Treatment sequencing

Treatment sequencing with EGFR TKIs in EGFR mutation-positive NSCLC

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are currently standard of care for first-line therapy in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, many patients eventually develop acquired resistance to these therapies, which most commonly occurs via T790M mutation, especially in patients with tumors harboring exon 19 deletions.1–7

Illustration of the potential for sequential therapy in patients treated with first-line afatinib2-8

Proportion of patients who could benefit from sequential therapy

*The percentage of patients receiving a second-line therapy is based on data from patients in countries with universal reimbursement policies in LUX-Lung 3 and 6.8

EGFR+, epidermal growth factor receptor mutation positive; NSCLC, non-small cell lung cancer.

The clinical development of third-generation TKIs that have demonstrated efficacy in patients with T790M mutations provides additional treatment options for these patients, but raises questions about the optimal sequence of EGFR TKIs.

In this video, filmed during the European Lung Cancer Congress (ELCC 2019), Professor Nicolas Girard considers how the treatment sequence for patients with EGFR mutation-positive NSCLC can be personalized based on molecular alterations. Treatment sequencing with a first- or second-generation EGFR TKI, followed by osimertinib in the setting of T790M acquired resistance, offers the opportunity to delay chemotherapy.

Rate this

Professor Nicolas Girard considers how the treatment sequence for patients with EGFR mutation-positive NSCLC can be personalized based on molecular alterations. Filmed at ELCC in April 2019.

Although it is not currently possible to predict which patients will develop the T790M mutation after treatment with a first- or second-generation EGFR TKI, EGFR mutation subtype5-7 has been identified as a candidate biomarker. Patients with the Del19 EGFR mutation, for instance, are significantly more likely to develop T790M than patients with L858R mutations.5-7 

Patients receiving the third-generation EGFR TKI osimertinib as first-line therapy have been reported to acquire a range of resistance mutations, including MET amplification (15%), HER2 amplification (2%), EGFR C797S mutation (7%), and PIK3CA (7%) and KRAS mutations (3%).9 Of note, 60% of patients who progressed on second-line osimertinib had no known mechanism of resistance identified.10 In this setting of heterogeneous acquired resistance mechanisms, there are ongoing efforts to develop more treatment options after progression on osimertinib.

Possible treatment sequences with EGFR TKIs in EGFR mutation-positive NSCLC11

Treatment sequences in EGFR mutation-positive NSCLC

Adapted from Takeda M, Nakagawa K. Int J Mol Sci 2019;20(1):pii: E146.

Figure is only for illustrative purposes; not drawn to scale.

EGFR, epidermal growth factor receptor; OS, overall survival; TKI, tyrosine kinase inhibitor.

Selecting the optimal EGFR TKI sequence

The various factors that can influence selection of first-line TKI and treatment sequencing have been discussed in reviews.

Clinical considerations: in a comprehensive review of EGFR TKI clinical trial data, Professor Vera Hirsh considers the optimal sequencing approach from the perspective of maximizing patient outcomes.14

Molecular considerations: in another review, Professor Shinji Kohsaka and colleagues consider cellular heterogeneity within EGFR mutation-positive NSCLC and the potential role that molecular complexity may play in clonal divergence, resistance mechanisms and treatment response.15 While a targeted approach is possible for homogenous tumors with acquired T790M resistance, options remain less clear for tumors adopting heterogeneous acquired resistance mechanisms.15 In the future, the authors propose the use of molecular tumor dissection to tailor TKI sequencing to the resistance signature of individual tumors, in order to maximize patients’ chemotherapy-free time.15 Read the full review by Professor Kohsaka here.

Other molecular considerations include the range of potential resistance mutations that may develop in response to a therapy, the availability of approved agents that target these mutations, and the proportion of patients who would be expected to develop known resistance mechanisms. For example, mechanisms of resistance to the third-generation EGFR TKI osimertinib include MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation.16 However, in many cases, the mechanism of resistance is not known, with 60% of patients who progressed on second-line osimertinib having no identifiable mechanism of resistance.10

Hypothesized representation of tumor clonality and resistance mechanisms in EGFR mutation-positive NSCLC15

Tumor clonality and resistance mechanisms in EGFR mutation-positive NSCLC

Reproduced from Kohsaka S, et al. Future Oncol 2018 [Epub ahead of print].

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

A questionnaire-based study involving 310 clinicians from Germany, the USA, China and Japan between April 2018 and May 2018 has provided some insight into the factors that influence the selection of first-line TKIs in routine patient care.17

The majority of clinicians participating in the study agreed that the primary goal of TKI therapy is to extend patients’ overall survival (OS) and improve their quality of life. There was general consensus that the preferred first-line treatment is one that maximizes clinically meaningful OS and progression-free survival (PFS), while offering a predictable treatment response and manageable side effects. Over one-third of participating clinicians agreed that there remains a need for more clinical evidence to prompt and guide changes to current practice.17 

The GioTag study: sequential therapy with afatinib followed by osimertinib in clinical practice

The GioTag study was a global, real-world, retrospective, unblinded observational study of sequential therapy with afatinib** followed by osimertinib in routine clinical practice.12,18 Eligible patients (N=204) had EGFR mutation-positive advanced NSCLC and were treated with first-line afatinib followed by second-line osimertinib on development of the T790M mutation.12,18 The study reflected the situation in clinical practice more closely than traditional randomized controlled trials as it included patients with an Eastern Cooperative Oncology Group performance status ≥2 (15% of patients) and those with central nervous system metastases at baseline (10% of patients).12 

GioTag study results: OS and time on treatment

At the time of the final analysis (December 2019), median follow-up was 33.9 months.12 Median OS was 37.6 months (90% confidence interval [CI]: 35.5–41.3) in the overall patient population, 44.8 months (90% CI: 37.0‒57.8) in Asian patients (n=50), and 41.6 months (90% CI: 36.9‒45.0) in patients with the Del19 EGFR mutation (n=149) (73% of patients had a Del19 mutation; 26% had the L858R mutation).12 The 2-year OS rate from the start of afatinib treatment was 80% in the overall patient population, 90% in Asian patients, and 84% in patients with Del19-positive tumors.12

The median overall time on sequential afatinib and osimertinib treatment was 27.7 months (90% CI: 26.7–29.9) in the overall patient population, 37.1 months in Asian patients (90% CI: 28.1–40.3), and 30.0 months (90% CI: 27.6–31.9) in patients with Del19-positive tumors.12


For more information, view the GioTag study page here and the online publication here.

OS and time on treatment in patients treated with sequential afatinib and osimertinib in the GioTag study12

GioTag study: overall survival and time on treatment

CI, confidence interval; OS, overall survival.

Implications of the GioTag study for clinical practice

The results of the GioTag study show that sequential afatinib followed by osimertinib can be a feasible and effective therapeutic strategy in real-world patients with EGFR mutation-positive NSCLC who develop T790M, particularly in Asian patients and patients with Del19-positive tumors.12

Treatment sequencing outcomes in LUX-Lung 3, 6 and 7

The LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7 clinical trials investigated afatinib in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC. Of the 553 patients with common EGFR mutations (Del19 and L858R) who received first-line afatinib in the LUX-Lung 3, 6 and 7 trials and later discontinued treatment, second-line therapy was given in 394 (71%) patients.19 A subanalysis of the LUX-Lung 3 and 6 trials by national reimbursement policy suggests that up to 88% of patients in countries with universal reimbursement policies may receive second-line therapy after discontinuation of first-line afatinib.8

Across the LUX-Lung 3, 6 and 7 trials, median time on second-line treatment was comparable for the Del19 and L858R mutation subgroups.19 Thirty-seven (7%) patients received osimertinib after first-line afatinib (the majority in third-line treatment or beyond), possibly reflecting the recent approval and limited availability of osimertinib at the time of the trials. Median time on osimertinib in any treatment line was 20.2 months (95% CI: 12.8–31.5 months).19 With a median follow-up of >4 years, median OS for osimertinib-treated patients is not yet reached.

In LUX-Lung 7 there was a trend towards improved OS with afatinib versus gefitinib in patients who received a third-generation EGFR TKI (non-estimable [NE] vs 48.3 months; hazard ratio [HR]=0.49; 95% CI: 0.20‒1.19).20

OS in patients who received a subsequent third-generation EGFR TKI following afatinib or gefitinib in LUX-Lung 720

OS in LUX-Lung 7 patients treated with a subsequent third-generation EGFR TKI

CI, confidence interval; NE, non-estimable; OS, overall survival.

Investigating mechanisms of resistance to afatinib

A single-center, retrospective analysis of 48 Austrian patients with EGFR mutation-positive Stage IV lung adenocarcinoma who had been treated with afatinib for at least 3 months was carried out and 23% of patients had received first-generation EGFR TKIs prior to afatinib.21 In this study, the objective response rate (ORR) in all patients was 90% and the median duration of response was 12.5 months (95% CI: 9–14).21 The EGFR T790M mutation was present in 27/48 (56%) of patients who progressed after initially achieving disease control for ≥3 months with afatinib; the ORR with afatinib in these patients was 93%.21 These 27 patients were then treated with osimertinib, with an ORR of 81%.21 At the time of analysis, osimertinib treatment was ongoing in 11 (41%) patients. Median time on sequential treatment with afatinib and osimertinib was 25.0 months (95% CI: 20–33 months).21 Emergence of the EGFR T790M mutation did not appear to correlate with any baseline characteristics.21

A separate Austrian, single-center retrospective study evaluated the prevalence of the EGFR T790M mutation at time of afatinib failure, and response to subsequent osimertinib therapy. The predominantly Caucasian population (n=67) had Stage IV EGFR mutation-positive NSCLC and received first-, second-, or third-line afatinib (81%, 15% and 4%, respectively). Both liquid biopsy and tissue rebiopsy, with a highly sensitive droplet digital PCR assay, were used to assess T790M mutation status following progression on afatinib.3

T790M mutation was identified in 73% of patients following failure on afatinib; this proportion was 67% in patients who received afatinib first line.3 All patients with T790M-positive tumors received osimertinib after progression on afatinib. Three-quarters of patients (76%) had an objective response to osimertinib (22% complete; 53% partial), supporting its use after afatinib failure as part of sequential TKI therapy in EGFR T790M-positive NSCLC.3

Of potential interest for future T790M testing protocols, concordance between liquid biopsy and tissue rebiopsy in the study was high (approximately 80% of cases), suggesting a possible role for liquid biopsy as a reliable, less invasive alternative to tissue rebiopsy that can be used to guide treatment decisions.3

Correlations between clinical features and T790M positivity at the time of progression were investigated in a single-center retrospective Italian study in 122 patients with EGFR mutation-positive advanced NSCLC who were treated with first- or second-generation EGFR TKIs.22 T790M positivity was significantly higher in patients with Del19 mutations versus exon 21 mutations (77% vs 51%, p=0.008).22

In a Swedish study (N=30), a highly sensitive digital droplet PCR assay was used to detect the T790M mutation in plasma at the time of progression on EGFR TKI therapy.23 In this study, 8/11 (73%) patients with Del19 mutations acquired the T790M resistance mutation.23

In an exploratory analysis of the FLAURA study of first-line osimertinib in patients with EGFR mutation-positive advanced NSCLC, serial circulating tumor DNA was monitored for the early detection of progressive disease and potential resistance mechanisms.24 Using a sensitive digital droplet PCR assay, acquired T790M resistance was detected in 53/72 (74%) patients treated with the comparator first-generation EGFR TKI.24 The incidence of T790M mutations is higher than previously reported (47%) in a preliminary analysis of resistance mechanisms in this trial,9 which may reflect the sensitivity of the detection methods used.

Afatinib in Japanese patients with EGFR mutation-positive NSCLC

In a real-world study including 128 Japanese patients with advanced EGFR mutation-positive NSCLC, 76 patients received first-line afatinib and 52 received afatinib following a first-generation TKI.4 In patients treated with first-line afatinib, median PFS was 17.8 months (95% CI: 13.7–21.5), median OS was 39.5 months (95% CI: 34.4–NE) and the response rate was 64%.4 Of these patients, 28 had a biopsy following progressive disease and 16 (57%) were T790M positive.4 In patients who received afatinib following a first-generation TKI, median PFS was 8.0 months (95% CI: 4.9–9.5) and the response rate was 24%.4

Did you find this information useful?



Planchard D, et al. Ann Oncol 2018;29(Suppl. 4):iv192–237.


Wu SG, et al. Oncotarget 2016;7(11):12404–13.


Hochmair MJ, et al. Target Oncol 2019;14(1):75–83.


Tanaka H, et al. ASCO 2018 (Abstract e21173).


Jenkins S, et al. J Thorac Oncol 2017;12(8):1247–56.


Matsuo N, et al. Sci Rep 2016;6:36458.


Lau SC, et al. Clin Lung Cancer 2019;20(5):e576‒e583.


Yang JC, et al. Lancet Oncol 2015;16(2):141–51.


Takeda M, Nakagawa K. Int J Mol Sci 2019;20(1):pii: E146.


Ramalingam SS, et al. Ann Oncol 2018;29(Suppl. 8): Abstract LBA50.


Papadimitrakopoulou V, et al. Ann Oncol 2018;29(Suppl. 8): Abstract LBA51.


Hochmair MJ, et al. Future Oncol 2020. Aug 28. doi: 10.2217/fon-2020-0740 [Epub ahead of print].


Ramalingam SS, et al. N Engl J Med 2020; 382:41–50.


Hirsh V. Ther Adv Med Oncol 2018;10:1758834017753338.


Kohsaka S, et al. Future Oncol 2019;15(6):637–52.


Leonetti A, et al. Br J Cancer 2019;121(9):725–737.


Wehler T, et al. J Thorac Oncol 2018;13(10):S907.


Hochmair MJ, et al. Future Oncol 2018;14(27):2861–7.


Park K, et al. Lung Cancer 2019;132:126–31.


Corral J, et al. Ann Oncol 2017;28(Suppl. 2): Abstract 93PD.


Hochmair MJ, et al. Poster presented at WCLC 2017 (Poster P2.03-025).


Pignataro D, et al. Poster presentation at WCLC 2019 (Poster P2.14-17).


Jönsson M, et al. Poster presentation at WCLC 2019 (Poster EP1.14-16).


Gray JE, et al. Ann Oncol 2019;30(Suppl. 5): Abstract LBA85.

*Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list, please click here. Registration conditions differ internationally; please refer to locally approved prescribing information.


© 2020 Boehringer Ingelheim International GmbH. All rights reserved.


Page last updated: September 2020