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Real-world evidence: a major area of untapped potential?
What is meant by real-world evidence, and why does it matter for physicians? Watch the clip below for some thoughts on this topic.
Dr Claas Frohn considers what is meant by real-world evidence, and the role it can play in clinical research and clinical practice. Filmed in November 2018.
The value of real-world evidence to clinical practice
Real-world evidence complements clinical trials by providing information on the effectiveness and side-effect profile of therapies in patients treated in routine clinical practice.
Physicians consider the value of real-world evidence to clinical practice. Filmed in October 2018 at the European Society for Medical Oncology Congress.
RealGiDo: a real-world study of afatinib dose adjustment
Professor Angela Märten discusses the RealGiDo study of afatinib dose adjustment in a real-world setting. Filmed in October 2018.
RealGiDo was a global, non-interventional study of afatinib* dose adjustment in real-world clinical practice in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).1 Over a median time on treatment of 18.7 months (95% confidence interval [CI]: 15.1–21.5), using tolerability to guide afatinib dose adjustments reduced the frequency and intensity of adverse drug reactions (ADRs), without affecting clinical effectiveness.1 As reported in the LUX-Lung trials,2,3 the effectiveness of afatinib was consistent regardless of whether patients had a dose reduction or a modified starting dose.1
The results suggest that routine care clinical outcomes can be optimised by tailoring the afatinib dose to individual patient characteristics and ADRs. For more information on the RealGiDo study, view the study page here, a summary of the study here and the online publication here.
GioTag: a study of sequential therapy with afatinib followed by osimertinib in clinical practice
GioTag was a global, observational study of sequential therapy with afatinib followed by osimertinib in routine clinical practice.4 Eligible patients (N=204) had EGFR mutation-positive NSCLC and were treated with first-line afatinib followed by second-line osimertinib on development of the T790M mutation.4 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).4
Listen to our short podcast on GioTag, a study of sequential therapy with afatinib followed by osimertinib in clinical practice.
After a median follow-up of 28.2 months, the median overall time on sequential afatinib and osimertinib treatment was 27.6 months (90% CI: 25.9–31.3).4 The 2-year overall survival (OS) rate from start of afatinib treatment was 79% for the overall patient population and 84% for patients with an ECOG PS of 0 or 1.4 These findings suggest that patients with EGFR mutation-positive NSCLC who acquire resistance to afatinib via T790M mutation may benefit from sequential targeted therapy with afatinib and osimertinib, delaying the need for chemotherapy.
Safety and effectiveness of afatinib in routine clinical practice around the world
There is an increasing body of real-world evidence on the first-line use of afatinib in routine clinical practice. The combined literature supporting the safety and effectiveness of first-line afatinib in diverse patient populations treated in routine care are discussed in a recent systematic review by Professor Park and colleagues.5
Individual studies from Germany,6 Japan,7,8 South Korea,9‒11 Taiwan12 and Canada13 have also consistently demonstrated real-world clinical outcomes with first-line afatinib at least as good as those from the LUX-Lung 3,2 LUX-Lung 614 and LUX-Lung 715 clinical trials, with no additional safety signals.6‒13 Real-world evidence supporting the effectiveness of afatinib for patients with brain metastases and with uncommon EGFR mutations have also been reported.
GIDEON: a non-interventional study of the effectiveness and tolerability of afatinib in Germany
GIDEON is a prospective non-interventional study designed to evaluate the effectiveness and tolerability of first-line afatinib in patients with EGFR mutation-positive NSCLC managed in routine clinical practice in Germany (N=151).6
In the first interim analysis, objective response rate (ORR) was 73% and disease control rate was 90%. Response rates were similar across all patient subgroups. The progression-free survival (PFS) rate at 1 year was 55%, with overall median PFS being 12.9 months.6 Subgroup analyses suggested consistent PFS benefit in patients who received a starting dose of <40 mg/day (vs ≥40 mg/day), in patients aged ≥75 years (vs <75 years) and across all EGFR mutation subgroups.6 In the overall population, median OS was 33.6 months (95% CI: 23.1–not evaluable).6
The most common Grade 3/4 adverse events (AEs) were diarrhoea (21%), dermatitis acneiform (9%) and stomatitis (3%); 12% of patients discontinued treatment due to ADRs.6
For more information, view a summary of the study here.
Afatinib in Japanese patients with EGFR mutation-positive NSCLC
A prospective, observational study involving 1,602 Japanese patients with inoperable or recurrent EGFR mutation-positive NSCLC, found ORR with afatinib was higher in EGFR tyrosine kinase inhibitor (TKI)-naïve patients than in those who had received prior EGFR TKI treatment (68% vs 21%, respectively).7 ADRs were generally manageable and consistent with the known safety profile of afatinib.7 For more information, view the abstract of a World Conference on Lung Cancer presentation on this study here.
In another study conducted in Japan, real-world outcomes were evaluated for 76 patients with advanced EGFR mutation-positive NSCLC treated with first-line afatinib.8 In these patients, median PFS was 17.8 months (95% CI: 13.7–21.5), median OS was 39.5 months (95% CI: 34.4–not estimable) and ORR was 64%.8 Although 76% of patients who received first-line afatinib required a dose reduction due to AEs, it did not impair clinical outcomes.8 For more information, view an electronic American Society of Clinical Oncology abstract on this study here.
Afatinib compared with gefitinib or erlotinib in Korean patients with EGFR mutation-positive NSCLC
A retrospective study was carried out in 467 Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC who received first-line afatinib (n=165), gefitinib (n =230) or erlotinib (n=72).9 Overall, median PFS was significantly longer with afatinib versus gefitinib or erlotinib (19.1 [95% CI: 12.3–25.9], 13.7 [95% CI: 12.3–15.1] and 14.0 months [95% CI: 11.3–16.8], respectively; p=0.001; median follow up: 17.7 months).9
In afatinib-treated patients with brain metastases at baseline who had not received radiotherapy for brain tumours, median PFS was 15.7 months (n=39).10 Of these patients, 29 had follow-up magnetic resonance imaging data and 55% of these patients were described as having significantly decreased brain metastases with afatinib treatment.10
In patients with exon 19 deletions, median PFS with afatinib, gefitinib and erlotinib was 19.1, 15.0 and 16.3 months, respectively (p=0.01).9 However, in patients with L858R mutations, there was no significant difference in median PFS between treatment groups (p=0.46).9 In patients with uncommon EGFR mutations, median PFS was also longer with afatinib (median PFS had not been reached at the data cut-off) versus gefitinib (5.0 months) or erlotinib (6.1 months), but the difference did not reach statistical significance in this small sample (p=0.06; n=31).9
Overall toxicity profiles were comparable in the different groups but Grade 3 or 4 AEs were more frequent with afatinib (7%) versus gefitinib (3%) or erlotinib (2%).9 Common Grade 3 or 4 AEs in the afatinib group included diarrhoea (3%), paronychia (2%) and skin rash (2%).9 Dose reductions due to AEs were more frequent with afatinib (68%) versus gefitinib (2%) or erlotinib (6%). However, afatinib dose reduction did not impair effectiveness (median PFS in dose reduction vs no dose reduction groups, 23.5 vs 12.4 months).9
PFS with afatinib, gefitinib or erlotinib in Korean patients with EGFR mutation-positive NSCLC
PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
PFS in Korean patients with and without brain metastases
GKS, Gamma Knife surgery; PFS, progression-free survival; WBRT, whole-brain radiotherapy.
Clinical effectiveness in relation to dose and EGFR mutation type in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma
A retrospective, observational study evaluated whether afatinib dose adjustment and EGFR mutation type affected clinical effectiveness in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma (30% of patients had brain metastases; 23% had complex or rare EGFR mutations).11 Fifty-nine of 140 patients received an afatinib dose of <40 mg in the first 6 months of treatment; there was no significant difference in median PFS between the 40 mg and <40 mg groups (12.0 vs 11.0 months; hazard ration [HR]=0.84; 95% CI: 0.53–1.31; p>0.05).11 After excluding patients with exon 20 insertions from the analysis, there was no significant difference in median PFS between patients who had common EGFR mutations (del19/L858R; n=108) and those who had uncommon EGFR mutations (n=22; median PFS, 12.2 vs 11.5 months; HR=0.85; 95% CI: 0.47–1.53; p>0.05).11
PFS in relation to afatinib dose in Taiwanese patients
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
PFS in relation to EGFR mutation type in Taiwanese patients (excluding patients with exon 20 insertions)
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
Clinical effectiveness in relation to EGFR mutation type and the presence or absence of brain metastases in Taiwanese patients with advanced EGFR mutation-positive NSCLC
In a retrospective study in 422 Taiwanese patients with advanced EGFR mutation-positive NSCLC, 104 patients received afatinib as first-line treatment.12 Of these patients, 56% had exon 19 mutations, 22% had L858R mutations and 22% had uncommon EGFR mutations.12 In patients who received afatinib, median PFS was 12.2 months in the overall patient group, 12.2 months in patients with exon 19 mutations, 11.7 months in patients with L858R mutations and 19.7 months in patients with uncommon EGFR mutations.12 Median PFS in patients with and without brain metastases at baseline was 9.9 and 13.1 months, respectively.12
First- compared with second-generation EGFR TKIs in Canadian patients with advanced EGFR mutation-positive NSCLC
In a retrospective study of 500 Canadian patients with advanced EGFR mutation-positive NSCLC, treatment with a second-generation EGFR TKI was associated with a longer OS than treatment with a first-generation EGFR TKI (median OS: 43 [n=110] vs 23 months [n=390]; HR=0.6; 95% CI: 0.4–0.8; p<0.01).13 The survival benefit favouring second-generation TKIs was significant in the overall patient cohort and in the exon 19 deletion patient cohort, but not the cohort with exon 21 L858R mutations.13 Skin and gastrointestinal side effects were common in patients receiving second-generation TKIs, but were manageable with dose reductions and only one patient discontinued treatment.13
Effectiveness of first- compared with second-generation EGFR TKIs in Canadian patients with advanced EGFR mutation-positive NSCLC
CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; TKI, tyrosine kinase inhibitor.
Afatinib in patients with advanced NSCLC who progressed following prior therapies: results of a global named patient use programme
This afatinib named patient use programme included 5,622 patients with advanced/metastatic NSCLC from 49 countries.16 Data from 3,966 patients in 41 countries were analysed. All patients had progressed after clinical benefit on erlotinib or gefitinib and/or had a mutation in EGFR or HER2 and had exhausted all other treatment options. Median time to treatment failure with afatinib was 4.4 months in 2,862 patients for which data were available.16 Of these, response assessments were available in 1,141 patients; ORR was 23.4% (267/1,141).16 In patients with an EGFR mutation, the ORR was 25.0% (181/723); ORR was 19.0% (11/58) in T790M mutation-positive patients and 35.0% (7/20) in patients with insertions in exon 20.16 The safety profile of afatinib was as expected in this patient population. Overall, these data suggest that afatinib can provide clinical benefit in heavily pretreated patients with NSCLC, including those with uncommon EGFR mutations. For more information, view the published article here.
Halmos B, et al. Lung Cancer 2019;127:103–11.
Sequist LV, et al. J Clin Oncol 2013;31(27):3327–34.
Hirsch V, et al. Poster presented at ASCO 2016 (Poster 369).
Hochmair MJ, et al. Future Oncol 2018;14(27):2861–7.
Park K, et al. Ther Adv Med Oncol 2019 (in press).
Brueckl W, et al. Poster presented at ESMO 2018 (Poster 1449P).
Yamamoto N, et al. Poster presented at WCLC 2017 (Poster P3.01-035).
Tanaka H, et al. J Clin Oncol 2018;36 (Abstract e21173).
Kim Y, et al. Cancer Res Treat 2018 Jun 13. doi: 10.4143/crt.2018.117. [Epub ahead of print].
Kim Y, et al. Poster presented at WCLC 2017 (Poster P3.01-023).
Liang S-K, et al. Oncotarget 2017;8(52):90430–43.
Tu C-Y, et al. Oncotarget 2018;9(36):24237–47.
Lau S, et al. Poster presented at WCLC 2017 (Poster P3.01-015).
Wu YL, et al. Lancet Oncol 2014;15(2):213–22.
Park K, et al. Lancet Oncol 2016;17(5):577–89
Cappuzzo F, et al. Future Oncol 2018;14(15):1477–86.
*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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Page last updated: March 2019
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