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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 with EGFR mutation-positive disease eventually develop acquired resistance to these therapies, which most commonly occurs via T790M mutation, especially in patients with tumours harbouring 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.

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 and tumour mutational burden (TMB)9 have been identified as candidate biomarkers.

Patients with the Del19 EGFR mutation, for instance, are significantly more likely to develop T790M than patients with L858R mutations.5-7

A recent study investigated TMB in 84 patients with EGFR mutation-positive NSCLC who underwent T790M testing at the time of the development of resistance to first- or second-generation EGFR TKIs.10 Median TMB was numerically lower in patients who developed the T790M mutation than those who did not (3.77 vs 4.77 mutations/Mb, respectively).10 These findings suggest that in a future scenario it may be possible to predict which patients are likely to develop the T790M mutation on the basis of an optimal TMB threshold and to tailor therapeutic approach accordingly.

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%).11 Of note, 60% of patients who progressed on second-line osimertinib had no known mechanism of resistance identified.12 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 NSCLC9

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; 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 maximising patient outcomes. Read the full review by Professor Hirsh here.15

Patient-related factors: in a Future Oncology review, Professor Nicolas Girard reflects on a number of patient-related (as well as clinical) factors that can affect EGFR TKI sequencing, e.g. presence of brain metastases, drug tolerability and drug–drug interactions. Read the full review by Professor Girard here.12

Molecular considerations: in another recent 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.16 While a targeted approach is possible for homogenous tumours with acquired T790M resistance, options remain less clear for tumours with more heterogeneous acquired resistance mechanisms.16 In the future, the authors propose the use of molecular tumour dissection to tailor TKI sequencing to the resistance signature of individual tumours, in order to maximise patients’ chemotherapy-free time.16 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.17 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.12

Hypothesised representation of tumour clonality and resistance mechanisms in EGFR mutation-positive NSCLC16

Tumour clonality and resistance mechanisms in EGFR mutation-positive NSCLC

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

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.18

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 maximises 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.18

The GioTag: 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.19 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.19 The study reflected the situation in clinical practice more closely than traditional randomised controlled trials as it included patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 (15% of patients) and those with brain metastases at baseline (10% of patients).19

You can find out more about the GioTag study by watching the study animation, below, or via the results that follow.


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Watch this overview of the GioTag study.

GioTag study results: OS and time on treatment

Updated electronic health record data were available for 94 GioTag study patients from the USA at the time of the most recent interim study analysis (database lock: April 2019).13 At the time of the analysis, median follow-up was 30.3 months and OS data were 42% mature.13 Median OS was 41.3 months (90% confidence interval [CI]: 36.8‒46.3) in the overall patient population, and 45.7 months (90% CI: 45.3‒51.5) in patients with the Del19 EGFR mutation (74% of patients had a Del19 mutation; 26% had the L858R mutation).13,19 The 2-year OS rate from the start of afatinib treatment was 80% in the overall patient population and 82% for patients with Del19-positive tumours.13

The median overall time on sequential afatinib and osimertinib treatment was 28.1 months (90% CI: 26.8–30.3) in the overall patient population and 30.6 months (90% CI: 27.6–32.0) in patients with Del19-positive tumours.13

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

OS and time on treatment in patients treated with sequential afatinib and osimertinib in the GioTag study13

overall survival and time on treatment

CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.

Implications of the GioTag study for clinical practice

The results of the GioTag study show that sequential afatinib and osimertinib conferred encouraging OS in a broad population of patients with EGFR mutation-positive NSCLC, especially in patients with Del19-positive tumours.13,19 Patients who acquired resistance to afatinib via the T790M mutation obtained sustained clinical benefit from this treatment sequence, delaying their need for chemotherapy.13,19

Watch Dr Maximilian Hochmair discuss the updated analysis of the GioTag study in the video below.


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This video accompanied an article on the updated analysis of the GioTag study that was first published online in Future Oncology in August 2019.

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.20 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.20 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).20 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).21

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-centre, 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.22 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).22 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%.22 These 27 patients were then treated with osimertinib, with an ORR of 81%.22 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).22 Emergence of the EGFR T790M mutation did not appear to correlate with any baseline characteristics.22

A separate Austrian, single-centre 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 tumours 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-centre retrospective Italian study in 122 patients with EGFR mutation-positive advanced NSCLC who were treated with first- or second-generation EGFR TKIs.23 T790M positivity was significantly higher in patients with Del19 mutations versus exon 21 mutations (77% vs 51%, p=0.008).23

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.24 In this study, 8/11 (73%) patients with Del19 mutations acquired the T790M resistance mutation.24

In an exploratory analysis of the FLAURA study of first-line osimertinib in patients with EGFR mutation-positive advanced NSCLC, serial circulating tumour DNA was monitored for the early detection of progressive disease and potential resistance mechanisms.25 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.25 The incidence of T790M mutations is higher than previously reported (47%) in a preliminary analysis of resistance mechanisms in this trial,11 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

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*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.


Page last updated: December 2019