective analysis from the AURA I trial demonstrated that patients who were T790M positive in plasma had outcomes with osimertinib that were equivalent in RR and PFS to patients found to be positive by a tissue-based assay. Indeed, T790M was detected in plasma in 31% of T790M-negative tumours [49]. In the AURA3 trial, patients with T790M-positive status on both tumour and plasma analysis (n = 172) had an RR of 77% with osimertinib, and median PFS with osimertinib was 8.2 months compared with 4.2 with chemotherapy (HR 0.42, 95% CI, 0.29–0.61), an outcome improvement similar to that in the intent-to-treat population [20]. However, all these data are retrospective and in a population with a known T790M status in the tumour. Prospective validation of liquid biopsy as a surrogate marker for making treatment decisions has started to emerge. Recently, in a cohort of heavily pretreated EGFR-mutant NSCLC patients with progression and unknown T790M status in the tumour were prospectively treated on the basis of the ctDNA analysis. Those patients with T790M positivity in plasma achieved an ORR of 62.5% and 6-month PFS of 66.7%, similar to those patients treated on the basis of tissue analysis [50]. Interestingly, responses were also seen in patients with very low allele fractions of T790M mutation in plasma (<0.5%) [50]. Liquid biopsies also have the potential to function as dynamic surrogate markers of treatment efficacy. Clearance of plasma EGFR mutations after 6 weeks of osimertinib therapy was found to be associated with improved RR (70% versus 35%) and median PFS (10.9 versus 5.5 months) among 143 patients with T790M-positive NSCLC included in the phase I AURA trial (NCT01802632) [51]. These results support the feasibility of detecting T790M from plasma ctDNA samples for making treatment decisions and evaluating efficacy. Additionally, a recent algorithm for plasma and tissue T790M testing in patients with AR has been proposed, suggesting that those patients with a negative plasma result should undergo a tissue test [49, 52]. At the present time, EMA and FDA have accepted the use of information from ctDNA analysis to help to select EGFR-mutant NSCLC patients for osimertinib [9, 10]. Future directions Optimal sequence of TKIs As therapeutic options for this patient population, the issue of optimal sequencing of available agents is still an important question. Moreover, it is unknown whether switching treatment according to molecular progression (i.e. ctDNA T790M mutation positivity without RECIST progression) instead of RECIST progression could have an impact on treatment outcomes. Based on the predictive value of liquid biopsies, the three-arm phase II APPLE trial (NCT02856893) [53] in treatment-naive and common EGFR mutation NSCLC patients will explore upfront osimertinib, upfront gefitinib switching to osimertinib in case of T790M-positivity in plasma and upfront gefitinib and switching to osimertinib according to RECIST criteria regardless of T790M status. The primary end point of the trial is 18-month PFS on osimertinib for assessing whether liquid biopsies could become the new standard procedure for defining disease progression versus RECIST progression in this population and also assessing whether a sequenced strategy is more appropriate than upfront osimertinib. Dual vascular endothelial growth factor receptor and EGFR blockade inhibit tumour growth in EGFR TKI resistance xenograft models [54]. Two phase II clinical trials have reported improvement in outcome with erlotinib plus bevacizumab combination as first-line treatment in EGFR-mutant NSCLC patients [55, 56]. Combination of osimertinib and bevacizumab as first-line strategy is being tested in a phase I/II clinical trial (NCT02803203) and osimertinib and ramucirumab as a second-line strategy among T790M-positive tumours in a phase I clinical trial (NCT02789345). Osimertinib in the adjuvant setting The role of EGFR TKIs in patients with early NSCLC has not been defined [57, 58]. Following surgical resection, adjuvant platinum-based chemotherapy remains the standard of care, even for patients with an activating EGFR mutation. The ADAURA trial (NCT02511106) is a double-blind, randomized, placebo-controlled trial that will study the efficacy of osimertinib in 700 completely resected EGFR-mutant stage IB–IIIA NSCLC patients after adjuvant chemotherapy. The primary end point of the study is disease-free survival. The study is presently accruing patients. Osimertinib and immune checkpoint inhibitors Immune checkpoint inhibitors are considered the standard second-line treatment in advanced NSCLC patients based on survival improvement reported in four randomized phase III clinical trials [59–62]. Recently, another phase III trial has reported significant improvement in PFS and ORR with pembrolizumab as first-line treatment compared with standard platinum-based chemotherapy among tumours with high PD-L1 expression (≥ 50%) [63]. However, a recent meta-analysis has reported lack of survival benefit with these agents among EGFR-mutant tumours [64] and a retrospective study has reported lower RR with immune checkpoint inhibitors in EGFR-mutant versus EGFR-wild-type NSCLC patients [65]. The lack of association with smoking and the limited mutational tumour burden of EGFR-mutant tumours [66, 67] may explain the lack of efficacy among this population. Preclinical data have reported T790M-positive tumours as immunogenic [68], and tumours with AR to EGFR TKIs express higher levels of PD-L1 than sensitive tumours [69]. However, in the clinic, T790M mutation correlates with lower PD-L1 expression and PD-L1 expression was a negative prognostic factor [70]. EGFR-mutant NSCLC patients and T790M-negative tumours were more likely to benefit from nivolumab after EGFR-TKI treatment, probably as a result of higher PD-L1 expression than is present in T790M-positive patients [71]. Other trials testing the combination of osimertinib and immune checkpoint inhibitors, such as the phase III CAURAL trial (NCT02454933) and the multi-arm phase IB TATTON trial (NCT02143466) investigating osimertinib (80 mg/d) in combination with durvalumab (anti-PD-L1 monoclonal antibody), were stopped for safety concerns regarding increased incidence of ILD. Exploratory analysis from the TATTON trial (n = 34) reported encouraging clinical activity with RR of 67% in 9 patients with T790M-positive tumours compared with 21% in 14 T790M-negative NSCLC. ILD was reported in 38% of patients, which is higher than would be expected with either drug alone, including five patients (15%) with grade 3–4 events [72]. Results from the other two arms in the TATTON trial (osimertinib plus selumetinib and osimertinib plus AZD6094) are awaited. Other third-generation EGFR TKIs Rociletinib and olmutinib are other third-generation TKIs in development. Rociletinib has demonstrated promising results with a 59% ORR for patients with an activating EGFR mutation and the T790M mutation. However, updated data decreased the observed ORR to 28–34% [73]. This decrease, along with toxicity issues such as hyperglycaemia, led to halting of the clinical development of rociletinib. Olmutinib also demonstrated initial successes with ORR of 56% and median PFS of 8.3 months in T790M-positive NSCLC patients [74]. While it was initially approved in South Korea, its clinical development is currently uncertain, as two cases of toxic epidermal necrolysis and one case of Stevens–Johnson syndrome have been reported. However, there are several other third-generation EGFR TKIs currently in clinical development. Avitinib is a third-generation irreversible EGFR TKI that targets both EGFR activating mutations as well as the T790M mutations. Enrolment is currently ongoing in a phase I trial for patients who progress on a first-generation EGFR TKI, with or without the T790M mutation. Overall, the drug has been well tolerated and ORR for 48 assessable patients was 41.7% with a DCR of 87.9% [75]. The drug ASP8273 is also an irreversible EGFR TKI that targets the T790M mutation. Preliminary results from the phase I study have been reported; 60 patients have been enrolled and no dose-limiting toxicities were noted. ORR is 36% and the median PFS is 6.7 months [76]. However, the phase III SOLAR trial (NCT02588261) comparing ASP8273 with erlotinib or gefitinib as first-line treatment in EGFR-mutant NSCLC patients has been discontinued and no further development programs for ASP8273 have been announced. The phase I with the EGFR TKI EGF816 enrolled 127 patients with a T790M mutation that could be evaluated for response, with an ORR of 44% and estimated PFS of 9.2 months [77]. Finally, the EGFR TKIs PF-06747775 and AZD3759 are at an early stage in clinical development. Interestingly, AZD3739 was specifically designed to penetrate the blood–brain barrier, as CNS metastasis is a common location of progression for EGFR patients. The early data are promising for this patient population, with 40% of patients demonstrating CNS tumour shrinkage [78]. Further studies are ongoing for these drugs and will potentially increase the therapeutic options. Discussion Conclusion Osimertinib is the first FDA and EMA approved third-generation EGFR TKI and has proven to be both well-tolerated and effective in patients with the acquired T790M resistance mutation, significantly improving the treatment options for this disease. The results of the FLAURA study support the use of osimertinib as first-line therapy and represent a new standard for this patient population. Further research into how to improve on these findings are currently under way, including combining osimertinib with other drugs, examining its use in adjuvant settings and furthering research into resistance mechanisms. The development of osimertinib has clearly improved the therapeutic landscape for EGFR-mutant NSCLC and presents exciting opportunities for clinicians and patients. Funding AstraZeneca has provided a sponsorship grant towards this independent publication. Disclosure Professor Vansteenkiste has acted as a consultant for Merck-Serono, GSK-Bio, and Lilly Oncology. key message Osimertinib was the first third-generation EGFR TKI to receive FDA and EMA approval for metastatic EGFR-mutant NSCLC patients that have acquired the EGFR T790M resistance mutation. Additional clinically relevant questions in this patient population, such as the efficacy of osimertinib in patients with brain metastases, role of liquid biopsies, and combination with immune checkpoint inhibitors are being studied. References 1 Reguart N, Remon J. Common EGFR-mutated subgroups (Del19/L858R) in advanced non-small-cell lung cancer: chasing better outcomes with tyrosine-kinase inhibitors. Future Oncol  2015; 1– 13. 2 Shi YK, Wang L, Han BH et al.   First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol  2017; 28( 10): 2443– 2450. Google Scholar CrossRef Search ADS PubMed  3 Sequist LV, Waltman BA, Dias-Santagata D et al.   Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med  2011; 3( 75): 75ra26. Google Scholar CrossRef Search ADS PubMed  4 Yun C-H, Mengwasser KE, Toms AV et al.   The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A  2008; 105( 6): 2070– 2075. Google Scholar CrossRef Search ADS PubMed  5 Yu HA, Arcila ME, Rekhtman N et al.   Analysis of tumour specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res  2013; 19( 8): 2240– 2247. Google Scholar CrossRef Search ADS PubMed  6 Engelman JA, Zejnullahu K, Mitsudomi T et al.   MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science  2007; 316( 5827): 1039– 1043. Google Scholar CrossRef Search ADS PubMed  7 Bean J, Brennan C, Shih J-Y et al.   MET amplification occurs with or without T790M mutations in EGFR mutant lung tumours with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A  2007; 104( 52): 20932– 20937. Google Scholar CrossRef Search ADS PubMed  8 Lee J-K, Lee J, Kim S et al.   Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol  2017; 35( 26): 3065– 3074. Google Scholar CrossRef Search ADS PubMed  9 http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. 10 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004124/WC500202022.pdf. 11 Cross DAE, Ashton SE, Ghiorghiu S et al.   AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov  2014; 4( 9): 1046– 1061. Google Scholar CrossRef Search ADS PubMed  12 Finlay MRV, Anderton M, Ashton S et al.   Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem  2014; 57( 20): 8249– 8267. Google Scholar CrossRef Search ADS PubMed  13 Planchard D, Brown KH, Kim D-W et al.   Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother Pharmacol  2016; 77( 4): 767– 776. Google Scholar CrossRef Search ADS PubMed  14 Vishwanathan K, Dickinson P, Bui K et al.   Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291. Mole Cancer Ther  2015; 14(12 Suppl 2): B153. doi: 10.1158/1535-7163.TARG-15-B153. Google Scholar CrossRef Search ADS   15 Jänne PA, Yang JC-H, Kim D-W et al.   AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med  2015; 372( 18): 1689– 1699. Google Scholar CrossRef Search ADS PubMed  16 Yang J, Ramalingam SS, Jänne PA et al.   LBA2_PR: osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results. J Thorac Oncol  2016; 11( 4): S152– S153. Google Scholar CrossRef Search ADS   17 Yang JC-H, Ahn M-J, Kim D-W et al.   Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA Study Phase II Extension Component. J Clin Oncol  2017; 35( 12): 1288– 1296. Google Scholar CrossRef Search ADS PubMed  18 Goss G, Tsai C-M, Shepherd FA et al.   Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol  2016; 17( 12): 1643– 1652. Google Scholar CrossRef Search ADS PubMed  19 Mitsudomi T, Ahn MJ, Bazhenova L et al.   Overall survival (OS) in patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) treated with osimertinib: Results from two phase II studies. AnnOncol  2017; 28(Suppl 5). https://doi.org/10.1093/annonc/mdx380.050. 20 Mok TS, Wu Y-L, Ahn M-J et al.   Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med  2017; 376( 7): 629– 640. Google Scholar CrossRef Search ADS PubMed  21 Rosell R, Molina MA, Costa C et al.   Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res  2011; 17( 5): 1160– 1168. Google Scholar CrossRef Search ADS PubMed  22 Watanabe M, Kawaguchi T, Isa S-I et al.   Ultra-sensitive detection of the pretreatment EGFR t790m mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res  2015; 21( 15): 3552– 3560. Google Scholar CrossRef Search ADS PubMed  23 Yu HA, Arcila ME, Hellmann MD et al.   Poor response to erlotinib in patients with tumours containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol  2014; 25( 2): 423– 428. Google Scholar CrossRef Search ADS PubMed  24 Ding D, Yu Y, Li Z et al.   The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Onco Targets Ther  2014; 7: 387– 393. Google Scholar PubMed  25 Costa C, Molina MA, Drozdowskyj A et al.   The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res  2014; 20( 7): 2001– 2010. Google Scholar CrossRef Search ADS PubMed  26 Eberlein CA, Stetson D, Markovets AA et al.   Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res  2015; 75( 12): 2489– 2500. Google Scholar CrossRef Search ADS PubMed  27 Ramalingam SS, Yang JC-H, Lee CK et al.   Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol  2017; JCO2017747576. 28 Mok TS, Wu Y-L, Thongprasert S et al.   Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med  2009; 361( 10): 947– 957. Google Scholar CrossRef Search ADS PubMed  29 Sequist LV, Yang JC-H, Yamamoto N et al.   Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol  2013; 31( 27): 3327– 3334. Google Scholar CrossRef Search ADS PubMed  30 Ramalingam S, Reungwetwattana T, Chewaskulyong B et al.   Osimertinib versus standard of care EGFT KI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA. Ann Oncol  2017; 28(Suppl_5): LBA2_PR. 31 Niederst MJ, Hu H, Mulvey HE et al.   The allelic context of the C797S mutation acquired upon treatment with third generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res  2015; 21( 17): 3924– 3933. Google Scholar CrossRef Search ADS PubMed  32 Iuchi T, Shingyoji M, Itakura M et al.   Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol  2015; 20( 4): 674– 679. Google Scholar CrossRef Search ADS PubMed  33 Liao B-C, Lee J-H, Lin C-C et al.   Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol  2015; 10( 12): 1754– 1761. Google Scholar CrossRef Search ADS PubMed  34 Kuiper JL, Hendriks LE, van der Wekken AJ et al.   Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer  2015; 89( 3): 255– 261. Google Scholar CrossRef Search ADS PubMed  35 Li Y-S, Jiang B-Y, Yang J-J et al.   Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol  2016; 11( 11): 1962– 1969. Google Scholar CrossRef Search ADS PubMed  36 Porta R, Sánchez-Torres JM, Paz-Ares L et al.   Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J  2011; 37( 3): 624– 631. Google Scholar CrossRef Search ADS PubMed  37 Park K, Tan E-H, O'Byrne K et al.   Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol  2016; 17( 5): 577– 589. Google Scholar CrossRef Search ADS PubMed  38 Schuler M, Wu Y-L, Hirsh V et al.   First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol  2016; 11( 3): 380– 390. Google Scholar CrossRef Search ADS PubMed  39 Ballard P, Yates JW, Yang Z et al.   Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res  2016; 22( 20): 5130– 5140. Google Scholar CrossRef Search ADS PubMed  40 Mok T, Ahn M-J, Han J-Y et al.   CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: data from a randomized phase III trial (AURA3). Jco  2017; 35(15_Suppl): 9005– 9005. 41 Yang JC-H, Kim D-W, Kim S-W et al.   Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a phase I study. ASCO Meeting Abstracts  2016; 34(15_Suppl): 9002. 42 Jovelet C, Ileana E, Le Deley M-C et al.   Circulating cell-free tumour DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO trial. Clin Cancer Res  2016; 22( 12): 2960– 2968. Google Scholar CrossRef Search ADS PubMed  43 Murtaza M, Dawson S-J, Pogrebniak K et al.   Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Comms  2015; 6: 8760. Google Scholar CrossRef Search ADS   44 Wan JCM, Massie C, Garcia-Corbacho J et al.   Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer  2017; 17( 4): 223. doi: 10.1038/nrc.2017.7. Google Scholar CrossRef Search ADS PubMed  45 Iwama E, Sakai K, Azuma K et al.   Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations. Ann Oncol  2017; 28( 1): 136– 141. Google Scholar PubMed  46 Sundaresan TK, Sequist LV, Heymach JV et al.   Detection of T790M, the acquired resistance EGFR mutation, by tumour biopsy versus noninvasive blood-based analyses. Clin Cancer Res  2016; 22( 5): 1103– 1110. Google Scholar CrossRef Search ADS PubMed  47 Jenkins S, Yang JC-H, Ramalingam SS et al.   Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol  2017; 12( 7): 1061– 1070. Google Scholar CrossRef Search ADS PubMed  48 Jovelet C, Madic J, Remon J et al.   Crystal digital droplet PCR for detection and quantification of circulating EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer. PLoS One  2017; 12( 8): e0183319. Google Scholar CrossRef Search ADS PubMed  49 Oxnard GR, Thress KS, Alden RS et al.   Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol  2016; 34( 28): 3375– 3382. Google Scholar CrossRef Search ADS PubMed  50 Remon J, Caramella C, Jovelet C et al.   Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol  2017; doi: 10.1093/annonc/mdx017. 51 Thress KS, Markovets A, Barrett JC et al.   Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial. Jco  2017; 35(15_Suppl): 9018– 9018. 52 Jenkins S, Yang C-H, Ramalingam SS et al.   Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol  2017; doi: 10.1016/j.jtho.2017.04.003. 53 Remon J, Menis J, Hasan B et al.   The APPLE trial: feasibility and activity of AZD9291 (Osimertinib) treatment on positive PLASMA T790M in EGFR-mutant NSCLC patients. EORTC 1613. Clin Lung Cancer  2017; 28( 4): 784– 790. 54 Naumov GN, Nilsson MB, Cascone T et al.   Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumour growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res  2009; 15( 10): 3484– 3494. Google Scholar CrossRef Search ADS PubMed  55 Seto T, Kato T, Nishio M et al.   Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol  2014; 15( 11): 1236– 1244. Google Scholar CrossRef Search ADS PubMed  56 Rosell R, Dafni U, Felip E et al.   Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med  2017; 5( 5): 435– 444. Google Scholar CrossRef Search ADS PubMed  57 Goss GD, O'Callaghan C, Lorimer I et al.   Gefitinib versus placebo in completely resected non–small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol  2013; 31( 27): 3320– 3326. Google Scholar CrossRef Search ADS PubMed  58 Kelly K, Altorki NK, Eberhardt WEE et al.   Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol  2015; 33( 34): 4007– 4014. Google Scholar CrossRef Search ADS PubMed  59 Brahmer J, Reckamp KL, Baas P et al.   Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med  2015; 373( 2): 123– 135. Google Scholar CrossRef Search ADS PubMed  60 Borghaei H, Paz-Ares L, Horn L et al.   Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med  2015; 373( 17): 1627– 1639. Google Scholar CrossRef Search ADS PubMed  61 Herbst RS, Baas P, Kim D-W et al.   Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet  2016; 387( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  62 Rittmeyer A, Barlesi F, Waterkamp D et al.   Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet  2017; 389( 10066): 255– 265. Google Scholar CrossRef Search ADS PubMed  63 Reck M, Rodríguez-Abreu D, Robinson AG et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  64 Lee CK, Man J, Lord S et al.   Checkpoint inhibitors in metastatic egfr-mutated non-small cell lung cancer—a meta-analysis. J Thorac Oncol  2017; 12( 2): 403– 407. Google Scholar CrossRef Search ADS PubMed  65 Gainor JF, Shaw AT, Sequist LV et al.   EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res  2016; 22( 18): 4585– 4593. Google Scholar CrossRef Search ADS PubMed  66 Rizvi NA, Hellmann MD, Snyder A et al.   Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science  2015; 348( 6230): 124– 128. Google Scholar CrossRef Search ADS PubMed  67 Spigel D, Schrock A, Fabrizio D et al.   Total mutation burden (TMB) in lung cancer and relationship with response to PD-1/PD-L1 targeted therapies. J Clin Oncol  2016; 34(Suppl): abstr 9017. 68 Ofuji K, Tada Y, Yoshikawa T et al.   A peptide antigen derived from EGFR T790M is immunogenic in non-small cell lung cancer. Int J Oncol  2015; 46( 2): 497– 504. Google Scholar CrossRef Search ADS PubMed  69 Lin K, Cheng J, Yang T et al.   EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB. Biochem Biophys Res Commun  2015; 463( 1–2): 95– 101. Google Scholar CrossRef Search ADS PubMed  70 Hata A, Katakami N, Nanjo S et al.   Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer. Lung Cancer  2017; 111: 182– 189. Google Scholar CrossRef Search ADS PubMed  71 Haratani K, Hayashi H, Tanaka T et al.   Tumour immune microenvironment and nivolumab efficacy in egfr mutation-positive non-small cell lung cancer based on T790m status after disease progression during EGFR-TKI treatment. Ann Oncol  2017; 28( 7): 1532– 1539. Google Scholar CrossRef Search ADS PubMed  72 Ahn M, Yang J, Yu H, et al.   Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. Elcc  2016; Abstract 136O. 73 Sequist LV, Soria J-C, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med  2016; 374( 23): 2296– 2297. Google Scholar CrossRef Search ADS PubMed  74 Park K, Lee J-S, Lee KH et al.   BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: efficacy and safety at the RP2D. ASCO Meeting Abstracts  2016; 34(15_Suppl): 9055. 75 Zhang L, Zhao H, Hu B et al.   First-in-human study of AC0010, a novel irreversible, mutant-selective EGFR inhibitor in patients with 1st generation EGFR TKI-resistant non-small cell lung cancer (NSCLC). Ann Oncol  2016; 27(Suppl_6): 3590. 76 Yu HA, Spira AI, Horn L et al.   Antitumour activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: Interim results from an ongoing phase 1 study. J Clin Oncol  2016; 34( Suppl 15): 9050– 9050. 77 Tan DS-W, Yang JC-H, Leighl NB et al.   Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M. J Clin Oncol  2016. 78 Ahn M-J, Kim D-W, Kim TM et al.   Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). ASCO Meeting Abstracts  2016; 34(15_Suppl): 9003. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Jan 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off