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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 Del19 disease.1–4 The clinical development of third-generation TKIs provides additional treatment options for these patients, but raises questions about the optimal sequence of EGFR TKIs.
Possible treatment sequences with EGFR TKIs in EGFR mutation-positive NSCLC
Figure is only for illustrative purposes and not to scale
EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
Two recent reviews discuss the sequential use of available EGFR TKIs in EGFR mutation-positive NSCLC and key considerations when assessing the optimal sequential therapy.2,3 In a review published in Future Oncology, Professor Nicolas Girard considers how optimal selection of a first-line treatment depends on patient-related factors, such as the presence/absence of brain metastases, resistance mechanisms, subsequent therapy options for long-term treatment and the tolerability profile of the overall treatment sequence.2 Read the review by Professor Girard and colleagues here, and a review by Professor Hirsch and colleagues here
Professor Nicolas Girard discusses treatment sequencing with EGFR TKIs in EGFR mutation-positive NSCLC
GioTag: A real-world study of afatinib followed by osimertinib
GioTag is a global, observational study of sequential therapy with afatinib followed by osimertinib in a real-world clinical practice setting.7 Patients (N=204) with EGFR mutation-positive NSCLC were treated with first-line afatinib, developed the T790M mutation and were then treated with second-line osimertinib.7 The patient population in GioTag included patients who were not well represented in randomised controlled trials, such as those with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 (15% of patients in GioTag).7
GioTag study design
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
Time on treatment in the GioTag study
After a median follow-up of 28.2 months, the median overall time on sequential afatinib and osimertinib treatment was 27.6 months (90% confidence interval [CI]: 25.9–31.3).7
Time on treatment with sequential afatinib and osimertinib in the GioTag study
Clinical benefit of sequential afatinib and osimertinib was observed across patient subgroups categorised by ethnicity, age, EGFR mutation type, presence of brain metastases and ECOG PS.7 There was a prolonged median time on treatment in Asian patients (46.7 months), patients with Del19 vs L858R mutations (30.3 vs 19.1 months) and patients with ECOG PS 0 or 1 vs ≥2 (31.3 vs 22.2 months).7
Overall survival in the GioTag study
The 2-year overall survival (OS) rate from start of afatinib treatment was 79% in the overall patient population and 84% for patients with an ECOG PS of 0 or 1.7
Landmark OS at 2 years in patients treated with sequential afatinib and osimertinib in the GioTag study
Implications of the GioTag study for clinical practice
The GioTag study provides real-world data on the sustained clinical benefit observed with first-line afatinib followed by osimertinib. The implications for clinical practice are that patients with EGFR-mutation positive NSCLC who acquire resistance to afatinib via T790M mutation may benefit from prolonged targeted therapy with afatinib and osimertinib, delaying the need for chemotherapy for approximately 28 months.7
GioTag more closely reflected the situation in everyday clinical practice than randomised clinical trials, with a broad patient population including elderly patients and patients with ECOG PS≥2 (15% of patients in GioTag).7
Importantly, the clinical benefit with sequential afatinib and osimertinib treatment was consistent across all patient subgroups, with particularly encouraging results in Asian patients (median time on treatment: 46.7 months) and patients with Del19-positive disease (median time on treatment: 30.3 months).7
TKI sequencing and insights from afatinib studies
The video below shows how the landscape for treatment for EGFR mutation-positive NSCLC has evolved, and how insights from afatinib studies can inform treatment sequencing for patients with EGFR mutation-positive NSCLC.
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 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. Median time on second-line treatment was not different between Del19 and L858R mutation subgroups.8 Interestingly, 37 patients received osimertinib after first-line afatinib, the majority in third-line treatment or beyond; median time on therapy was 20.2 months (95% confidence interval [CI]: 12.8–31.5 months).8 Median overall survival (OS) for osimertinib-treated patients is not yet evaluable.
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).9
OS in patients who received a subsequent third-generation EGFR TKI following afatinib or gefitinib in LUX-Lung 7
CI, confidence interval; NE, non-estimable; OS, overall survival.
Investigating mechanisms of resistance to afatinib
T790M is the major mechanism of acquired resistance to afatinib. No clinical characteristics or EGFR mutation types have been described that are associated with acquired T790M.10,11 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.12 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).12 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%.12 These 27 patients were then treated with osimertinib, with an ORR of 81%.12 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).12 Emergence of the EGFR T790M mutation did not appear to correlate with any baseline characteristics.12
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.13 In patients treated with first-line afatinib, median progression-free survival (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%.13 Of these patients, 28 had a biopsy following progressive disease and 16 (57%) were T790M positive.13 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%.13
Novello S, et al. Ann Oncol 2016;27(Suppl. 5):v1–27.
Jenkins S, et al. J Thorac Oncol 2017;12(8):1247–56.
Matsuo N, et al. Sci Rep 2016;6:36458.
Lau K-S, et al. Poster presented at ESMO 2016 (Poster 1243P).
Girard N. Future Oncol 2018;14(11):1117–32.
Hirsch V. Ther Adv Med Oncol 2018;10:1758834017753338.
Hochmair MJ, et al. Future Oncol 2018. Oct 19. doi: 10.2217/fon-2018-0711. [Epub ahead of print].
Sequist LV, et al. Poster presented at ESMO 2017.
Corral J, et al. Ann Oncol 2017;28(Suppl. 2): Abstract 93PD.
Wu SG, et al. Oncotarget 2016;7(11):12404–13.
Yang JC, et al. J Clin Oncol 2017;35(12):1288–96.
Hochmair MJ, et al. Poster presented at WCLC 2017 (Poster P2.03-025).
Tanaka H, et al. ASCO 2018 (Abstract e21173).
*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.
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Last updated: November 2018
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