Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A),1 which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B).2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed,1,3,4 but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype.5–7

Figure 1
Figure 1.A) Distribution of oncogenic driver mutations in NSCLC; B) OS targeted versus non-targeted treatment; and C) History of EGFR-mutant positive (EGFR M+) NSCLC

A) adapted from Skoulidis F et al. (2019);1 B) adapted from Kris MG et al. (2014);2 and C) adapted from Rotow J et al. (2017).8

The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signaling cascades.5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/RAF/MEK and PI3K/AKT pathways, among others.5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients.5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signaling.9 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C).10

Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, antitumor activity (Table 1A) and safety.11 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance.12 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation.13

Table 1
Table 1.A) IC 50 values of reversible EGFR-TKIs and afatinib; B) Progression-Free Survival (PFS) in EGFR M+ NSCLC patients achieved in phase III trials for first-line EGFR-TKIs; C) Overall Survival (OS) in EGFR M+ NSCLC patients achieved in phase III trials for first-line EGFR-TKIs

A) adapted from Hoffknecht P et al. (2015);14 B) adapted from Shah R et al. (2019);15 aCentral independent review, unless stated otherwise; bInvestigator review; C) adapted from Shah R et al. (2019).15

Figure 2
Figure 2.A) EGFR-TKI-Generations; and B) Schematic representation of EGFR signaling and EGFR-TKI inhibition

Adapted from Hsu PC et al. (2019).16 The Epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC). EGFR kinase domain mutations including Del19, L858R and T790M increase kinase activity of EGFR, leading to the hyperactivation of downstream signaling pathways including MAPK, PI3K/AKT/mTOR, and IL-6/JAK/STAT3 which promote tumorigenesis of NSCLC cells. The three generations of EGFR-TKIs differ with respect to how they bind to different EGFR mutations and which EGFR mutations are active or inactive.

Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progression-free survival (PFS) relative to those treated with first-generation EGFR-TKIs.17,18 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the T790M EGFR mutation who had disease progression with first- and second-generation EGFR-TKIs.19

Although the treatment landscape of advanced NSCLC has dramatically changed with the introduction of EGFR-TKIs, identifying methods to best select patients who are more likely to benefit from EGFR inhibition as well as selecting the optimal sequence of EGFR-TKIs, especially how best to use the third-generation EGFR-TKI, osimertinib, are emerging issues that still need to be addressed.

This critical review considers the evolving landscape of EGFR-TKI therapy and discusses the optimal sequence schedule to improve survival outcomes for EGFR-mutant positive (EGFR M+) advanced NSCLC patients.


For almost a decade now, first- and second-generation EGFR-TKIs have been widely established in place of traditional standard platinum-based chemotherapy as the first-line treatment of choice for patients with newly diagnosed EGFR M+ advanced NSCLC.20

Several randomized trials have demonstrated that first-line EGFR-TKI therapy can improve objective response rates (ORR) and promote longer PFS compared to standard chemotherapy (Table 1B).18,21–28 Median PFS in phase III trials comparing gefitinib with platinum-based chemotherapy as first-line treatment of patients with advanced NSCLC is about 9 months versus 6 months, respectively.22,23 However, no overall survival (OS) benefit was identified in these first-generation EGFR-TKI trial populations, which may be partly due to high crossover rates following disease progression (Table 1C).10,18,21–28


First-generation EGFR-TKIs were serendipitously found to be most effective in advanced NSCLC patients with tumors harboring recurrent activating mutations (mainly somatic)29,30 occurring in the exons encoding the kinase domain of EGFR.31–33 Approximately 93% of EGFR activating mutations occur in exons 19 to 21. Of these, deletions in exon 19 (Del19) and a point mutation in exon 21 leading to substitution of leucine for arginine at position 858 (L858R) are particularly common (44.8% and 39.8%, respectively).34 Indeed, the presence of an EGFR mutation in NSCLC patients is the strongest and most reliable predictor of improved PFS and ORR with EGFR-TKIs compared with chemotherapy in the first-line setting. The 2009 landmark IPASS (Iressa Pan-Asia Study) study reported significantly longer PFS with gefitinib versus standard chemotherapy in a subgroup of advanced lung tumor patients with EGFR mutations (hazard ratio, [HR] for progression to death: 0.48 [95% CI: 0.36–0.64]; p<0.001) but not in patients with EGFR wild-type tumors (HR for progression to death: 2.85 [95% CI: 2.05–3.98]; p<0.001).35

Much later in 2015, a pooled analysis of the LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) trial populations showed superiority of afatinib to platinum-based chemotherapy in terms of median OS in a subset of patients with EGFR Del19 mutations but not in patients with EGFR L858R mutations: 27.3 versus 24.3 months, respectively (HR: 0.81 [95% CI: 0.66–0.99]; p=0.037).36 This data revealed for the first time that EGFR-TKIs in the first-line setting could prolong OS in patients with EGFR L858R mutations: 27.3 versus 24.3 months, respectively (HR: 0.81; [95% CI: 0.66 to 0.99]; p=0.037).36 This data revealed for the first time that EGFR-TKIs in the first-line setting could prolong OS in patients harboring Del19 EGFR mutations, and that Del19 and L858R EGFR mutations constitute two distinct patient subgroups.36

In a small proportion of patients, primary resistance mutations can already be detected at diagnosis (Figure 3). The most prevalent are EGFR exon 20 insertions (4%) and EGFR T790M mutations (5%).1,3,4,8,37 While the latter are sensitive to third-generation EGFR-TKIs, EGFR exon 20 insertions can be targeted with the specific inhibitor TAK-788.38 Initial results from a phase I/II trial (NCT02716116) showed a disease control rate (DCR) of 89% with 54% of the patients achieving a partial response (confirmed + unconfirmed) and 35% stable disease. Overall, 23 of 24 evaluable patients (93%) showed a reduction in the tumor volume; side effects were consistent with other EGFR-TKIs. Therefore, a phase III trial (n=318, 1:1 randomization) comparing TAK-788 with platinum/pemetrexed combination chemotherapy was initiated with enrolment starting in late 2019 (NCT04129502).38 Furthermore, in March 2020 JNJ-61186372, a bi-specific antibody targeting EGFR and c-MET, received FDA breakthrough designation for the poor-prognosis subpopulation of EGFR M+ patients harboring EGFR exon 20 insertions. This status was granted after promising phase I results. JNJ-61186372 will be further evaluated in combination with lazertinib.39

Figure 3
Figure 3.Resistance mechanisms in EGFR-mutant positive (EGFR M+) NSCLC

Adapted from Rotow J et al. 2017.8


Although EGFR mutant NSCLC represents a prototypical oncogene-addicted cancer with a single driver, co-mutations are a frequent event.40 The most commonly mutated genes are TP53 (55–65%), RB1(10%), PI3KCA/PTEN (9–12%) and CTNNB1 (5–10%).1,41 TP53 alterations are associated with a poorer prognosis (lower ORR, shorter PFS and OS).41,42 Similar findings have been made for PTEN, MDM2 and RB1 mutations, especially for patients with EGFR mutations and RB1 loss; PFS with EGFR tyrosine kinase inhibition was extremely short (median PFS of 1.9 months).41 Alterations in TP53, RB1, and the combination of both in particular, are associated with increased genetic instability eventually leading to small cell transformation.41,42


Recent head-to-head trials have demonstrated that second-generation EGFR-TKIs are preferable to first-generation EGFR-TKIs as first-line treatment for patients with EGFR M+ NSCLC since they may prolong PFS and OS. First-line efficacy of erlotinib or gefitinib has been compared with second-generation EGFR-TKIs in randomized clinical trials. In the LUX-Lung 721 and ARCHER-1050 trials,18 gefitinib was compared with second-generation agents afatinib and dacomitinib, respectively. The LUX-Lung 7 was a large (N=319), multicenter and multi-ethnic phase IIb trial that showed a trend toward improved OS with afatinib versus gefitinib in treatment-naïve patients harboring Del19 or L858R mutations.21 Overall, analysis of the LUX-Lung 7 data together with the LUX-Lung 3 and LUX-Lung 6 data show that afatinib results in approximately 10% of patients achieving long-term clinical benefit (long-term response ≥3 year PFS and OS), which is greater than that observed with first-generation EGFR-TKIs.17 Stratification factors in these trials included: Del19 versus L858R EGFR and versus other ‘uncommon’ mutations in LUX-Lung 3 and LUX-Lung 6; race (Asian vs non-Asian) in LUX-Lung 3 only, and brain metastases (presence vs absence) in LUX-Lung 7 only.17 The frequency of Del19 mutation-positive NSCLC was slightly higher among long-term responders in the LUX-Lung 3, 6, 7 analysis, which supports its known role as a biomarker for improved outcomes with EGFR-TKIs versus other mutation types.17 These studies also demonstrate that afatinib can provide clinical benefit in advanced NSCLC patients with brain metastases or uncommon mutations.21,26,27 Although the LUX-Lung 7 trial showed that afatinib compared to gefitinib significantly improves PFS and the time-to-treatment failure, more serious drug-related adverse events were reported in the afatinib group than in the gefitinib group.43 Indeed, second-generation EGFR-TKIs typically have more frequent side effects than other EGFR-TKIs because of their broad inhibitory profile.11 However, post-hoc analyses from LUX-Lung 3 and LUX-Lung 6 suggest that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related adverse events, as well as reduce interpatient variability of afatinib exposure, without affecting treatment efficacy.44 A more recent study by Yokoyama et al. (2019) shows that a low starting dose of afatinib therapy (20 mg daily dose) with dose modification according to severity of adverse events is a better strategy in treatment-naïve patients who have NSCLC associated with common activating EGFR mutations, both in terms of effectiveness and tolerability, than starting with a standard afatinib dose (40 mg daily).45 In this phase II trial, the PFS was 15.2 months, which was similar to previous reports with the standard 40 mg dose of afatinib, and toxicities were generally mild. Importantly, the low starting dose of afatinib was also effective in high-risk patients with common EGFR M+ NSCLC who had asymptomatic brain metastasis.45

The ARCHER 1050 trial is the first randomized, phase III study that directly compared a second-generation versus a first-generation EGFR-TKI to demonstrate an OS benefit.46 Although, in contrast to the LUX-Lung 3,26 6,27 and 721 trials, the ARCHER 1050 trial identified a significant improvement in OS with dacomitinib versus gefitinib (median OS: 34.1 vs 26.8 months, respectively; HR: 0.76 [95% CI: 0.582–0.993]; p=0.044), it did not include patients with uncommon mutations or brain metastases.46


The majority of NSCLC patients who harbor EGFR activating mutations show an initial pronounced response to EGFR-TKI treatment, but ultimately acquire resistance to these drugs after approximately 9 to 14 months of therapy.47 The threonine 790 to methionine (T790M) secondary mutation in exon 20 of EGFR is the most common mechanism conferring acquired resistance; it is detected in approximately 50% of patients treated with first-generation EGFR-TKIs.13 Several other EGFR-dependent and EGFR-independent mechanisms of acquired resistance have been described, including secondary site EGFR mutations (T290M, C797S), mesenchymal-epithelial transition factor (MET) amplification, human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations or amplification, phosphatase and tensin homolog (PTEN) loss, mitogen-activated protein kinase (MAPK) pathway activation, BRAF mutation, insulin-like growth factor receptor-1 (IGF-1R), fibroblast growth factor receptor (FGFR) activation, and small cell lung cancer (SCLC) transformation, among others.48–50 It has been proposed that the common T790M resistance mutation reduces the potency of ATP-competitive kinase inhibitors and that irreversible inhibitors could overcome this resistance via covalent binding, rather than an alternative binding mode.51 Amplification of MET occurs in approximately 5% to 20% of patients whereas HER2 amplification is estimated to occur in up to 8% of patients.52 Lineage plasticity, specifically small cell histologic transformation, occurs in 5%–14% of patients with resistance to earlier generation EGFR inhibitors.53,54

Second-generation irreversible EGFR-TKIs were initially designed and developed to delay or overcome T790M-mediated resistance, however evidence from the literature indicates a similar frequency of T790M-mediated resistance in patients receiving first-line treatment with the second-generation EGFR-TKI afatinib.55,56 Despite a delay in the expression of T790M when used in the first-line setting, the T790M mutation is still detected in 36.4% or 47.6% of patients treated with afatinib.55,56 Although preclinical data showed promising results of afatinib against EGFR T790M,57 the clinical trial data was disappointing, showing no OS benefit in patients after failure of platinum doublet chemotherapy and first-generation EGFR-TKIs.58 Notably, T790M is rarely identified in tumors before exposure to EGFR-TKIs concurrently with other more common activating mutations.48

Presently, the clinical efficacy of dacomitinib and osimertinib against uncommon mutations is being evaluated in ongoing phase II trials.59 In addition, an exploratory phase II trial (ZENITH20) with poziotinib, a new pan-HER TKI, in NSCLC patients harboring exon 20 insertions failed to reach its primary endpoint in a cohort of 115 patients.60

Patients with wild-type EGFR may present concurrent oncogenic mutations in KRAS proto-oncogene GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and tumor protein p53, resulting in differential clinical features, treatment outcomes and survival prognoses.61 Zhao et al (2019) showed that patients with the wild-type genes experienced longer PFS times than those with KRAS, TP53, KRAS/TP53 or PIK3CA/TP53 mutations.61 Moreover, the authors suggest that patients with NSCLC should receive routine KRAS, PIK3CA and TP53 gene sequencing to determine mutations for the analysis of clinical characteristics and prognosis.61 As mentioned above, these mutations may be detected as part of the initial mutational spectrum where they mediate primary resistance, but they may also emerge during the course of EGFR-TKI treatment (i.e., secondary resistance) (Figure 3).1


Osimertinib is an irreversible, third-generation EGFR-TKI that was developed based on its ability to inhibit the T790M resistance mutation and its selectivity for the mutant receptor. Since it also inhibits the common EGFR-activating mutations, namely Del19 and L858R, its role as first-line therapy represents a new milestone for patients with EGFR mutations.10,19

In the recent phase III FLAURA study, median OS was positive for osimertinib compared to older generation EGFR-TKIs in patients with Del19 or L858R EGFR mutated advanced NSCLC (38.6 months vs 31.8 months; HR for death, 0.80 [95.05% CI: 0.64 to 1.00]; p=0.046).62 In the first-line setting when compared with gefitinib or erlotinib, osimertinib met its primary endpoint showing significant improvement in PFS (10.2 vs 18.9 months, respectively; HR: 0.46 [95% CI: 0.37–0.57]; p<0.001)10 and OS (31.8 vs 38.6 months; HR: 0.8 [95% CI: 0.641–0.997]; p=0.0462).62 The superior PFS results with osimertinib were consistent across common types of EGFR mutations, namely Del19 and L858R, and against patients with or without baseline brain metastases. Osimertinib is also highly active against confirmed metastatic or recurrent NSCLC with uncommon activating EGFR mutations, e.g., mutations other than Del19, L858R, T790M and exon 20 insertions; notably, 63% of patients in this study received first-line osimeritinib.63 Taken together these data suggest that osimertinib is more effective and better tolerated than first-generation EGFR-TKIs, and thus osimertinib monotherapy has emerged as the new standard-of-care for first-line treatment of EGFR-mutated NSCLC patients.10,62 Notably, however, FLAURA compared osimertinib with either gefitinib or erlotinib but not with afatinib.64


In addition to monotherapy, EGFR-TKIs in combination with chemotherapy65 or immunotherapy66,67 have shown improvement in PFS in patients with advanced NSCLC harboring EGFR mutations.

One strategy that attempts to decrease the emergence of resistance involves combining cytotoxic chemotherapy with an EGFR-TKI.68,69 A recent study by Noronha et al. (2019) demonstrated that first-line gefitinib combined with pemetrexed and carboplatin chemotherapy significantly improved PFS compared with gefitinib alone (16 months vs 8 months [95% CI: 7.0–9.0 months], respectively; HR for disease progression or death: 0.51 [95% CI: 0.39–0.66]; p<0.001) and OS (not reached vs 17 months [95% CI: 13.5–20.5 months]; HR for death: 0.45 [95% CI: 0.31–0.65]; p<0.001), but increased toxicity in patients with NSCLC.68 However, results with the first-generation EGFR-TKI and pemetrexed as first-line treatment for NSCLC does not exceed osimertinib monotherapy in terms of PFS in this setting.10,68,70 Moreover, grade ≥3 toxicities occurred in 34% and 51% of patients in the osimertinib trial versus the gefitinib plus chemotherapy trial, respectively.10,70

Results from the randomized phase III RELAY trial showed that in the first-line setting erlotinib in combination with ramucirumab reduces the risk of disease progression or death by over 40% versus erlotinib alone in EGFR-positive NSCLC.71 At a median follow-up of 20.7 months, the median PFS was 19.4 months (95% CI: 15.4–21.6) with the ramucirumab combination compared with 12.4 months (95% CI: 11.0–13.5) with erlotinib alone (HR: 0.591 [95% CI: 0.461–0.760]; p<0.0001).71

Bevacizumab is a promising antibody for blocking vascular endothelial growth factor receptor 2 (VEGFR2). It is being evaluated in combination with EGFR-TKI as a first-line treatment for NSCLC in clinical trials.72 Compared with erlotinib alone, bevacizumab plus erlotinib combination therapy improved PFS in patients with EGFR-positive NSCLC. This study is ongoing and further follow-up is required to assess OS and overall efficacy of this combination in the first-line setting.66


Uncommon mutations may occur singularly or co-exist with a common or another uncommon EGFR mutation.73 Up to 25% of all EGFR mutation-positive tumors may have uncommon mutations together with a common EGFR mutation within the same tumor.73–75 Moreover, individuals with EGFR co-mutations exhibit shorter PFS and lower response rates than those with single EGFR mutations.76 The substitution mutations of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and exon 20 insertions are most prevalent among uncommon mutations described to date.77 Patients with these uncommon substitution mutations benefit from first-generation EGFR-TKIs such as erlotinib and gefitinib,78–80 however, based on extensive and robust data, afatinib is the preferred agent for the first-line treatment of NSCLC harboring these mutations.74

Afatinib has demonstrated clinical activity against G719X, L861Q and S768I in a post-hoc analysis of the LUX-Lung trials81 as well as in the real-world.74 Of 75/600 (12%) NSCLC patients with uncommon EGFR mutations in a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 clinical trials, the ORR was 78% with a PFS of 13.8 months for G719X (n=14), 56% with a PFS of 8.2 months for L861Q (n=9), and 100% with a PFS of 14.7 months for S768I (n=8).36 In a recent large, real-world dataset identifying patients with 98 different uncommon mutations, the ORR with afatinib was 60% in EGFR-TKI naïve patients (G719X: 63.4%; L861Q: 59.6%; and S768I: 62.5%) and 25% in EGFR-TKI pretreated patients.71 Seven (6.8%) EGFR-TKI naïve patients in the real-world dataset continued with afatinib treatment for more than three years; this is only marginally lower than reported in clinical trials (10–12%).17 Furthermore, whilst exon 20 insertions are traditionally not considered responsive to EGFR-TKIs based on retrospective analyses,80,82,83 analysis of the aforementioned real-world dataset demonstrated that some exon 20 insertions are clinically sensitive to afatinib; analysis of 70 NSCLC patients with exon 20 insertions treated with afatinib showed an ORR of 24.3% with a median duration of response (DoR) of 11.9 months.74

In a preclinical study by Kohsaka et al. (2019), it was shown that afatinib, possibly due to its alternative mechanism of action, reduced the viability of cells expressing numerous compound mutations, including those involving Del19, G719X and/or S768I mutations; only compound mutations involving T790M were considered to be resistant to afatinib.84


Osimertinib monotherapy has demonstrated superior activity versus platinum-pemetrexed chemotherapy as second-line treatment for EGFR T790M M+ NSCLC and is the current standard treatment in this setting.19,85 In addition, afatinib and osimertinib have been shown to inhibit EGFR phosphorylation in cells harboring uncommon secondary resistance mutations.86–89 For patients without EGFR T790M mutations, platinum-based chemotherapy is the currently recommended second-line treatment.90–92 Unlike the emergence of EGFR T790M in response to earlier generation EGFR-TKIs, there is no predominant mechanism of resistance to target on progression to osimertinib.52 Hence, there is no established targeted treatment following the failure of osimertinib, so it is widely debated whether osimertinib should be reserved for second-line use following progression with a second-generation EGFR-TKI.93

In the confirmatory phase III (AURA 3) trial, osimertinib was superior to platinum-pemetrexed in patients with T790M-positive advanced NSCLC, who had disease progression after first- or second-generation EGFR-TKI therapy.19 The median PFS was 10.1 months in the osimertinib arm and 4.4 months in the platinum-pemetrexed arm (HR: 0.30 [95% CI: 0.23–0.41]; p<0.001). The ORR was significantly better with osimertinib (71% [95% CI: 65–76]) than with platinum-pemetrexed (31% [95% CI: 24–40]) (odds ratio: 5.39 [95% CI: 3.47–8.48]; p<0.001). The median duration of response was 9.7 months (95% CI: 8.3–11.6) with osimertinib and 4.1 months (95% CI: 3.0—5.6) with platinum-pemetrexed.19 At data cut-off, the median OS was 26.8 months (95% CI: 23.5–31.5) versus 22.5 months (95% CI: 20.2–28.8) respectively (HR: 0.87 [95% CI: 0.67–1.12]; p=0.277); the survival rate at 24 months was 55% versus 43% and at 36 months was 37% versus 30%, respectively.94

In a real-world clinical practice setting, EGFR-TKI-naïve patients who received first-line afatinib and went on to develop T790M-positive acquired resistance subsequently received second-line osimertinib.93 At the initial database lock the median time to treatment failure (TTF), the primary outcome, was 27.6 months (90% CI: 25.9–31.3 months).95 Results were also promising in patients with an EGFR Del19 activating mutation (30.3 months) and Asian patients (46.7 months).95 An interim analysis has demonstrated a median OS of 41.3 months (90% CI: 36.8–46.3) overall and 45.7 months (90% CI: 45.3–51.5) in patients with Del19-positive tumors (n=149).96 The 2-year survival was 80% and 82%, respectively, for patients overall and those with Del19 tumors.96

A key challenge of the second-line use of osimertinib is to ensure that all patients who develop T790M-dr