GIOTRIF®
Efficacy
Clinical Trials
Afatinib clinical trials results in NSCLC
Afatinib has been extensively investigated as part of the LUX-Lung clinical trial programme.
The table below gives an overview of the pivotal trials for afatinib, LUX-Lung 3, 6 and 8, as well as LUX-Lung 7, a head-to-head trial comparing afatinib and gefitinib for 1st-line use in EGFR M+ NSCLC.1–4
Explore the data and find out how your NSCLC patients could benefit from afatinib.
aKey secondary endpoint
LUX-Lung 3 Clinical Trial
Afatinib compared with chemotherapy for 1st-line treatment in EGFR M+ NSCLC.
Study design
Global, randomised, open-label, Phase III study in patients with advanced lung adenocarcinoma, proven EGFR mutations (N=345) and stable brain metastases, comparing 1st-line afatinib with cisplatin plus pemetrexed chemotherapy. Patients were randomly assigned in a 2:1 fashion to oral afatinib 40 mg once per day (n=230) or intravenous cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 once every 21 days up to a maximum of six cycles (n=115). Treatment continued until investigator-assessed progression or death. The primary endpoint was PFS by independent review. Secondary endpoints included ORR, OS, AEs, and patient-reported outcomes.1,5
PFS
Afatinib in 1st-line significantly improved PFS compared with chemotherapy1,6
Adapted from Sequist L, et al. 2013.1
- In the overall population, median PFS was 11.1 months for afatinib compared with 6.9 months with pemetrexed/cisplatin (HR: 0.58; 95% CI: 0.43–0.78; p<0.001)1
- In Del19 patients, median PFS was 13.8 months for afatinib compared with 5.6 months with pemetrexed/cisplatin (HR: 0.26; 95% CI: 0.17–0.42; p<0.0001)6
OS (pre-planned analyses)
Afatinib in 1st-line demonstrated a median OS of 31.6 months in patients with common mutations7
Adapted from Yang JC, et al. 2015.7
Afatinib in 1st-line resulted in a median OS of almost 3 years in patients with a Del19 mutation7
Adapted from Yang JC, et al. 2015.7
HRQoL
Afatinib in 1st-line significantly delayed time to deterioration of cough and dyspnea compared with chemotherapy8,9
Adapted from Wu YL, et al. 2014.8
Afatinib in 1st-line demonstrated significantly superior HRQoL scores compared with chemotherapy, including physical, role and cognitive functioning9
Adapted from Yang JC, et al. 2013.9
Safety
The most common AEs with afatinib were diarrhoea, stomatitis, rash, acne and paronychia.1
Adapted from Yang JC, et al. 2016.10
Post hoc analysis: dose modification effectively reduced AE incidence and severity, with no effect on treatment efficacy10
There was no significant difference in PFS in patients receiving a dose reduction in the first 6 months compared with those who remained on ≥40 mg.10
- Median PFS 11.3 vs. 11.0 months (HR:1.25; 95% CI:0.91–1.72; p=0.175)
Average trough plasma concentrations of afatinib were higher in the patient population that subsequently received a reduced dose compared with those that remained on a 40 mg dose, with similar trough plasma concentrations achieved following dose modification.10
LUX-Lung 6 Clinical Trial
Afatinib compared with chemotherapy for 1st-line treatment in EGFR M+ NSCLC.
Study design
Randomised, open-label, Phase III study at 36 centres in China, Thailand, and South Korea, comparing 1st-line afatinib with gemcitabine and cisplatin in Asian patients with EGFR M+ advanced NSCLC (N=364). Patients were randomly assigned (2:1) to receive either oral afatinib 40 mg once per day (n=242) or intravenous gemcitabine 1000 mg/m² on Day 1 and Day 8 plus cisplatin 75 mg/m² on day 1 of a 3-week schedule for up to six cycles (n=122). Patients with stable brain metastases were permitted in the trial. The primary endpoint was PFS by independent review or death. Secondary endpoints included ORR, OS, duration of response, AEs, and patient-reported outcomes.2,7
PFS
Afatinib in 1st-line significantly improved PFS compared with chemotherapy2
Adapted from Wu YL, et al. 2014.2
OS (pre-planned analysis)
Afatinib in 1st-line provided >1 year median OS improvement in patients with Del19 mutations compared with chemotherapy7
Adapted from Yang JC, et al. 2015.7
Safety
The most common AEs with afatinib were diarrhoea, stomatitis, rash, acne and paronhychia.7
Adapted from Yang JC, et al. 2016.10
There was no significant difference in PFS in patients receiving a dose reduction in the first 6 months compared with those who remained on ≥40 mg.10
- Median PFS 12.3 vs. 11.0 months (HR=1.00; 95% CI:0.69–1.46; p=0.982)
Average trough plasma concentrations of afatinib were higher in the patient population that subsequently received a reduced dose compared with those that remained on a 40 mg dose, with similar trough plasma concentrations achieved following dose modification.10
LUX-Lung 7 Clinical Trial
Afatinib compared with gefitinib for 1st-line treatment in EGFR M+ NSCLC.
Study design
Global, open-label, exploratory, randomised controlled Phase IIB trial comparing 1st-line afatinib with the 1st-generation EGFR-TKI gefitinib in patients with EGFR mutation-positive advanced NSCLC (N=319). Patients were randomly assigned (1:1) to receive afatinib 40 mg once per day (n=160) or gefitinib 250 mg once per day (n=159) until disease progression, or beyond if deemed beneficial by the investigator. Co-primary endpoints were PFS by independent central review, TTF, and OS. Secondary endpoints included ORR, AEs and HRQoL.3
PFS
Adapted from Park K, et al. 2016.3
Afatinib in 1st-line significantly improved PFS* and reduced the risk of progression by 27% compared with gefitinib, with over twice as many patients progression-free at 2 years3
PFS at 2 years of 18% (n=21) compared with 8% (n=7) for afatinib compared with gefitinib, respectively.3
TTF
Afatinib in 1st-line significantly improved TTF* compared with gefitinib3
Adapted from Park K, et al. 2016.3
ORR
Afatinib in 1st-line significantly improved response rates compared with gefitinib3
Adapted from Park K, et al. 2016.3
Safety
The most common AEs with afatinib were diarrhoea, stomatitis, rash, acne and paronychia.3
LUX-Lung 8 Clinical Trial
Afatinib compared with erlotinib for the treatment of 2nd-line SqCC after prior platinum-based chemotherapy.
Study design
An open-label, phase III, randomised and controlled trial which compared afatinib with erlotinib in patients with stage IIIB or IV squamous cell carcinoma of the lung, who had progressed after at least 4 rounds of platinum-based chemotherapy (n=795). Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The primary endpoint was PFS by independent review and the key secondary endpoint was OS.4
PFS
OS
Afatinib significantly improved PFS compared with erlotinib in unselected NSCLC patients who received prior chemotherapy4
Adapted from Soria JC, et al. 2015.4
Afatinib showed superior OS compared with erlotinib in patients with unselected 2nd-line SqCC after chemotherapy4
Adapted from Soria JC, et al. 2015.4
HRQoL
Afatinib improved cough and quality of life compared with erlotinib in 2nd-line SqCC following chemotherapy4
Adapted from Soria JC, et al. 2015.4
Safety
The most common AEs for afatinib were diarrhoea, rash, acne, stomatitis and fatigue.4
Real-World Evidence
Afatinib’s real-world evidence
Real-world evidence demonstrates therapy effectiveness under a clinical setting, complementing data obtained from controlled clinical trials.12,13
Clinical trials are necessary for establishing comparative efficacy and safety under optimal conditions.12 However, they can be limited in terms of extrapolation to the general public.13 This is where real-world evidence is useful, indicating the level of success across the whole patient population without controlled variables.12,13
- Real-world studies include everyday patients with characteristics which might otherwise preclude them from participation in randomised controlled trials14
- Real-world studies can help to identify rare or late AEs12,14
- Real-world studies and randomised controlled trials have different set ups and priorities13
An overview of some of the studies providing real-world evidence for afatinib are described in the table below. Discover how patients in real-world clinical practice benefited from afatinib.
Final analysis of the real-world GioTag study: survival and time to treatment failure data
The GioTag study is a global, real-world, retrospective, observational, unblinded study that assessed the impact of 1st-line treatment with afatinib followed by osimertinib in patients with EGFR M+ NSCLC who acquired a T790M mutation on afatinib progression.17
The study was conducted across 10 countries, with patients enrolled between December 2017 and May 2018.15,17
Data were collected between December 2017 and December 2019. Data were sourced either from sites directly approached by Boehringer Ingelheim (n=77; 38%) or from electronic health records (n=126; 62%).17
Final TTF and OS analyses of patients in the GioTag study have now been conducted.17
Final results indicate that afatinib followed by osimertinib was an effective therapeutic strategy in a broad, real-world population of patients with EGFR M+ NSCLC,* with encouraging results in patients with a Del19 mutation and patients of Asian ethnicity17
Study design
- To limit selection bias each participating centre assessed the health records of a maximum of 15 consecutive patients17
- All patients must have initiated osimertinib ≥10 months prior to enrolment to avoid early censoring and ensure mature data17
- Data cut-off for the final analysis was 28 November 2019. Data for all enrolled patients were included, apart from 1 patient who was excluded due to reports of conflicting data17
For the final analysis, data were collected from 203 EGFR-TKI-naïve patients with T790 Macquired resistance, including 149 patients with a Del19 mutation and 50 patients of Asian ethnicity.17
- At baseline, 10% of patients had CNS metastases and 15% of patients had ECOG performance status ≥217
This final analysis represents the most mature analysis to date of OS with sequential afatinib and osimertinib.17
Data for the overall population are 59% mature and data for patients of Asian ethnicity are 50% mature.18
Patients with a Del19 mutation
In patients with a Del19 mutation, median OS was 3.5 years (41.6 months)17‡
- In the overall population, median OS was 37.6 months (90% CI: 35.5–41.3) and TTF was 27.7 months (90% CI: 26.7–29.9)17‡§
Patients of Asian ethnicity
Afatinib maintained consistent effectiveness regardless of dose modification16
- In patients of Asian ethnicity with a Del19 mutation (n=31), median OS was 45.7 months (90% CI: 38.2–57.8) and TTF was 40.0 months (90% CI: 36.4–45.0)17‡
Limitations of the GioTag study
Real-world evidence has the potential to complement clinical trial data and may help to support treatment decisions based upon outcomes from clinical practice14
Real-world evidence has limitations14
- Real-world studies are often retrospective in nature and results may be impacted by confounding factors4
Results from the GioTag study may be impacted by limitations of the study design
- The main limitations were its retrospective nature and potential for selection bias17
- The other main limitation was a lack of a comparator arm, which limits interpretation of the results17
- Patients who died on 1st-line afatinib were excluded from the study, which introduced an immortal time bias15
- Owing to the study timelines and dates of drug approvals and availability, patients who derived long-term benefit from 1st-line afatinib had little chance of being enrolled in the study and may therefore have been under-represented15
Results are not intended for direct comparison with prospective clinical trials because the real-world study was a retrospective, observational trial with no comparator arm. Differences in study designs, patient populations, definitions of safety or efficacy outcomes, as well as data collection methods, make it difficult to compare real-world studies with clinical trials.
RealGiDo real-world evidence study
Real-world evidence demonstrates therapy effectiveness under a clinical setting, complementing data obtained from controlled clinical trials.12,13
The RealGiDo study is a global study of afatinib 1st-line which analysed the impact of afatinib dose adjustments on effectiveness and safety in EGFR M+ NSCLC patients.16
It confirmed the results seen in clinical trials, demonstrating that afatinib dose adjustments reduce AEs without affecting efficacy.10,16,19
Study design
Global, non-interventional, observational study assessing afatinib dose modification effectiveness as a means of reducing ADRs and impact on outcome. Medical records of 228 patients with EGFR mutations prescribed afatinib 1st-line as part of routine care were assessed. Primary outcomes were to assess the effects of afatinib dose modification on the frequency and severity of ADRS, time on treatment and time to progression with afatinib in the real-world setting and compare with data from the LUX-Lung 3 trial in a descriptive manner. Secondary outcomes were the percentage of patients receiving a modified starting dose of afatinib, and reasons for modifying the starting dose.16
Study population
- 44% (n=100), 42% (n=96), 1% (n=3) and 13% (n=29) of patients were of Asian, Caucasian, other or had missing ethnicity, respectively16
- 12% (n=19) of all patients had an ECOG PS score of 2–316
- 32% (n=73) of patients had a modified starting dose of afatinib: 1% (n=2), 30% (n=69) and 1% (n=2) starting on a 50 mg/day, 30 mg/day and 20 mg/day dose, respectively16¶
Safety
Afatinib dose modifications reduced the incidence and severity of ADRs in real-world clinical practice16
Adapted from Halmos B, et al. 2018.16
TTF
Afatinib maintained consistent effectiveness regardless of dose modification16
Adapted from Halmos B, et al. 2018.16
- Median TTF was 18.7 months, which was not impacted by starting dose or dose modifications16¶
Uncommon EGFR pooled analysis: comprehensive data from patients with uncommon mutations receiving afatinib
The pooled analysis assessed the clinical outcomes of 693 EGFR M+ NSCLC patients harboring uncommon mutations that were treated with afatinib. Published data were obtained from: LUX-Lung 3 & 6 randomised controlled trials, LUX-Lung 2 single arm Phase ll clinical trial, compassionate use and expanded access programmes, Phase lllb trials, real-world trials and series/reports. Clinical outcomes by individual genotype were generated into a searchable database.
Afatinib demonstrated clinical activity in patients with NSCLC with major uncommon and compound EGFR mutations, with broad activity in other uncommon EGFR mutations and some exon 20 insertions.||
Study design
Adapted from Yang JCH, et al. 2020.
Data in EGFR-TKI naive patients and EGFR-TKI pre-treated patients with uncommon EGFR mutations who received afatinib were included, using prospectively collected published data since the beginning of clinical development of afatinib by Boehringer Ingelheim medical information as well as from a systematic literature review. All cases with ORR and TTF outcomes were included in the analysis.20
ORR values of up to 78.3% were reported in the Uncommon EGFR pooled analysis for patients
treated with afatinib20
Data taken from JCH, et al. 2020.
Data taken from Yang JCH, et al. 2020.
TTF durations of up to 16.6 months were reported in the Uncommon EGFR pooled analysis20
- TTF responses to afatinib treatment were seen in patients with major uncommon mutations20
Data taken from Yang JCH, et al. 2020.
Data taken from Yang JCH, et al. 2020.
Footnotes:
-
*Co-primary endpoints were PFS, TTF, and OS. OS for afatinib compared with gefitinib was not statistically significant (median 27.9 vs. 24.5 months, respectively; HR=0.86; 95%
CI: 0.66–1.09; p=0.1950).3,11 -
†Displayed are the results of the PFS assessment performed at the time of OS assessment. Primary analysis of PFS was performed once the requisite number of events judged by
central independent review had been reached and occurred while recruitment was ongoing. Median PFS for afatinib and erlotinib was 2.6 and 1.9 months, respectively (HR: 0.81;
95% CI: 0.69–0.96; p=0.0103).4 -
‡ Patients who acquire a T790M mutation on progression with afatinib.
-
§At the start of treatment with afatinib, 73.5% of patients had a Del19 mutation.
-
¶The recommended starting dose for afatinib is 40mg once daily
-
|| T790M, exon 20 insertion and major uncommon mutation negative.
-
**Compound mutations were defined as cases where at least 2 uncommon mutations were present with or without a common mutation.20
-
ADRs, adverse drug reactions; AE, adverse event; CI, confidence interval; CNS, central nervous system; Del19, deletion 19; ECOG, Eastern Cooperative Oncology Group; EGFR,
epidermal growth factor receptor; EGFR M+, pidermal growth factor receptor mutation positive; EORTC QLQ-30, European Organisation for Research and Treatment of Cancer 30-
question quality of life questionnaire; HR, hazard ratio; HRQoL, health-related quality of life; mTTF, median time to treatment failure; NSCLC, non-small cell lung cancer; ORR,
objective response rate; OS, overall survival; PFS, progression-free survival; SqCC, squamous cell carcinoma; TKI, tyrosine kinase inhibitor; TTD, time to
deterioration; TTF, time to treatment failure.
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