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Real-World Evidence with GILOTRIF® (afatinib) in 3 separate studies2-4,35,36

Results are not intended for direct comparison with clinical trials. 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.

GIOTAG REAL-WORLD STUDY

GioTag Study2,3,35

GioTag is the first retrospective, global, real-world study that assessed total treatment duration of GILOTRIF followed by osimertinib

Real-world results are not intended for direct comparison with clinical trials because the real-world study was an 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.

Limitations: The main limitations of this study were its retrospective nature and potential for selection bias. The other main limitation of the study was a lack of a comparator arm, which limits interpretation of the results.

Observational Study: Sequencing treatments with afatinib and osimertinib in patients with EGFR M+ mNSCLC

  • GioTag is a real-world, global, multicenter, observational study of 204 adult patients with EGFR M+ mNSCLC (del19/L858R)
  • The study used existing data from medical records or electronic health records (US only)
  • Patients had T790M disease following first-line afatinib and had started on osimertinib treatment ≥10 months prior to data entry
  • The primary outcome was median time to treatment failure, also referred to as time on treatment (defined as the time from the first dose of afatinib to the time of the last dose of osimertinib or death)
  • The secondary outcome was the type and proportion of acquired resistance mechanisms after osimertinib treatment
  • Although overall survival (OS) was not a primary outcome of the study, it was measured and included as a part of the statistical analysis plan

GioTag exploratory analysis of OS observed median OS of 41.6 months in del19 patients with EGFR M+ mNSCLC that had developed T790M35*

Many patients (range: 40% to 73%) with del19 mutations may develop T790M mutations after treatment with first- or second‑generation EGFR TKIs10-13

Patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy may be treated with osimertinib, the only approved T790M inhibitor, in second-line therapy.14

GioTag Final Analysis Exploratory Endpoint Data: Median Overall Survival (OS)35

GioTag median OS chart

Median time on treatment35

median time on treatment chart

GILOTRIF first-line may offer patients with a del19 mutation the opportunity of a targeted treatment sequence2,3,35

Real-world results are not intended for direct comparison with clinical trials because the real-world study was an 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. The main limitations of this study were its retrospective nature and potential for selection bias. The other main limitation of the study was a lack of a comparator arm which limits interpretation of the results.4

GioTag is a real-world, global, multicenter study of 204 adult patients with EGFR M+ NSCLC (del19/L858R). The study used existing data from medical records or electronic health records (US only).

SQUAMOUS mNSCLC REAL WORLD STUDY

Squamous mNSCLC Real-World Study36

The objectives of this real-world study were to determine time on second-line (2L) GILOTRIF treatment for squamous mNSCLC patients who progressed on 1L immunotherapy (IO) plus platinum-based chemotherapy and incidence of severe immune-related AEs (irAEs). Time on treatment was defined as time from start to end of 2L treatment on GILOTRIF; severe irAEs were defined as Grade 3/4 AEs.

Study design: Physicians retrospectively abstracted data from medical records of adult patients (n=200) with advanced/metastatic NSCLC of squamous or mixed histology who had received 1L treatment with pembrolizumab plus platinum-based chemotherapy, followed by 2L GILOTRIF or chemotherapy.

Results are not intended for direct comparison with clinical trials. 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.

Limitations: This study reports real-world data from retrospective medical chart reviews. It is intended to supplement, not replace, randomized controlled clinical trials. The limitations of this study include: 1) Potential for significant patient selection bias due to its retrospective nature and risk of under-reporting of adverse events including unverified severe irAEs; 2) The study was not powered to formally compare outcomes between cohorts; 3) Risk of censoring bias (54% of afatinib-treated/41% of non-afatinib treated still receiving 2L at data collection); 4) All data were abstracted by trained physicians personally managing each patient and source EMR data were not reviewed; 5) Confounding factors that might have influenced prescribing behaviors and treatment decisions were not captured. See publication for complete list of study limitations.36

Real-world outcomes with GILOTRIF following first-line (1L) pembrolizumab plus platinum-based chemotherapy36

Median time on treatment from initiation of second-line (2L) therapy36

The study was not powered to compare characteristics or outcomes between the 2L afatinib and 2L chemotherapy cohorts.

Please note that this study is real-world data, not the results of a randomized clinical trial and is provided for informational purposes, not to be the basis of treatment decision. Treatment decisions should be based on clinical experience and Prescribing Information.

median time on afatinib and chemo

Immune-related adverse events (irAEs) in patients treated with GILOTRIF following 1L pembrolizumab plus platinum-based chemotherapy36

PatientirAE in first lineirAE in second line
1Grade 3 pneumonitisGrade 4 pneumonitis
2Grade 3 hepatitisGrade 2 hepatitis
3Grade 3 colitisGrade 3 pneumonitis
4Grade 3 pneumonitisGrade 3 colitis
5Grade 3 indeterminant pulmonary eventGrade 3 pneumonitis
6Grade 3 pneumonitisGrade 3 colitis

6 patients had Grade 3/4 immune-related adverse events (irAEs included colitis, hepatitis, and pneumonitis) during 2L GILOTRIF treatment; all 6 patients previously had a Grade 3/4 irAE during 1L therapy.3

Other adverse events (AEs) (≥5%), n (%), 2L GILOTRIF (n=99)

Any AEs37 (37%)
Diarrhea‡26 (26%)
Skin rash6 (6%)
Stomatitis5 (5%)
Fatigue5 (5%)

‡The most common adverse drug reaction in the 2L GILOTRIF cohort was diarrhea.

REALGIDO REAL-WORLD STUDY

RealGiDo Study4

Limitations: The main limitations of the study were its retrospective nature and potential for selection bias. Sites that had experience prescribing afatinib and managing adverse events regularly were included in the study, however, enrollment was capped at 15 patients per site.

Results are not intended for direct comparison with clinical trials. 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.

Study design

  • A non-interventional, observational, global, retrospective study conducted in 228 patients enrolled from 13 countries treated with GILOTRIF tablets
  • Sites were included based on the commercial availability of afatinib prior to January 1, 2015 and the use of afatinib having been adopted as routine care for patients with EGFR mutations
  • Medical records of consecutive patients who met the following criteria were reviewed: aged ≥18 years with EGFR-mutated (del19/L858R), TKI-naïve, advanced NSCLC who were treated with first-line afatinib within the approved label and provided written informed consent where required
  • Inclusion was also restricted to patients with treatment initiation ≥6 months prior to enrollment
  • Patients were excluded if they had any contraindications to afatinib based on the label, had NSCLC with uncommon mutations, or had been treated within a clinical trial

Primary safety and efficacy outcomes

  • Percentage of patients with adverse drug reactions by severity
  • Time to treatment failure; synonymous with time on treatment
  • Time to progression

Secondary outcomes

  • Percentage of patients with a starting dose modification
  • Reasons for a starting dose modification

TKI=tyrosine kinase inhibitor.

Real-world evidence reinforces that GILOTRIF dose adjustments may reduce the frequency and severity of adverse reactions (ARs) with no apparent compromise on effectiveness4,6

  • GILOTRIF starting dose in RealGiDo: 73 patients received a starting dose other than 40 mg/day; 155 patients received recommended starting dose of 40 mg/day†
  • Primary outcomes were adverse drug reaction (ADR) incidence and severity, time to treatment failure (TTF), and time to progression (TTP), relative to LUX-Lung 3

†Although assessed as part of a global study, not all are approved doses in the US.

RealGiDo: Safety profile in patients who received a modified GILOTRIF dose ≤6 months after starting on GILOTRIF 40 mg4,6

Overall (grade ≥3) incidences of most common ARs (n=56)

ARPre-dose modification (%)Post-dose modification (%)
Diarrhea13.71.4
Oral mucositis8.21.4
Rash acneiform9.62.7
Paronychia1.42.7

Overall incidence of ARs pre- and post-dose modification (n=91)

ARs (all grades)98.671.2

Median time to treatment failure and progression in RealGiDo4

Median time to treatment failure§

chart median TTF

Median time to progression§

chart median TTP

NE=not evaluable.

§Time to treatment failure is defined as the time from the first dose of afatinib to the last dose of afatinib. Time to progression is defined as the time from the first dose of afatinib to the earliest occurrence of documented progression or death.

RealGiDo Study: Common adverse drug reactions (>10% incidence) pre- and post-dose reduction within the first 6 months after starting on GILOTRIF 40 mg/day (n=91)4

RealGiDo study adverse reaction chart

Results are not intended for direct comparison with clinical trials. 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.

Limitations: The main limitations of the study were its retrospective nature and potential for selection bias. Sites that had experience prescribing afatinib and managing adverse events regularly were included in the study, however, enrollment was capped at 15 patients per site.

ARs reported in LUX-Lung 3 in ≥10% of GILOTRIF-treated patients1*

Adverse reactionGILOTRIF (n=229) Grade 3,† %Pemetrexed-cisplatin (n=111) Grade 3,† %GILOTRIF (n=229) All grades, %Pemetrexed-cisplatin (n=111) All grades, %
Gastrointestinal disorders
Diarrhea1529623
Stomatitis‡917115
Cheilitis00121
Skin and subcutaneous tissue disorders
Rash/acneiform dermatitis§1609011
Pruritus00211
Dry skin00312
Infections
Paronychia||110580
Cystitis10135
Respiratory, thoracic, and mediastinal disorders
Epistaxis01172
Rhinorrhea00116
Investigations
Weight decreased111714
General disorders and administration site conditions
Pyrexia00126
Eye disorders
Conjunctivitis00113

*NCI CTCAE v3.0.

†None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity.

‡Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration.

§Includes acne, acne pustular, dermatitis, acneiform dermatitis, dermatosis, drug eruption, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin disorder, skin erosion, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer.

||Includes paronychia, nail infection, nail bed infection.

Other clinically important ARs observed in patients treated with GILOTRIF include decreased appetite (29%), nausea (25%), and vomiting (23%)1

Serious ARs reported in LUX-Lung 3

  • Serious ARs were reported in 29% of patients treated with GILOTRIF. The most frequent serious ARs reported in patients treated with GILOTRIF were diarrhea (6.6%), vomiting (4.8%), and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal ARs in GILOTRIF-treated patients included pulmonary toxicity/ILD-like ARs (1.3%), sepsis (0.43%), and pneumonia (0.43%)

Discontinuations in LUX-Lung 3

  • Discontinuation of therapy in GILOTRIF-treated patients for ARs was 14%
  • The most frequent ARs that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%)

These results suggest afatinib was an effective 1st-line treatment for patients with EGFR M+ mNSCLC and that modifying the afatinib dose based on adverse events may reduce the frequency and intensity of ADRs without compromising effectiveness4

Results are not intended for direct comparison with clinical trials. 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.

Dose Modification strategies

ARs=adverse reactions; TTF=time to treatment failure; TTP=time to treatment progression.

INDICATIONS AND USAGE

GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.

Limitations of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations.

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (afatinib) TABLETS WARNINGS AND PRECAUTIONS
Diarrhea
  • GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
  • For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
  • Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.
Bullous and Exfoliative Skin Disorders
  • GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
  • Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
  • Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.
Interstitial Lung Disease
  • Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
  • Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
  • Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
  • Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.
Gastrointestinal Perforation
  • Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
  • Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
  • Permanently discontinue GILOTRIF in patients who develop GI perforation.
Keratitis
  • Keratitis has been reported in patients taking GILOTRIF.
  • Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryo-Fetal Toxicity
  • GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
  • Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
ADVERSE REACTIONS
Adverse Reactions observed in clinical trials were as follows:
First-line treatment of EGFR mutation-positive, metastatic NSCLC
  • In GILOTRIF-treated patients (n=229) the most common adverse reactions (≥20% all grades & vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/acneiform dermatitis (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%) and pruritus (21% vs 1%). Other clinically important adverse reactions observed in patients treated with GILOTRIF include: decreased appetite (29%), nausea (25%), and vomiting (23%).
  • Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
  • More GILOTRIF-treated patients (2.2%) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%).
Previously Treated, Metastatic Squamous NSCLC
  • In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
  • Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
  • Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
  • Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
  • GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.
Renal Impairment
  • Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.
Hepatic Impairment
  • GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI 10.21.19

Please see full Prescribing Information, including Patient Information.

  1. GlLOTRIF [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.
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NCCN=National Comprehensive Cancer Network® (NCCN®).