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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 helping to inform physicians and patients about the optimal treatment tailored to the individual in everyday clinical practice. Many patients in clinical practice have poor Eastern Cooperative Oncology Group performance status (ECOG PS) or comorbidities and would not meet the strict inclusion and exclusion criteria of a clinical trial. Real-world evidence provides valuable information on the differing efficacy and side-effect profile of therapies in a real-life patient population.
Physician insights into the value of real-world evidence
Physicians consider the value of real-world evidence to clinical practice at ESMO 2018. Filmed in October 2018.
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, observational, non-interventional study of afatinib* dose adjustment in a real-world clinical practice setting.1 The aim of RealGiDo was to determine whether afatinib dose modification in a real-world setting had a similar impact on afatinib safety and efficacy as observed in LUX-Lung 3. Patients (N=228) with advanced epidermal growth factor receptor (EGFR) mutation-positive, EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC; Del19, L858R) were treated with afatinib according to the approved label.1 Analysis groups included patients with a dose reduction during treatment (<40 mg), and those with no dose reduction (≥40 mg).1 The primary outcome measures were the percentage of patients with adverse drug reactions (ADRs) by severity, time to treatment failure (TTF), and time to progression (TTP).1 The secondary outcome measure was the percentage of patients receiving a modified starting dose, and the reasons for modifying the starting dose.1
Afatinib starting dose in the RealGiDo study
Thirty-one percent of patients received a modified afatinib starting dose of <40 mg/day and the reasons for modifying the starting dose were broad but most commonly related to patient characteristics.1
Afatinib starting dose in the RealGiDo study
Reasons for modifying the afatinib starting dose in the RealGiDo study
Dose reduction in the RealGiDo study
Overall, 177 (78%) patients in RealGiDo had a dose modification and 149 had a dose reduction.1 Among patients who received afatinib 40 mg/day as their starting dose, 86% of dose reductions occurred within the first 6 months of treatment.1
Safety profile of afatinib in the RealGiDo study
All-grade ADRs and Grade ≥3 ADRs occurred in 94% and 25% of patients participating in the RealGiDo study, respectively.1 Among patients who received a starting dose of afatinib 40 mg/day (n=155), 94% had an ADR, 28% had a Grade ≥3 ADR and 5% had a serious adverse event (AE).1 There were fewer Grade ≥3 ADRs (28% vs 49%) and serious AEs (5% vs 14%) reported in patients treated with afatinib 40 mg/day in RealGiDo than in the LUX-Lung 3 trial.1,2
The most common ADRs in the overall population in RealGiDo were diarrhoea, rash/acne, paronychia/nail effect and stomatitis/mucositis.1 The incidences of these ADRs were lower in RealGiDo than in LUX-Lung 3 (diarrhoea, 75% vs 95%; rash/acne, 63% vs 89%; paronychia/nail effect, 49% vs 57%; stomatitis/mucositis, 34% vs 72%).1,2 Overall, no new safety signals were identified in RealGiDo.1
Among the 91 patients who had a dose reduction within the first 6 months after starting on afatinib 40 mg/day, 99% experienced an ADR of any grade prior to dose modification, compared with 71% after dose modification.1 The severity of ADRs reduced following dose modification with a reduction in the incidence of Grade 3 ADRs from 27.4% to 12.3% and Grade 4 ADRs from 2.7% to 1.4% (see figure).1 In summary, dose reductions led to decreases in the incidence and severity of ADRs, including the most commonly reported ADRs.1
Overall safety profile (ADRs by severity) in RealGiDo before and after dose reduction in patients who had a dose reduction within 6 months of starting afatinib at 40 mg/day
Overall safety profile by starting dose in the RealGiDo study
The overall safety profile in patients who received a modified afatinib starting dose of ≤30 mg/day (n=71) is shown in the figure below.
Overall safety profile (ADRs by severity) by starting dose in the RealGiDo study
TTF in RealGiDo
Median TTF was reasonably consistent across subgroups: 18.7 months (95% confidence interval [CI]: 15.1–21.5) in the overall population, 19.5 months (95% CI: 13.4–not evaluable [NE]) in patients who remained on afatinib ≥40 mg/day for the first 6 months (n=66), 17.7 months (95% CI: 14.5–21.5) in patients who had a dose reduction to <40 mg/day within the first 6 months (n=91), and 19.4 months (95% CI: 12.9–NE) in patients who started with afatinib ≤30 mg/day (n=71).1
TTF among patients in RealGiDo, by afatinib dose
CI, confidence interval; NR, no response.
TTP in RealGiDo
Median TTP was 20.8 months (95% CI: 19.1–25.9) in the overall population, 29.0 months (95% CI: 17.9–NE) in patients who remained on afatinib ≥40 mg/day, 20.0 months (95% CI 14.7–23.0) in patients who had a dose reduction to <40 mg/day within the first 6 months, and 25.9 months (95% CI: 17.3–NE) in patients who started on afatinib ≤30 mg/day.1
TTP among patients in RealGiDo, by afatinib dose
CI, confidence interval; NR, no response.
Conclusions from the RealGiDo study
Tolerability-guided afatinib dose adjustment in real-world clinical practice reduced the frequency and intensity of ADRs, without impacting effectiveness.1 As seen 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 Overall, these results show that outcomes can be optimised by tailoring the afatinib dose according to individual patient characteristics and ADRs.
Sequential therapy in clinical practice: the GioTag 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.4 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.4 The patient population in GioTag included patients who were not well represented in randomised controlled trials, such as those with ECOG PS ≥2 (15% of patients in GioTag).4
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% CI: 25.9–31.3).4
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.4 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).4
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 1.4
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.4
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).4
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).4
Real-world data on the efficacy and safety of afatinib in clinical practice
Real-world data from patients in Germany, Austria, Canada, Japan, South Korea and Taiwan provide evidence of the efficacy and safety of afatinib in the treatment of NSCLC in clinical practice. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) data were comparable or better than in the LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7 clinical trials, and there were no new safety signals. Efficacy data for patients with brain metastases and patients with uncommon epidermal growth factor receptor (EGFR) mutations have also been reported. Dose adjustments were necessary in many patients but did not affect efficacy.
GIDEON: a non-interventional study of the effectiveness and tolerability of afatinib in Germany
GIDEON is a prospective non-interventional study of the effectiveness and tolerability of first-line afatinib in routine clinical practice in Germany.5 Of 151 patients with advanced EGFR mutation-positive NSCLC, 65% had EGFR del19 mutations, 22% had EGFR L858R mutations and 13% had uncommon EGFR mutations.5 Seventy-three percent of patients received an afatinib starting dose of ≥40 mg/day; of these, 62% had a dose reduction.5
In the first interim analysis of the GIDEON study, ORR was 73% and disease control rate was 90%; response rates were similar across all patient subgroups.5 The PFS rate at 1 year was 55%, with overall median PFS being 12.9 months.5 Median PFS was reasonably consistent across all EGFR mutation subgroups (see figure).5
PFS by EGFR mutation subgroup in the GIDEON study
CI, confidence interval; PFS, progression-free survival.
With regard to efficacy by starting dose, median PFS was 16.4 months (95% CI: 9.5–20.7) in patients who received a modified afatinib starting dose of <40 mg/day (n=35) versus 12.3 months (95% CI: 10.1–16.0) in patients who started with an afatinib dose of 40 mg/day (n=107).5
In elderly patients (aged ≥75 years; n=41), a patient population underrepresented in clinical trials, median PFS was 14.2 months (95% CI: 9.3–21.4) versus 12.2 months (95% CI: 10.3–16.4) in patients aged <75 years (n=101).5
PFS in elderly patients in the GIDEON study
CI, confidence interval; PFS, progression-free survival.
Median PFS was 16.0 months (95% CI: 11.0–19.7) in patients without brain metastases (n=94) versus 10.6 months (95% CI: 9.2–13.9) in patients with brain metastases (n=48).5
In this preliminary analysis, median OS was: 33.6 months (95% CI: 23.1–not evaluable) in the overall population (median maturity 23.4 months; n=143); 33.6 months (95% CI: 13.6–not evaluable) in patients with L858R mutations (n=33); 18.7 months (95% CI: 7.3–38.1) in patients with exon 18–21 point mutations (n=20); and had not been reached at the time of analysis in patients with del19 mutations (n=90).5
OS by EGFR mutation subgroup in the GIDEON study
CI, confidence interval; NE, not evaluable, OS, overall survival.
The most common Grade 3/4 AEs were diarrhoea (21%), dermatitis acneiform (9%), and stomatitis (3%); 12% of patients discontinued treatment due to ADRs.5
Afatinib in Japanese patients with EGFR mutation-positive NSCLC
In a prospective, post-marketing observational study in 1,602 Japanese patients with inoperable or recurrent EGFR mutation-positive NSCLC (40.1%, 46.1% and 13.8% of patients had an Eastern Cooperative Oncology Group performance status of 0, 1 and ≥2, respectively), ORR with afatinib was higher in EGFR tyrosine kinase inhibitor (TKI)-naïve patients than in patients who had previously been treated with EGFR TKIs (68% vs 21%).6 In EGFR TKI-naïve patients who started on a daily afatinib dose of 40 mg, ORR was 71% in those aged ≥75 years (n=49) and 74% in those aged <75 years (n=362).6 ADRs were predictable, generally manageable and consistent with the known safety profile of afatinib.6
In another Japanese study in 128 patients with advanced EGFR mutation-positive NSCLC, 76 patients received first-line afatinib and 52 received afatinib following a first generation TKI.7 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–not estimable) and the response rate was 64%.7 Although 76% of these patients required a dose reduction due to AEs, this did not impair efficacy.7 In all patients, the most common AEs leading to dose modification or treatment discontinuation were diarrhoea, paronychia and oral mucositis.7
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).8 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).8
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).9 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.9
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).8 However, in patients with L858R mutations, there was no significant difference in median PFS between treatment groups (p=0.46).8 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).8
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%).8 Common Grade 3 or 4 AEs in the afatinib group included diarrhoea (3%), paronychia (2%) and skin rash (2%).8 Dose reductions due to AEs were more frequent with afatinib (68%) versus gefitinib (2%) or erlotinib (6%). However, afatinib dose reduction did not impair efficacy (median PFS in dose reduction vs no dose reduction groups, 23.5 vs 12.4 months).8
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 efficacy 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 efficacy in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma (30% of patients had brain metastases; 23% had complex or rare EGFR mutations).10 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).10 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).10
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 efficacy 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.11 Of these patients, 56% had exon 19 mutations, 22% had L858R mutations and 22% had uncommon EGFR mutations.11 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.11 Median PFS in patients with and without brain metastases at baseline was 9.9 and 13.1 months, respectively.11
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).12 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.12 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.12
Efficacy 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.13 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.13 Of these, response assessments were available in 1,141 patients; ORR was 23.4% (267/1,141).13 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 20.13 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.
Halmos B, et al. Lung Cancer 2018. doi: https://doi.org/10.1016/j.lungcan.2018.10.028 [Epub ahead of print].
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. Oct 19. doi: 10.2217/fon-2018-0711 [Epub ahead of print].
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).
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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