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Consider a potential TKI sequencing treatment opportunity for your EGFR M+ mNSCLC patients with del192,3,35

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LUX-LUNG 3 DATA

In a pre-specified exploratory subgroup analysis, GILOTRIF achieved nearly 3 years overall survival (OS) in patients with del19 mutations in LUX-Lung 38

Prespecified exploratory subanalysis of a secondary endpoint: Median OS in patients with del19 mutations

Prespecified exploratory subanalysis of the primary endpoint: Median progression-free survival (PFS) in patients with del19 mutations

Prespecified exploratory subanalysis of a secondary endpoint: Median OS in patients with del19 mutations

median os 33.3 months vs. 21.1 months comparison

HR, 0.55† (95% CI, 0.36-0.79)8

Prespecified exploratory subanalysis of the primary endpoint: Median progression-free survival (PFS) in patients with del19 mutations

median pfs 13.7 months vs. 5.6 months comparison

HR, 0.28† (95% CI, 0.18-0.44)1,9

  • A randomized (2:1), multicenter, open-label trial in patients with EGFR M+ metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer [AJCC, 6th edition]) NSCLC

    Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen® EGFR RGQ PCR Kit

  • GILOTRIF 40 mg orally once daily (n=230) vs IV pemetrexed (500 mg/m2)-cisplatin (75 mg/m2) once every 21 days for up to 6 cycles (n=115)

  • Randomization was stratified according to EGFR mutation category (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian)

  • Primary endpoint was PFS, as assessed by an IRC; secondary endpoints included OS

Pre-specified exploratory subgroup analysis of LUX-Lung 3 secondary endpoint (OS): Median OS in del19 population1,*

chart LL3 median OS KM curve

Adverse reactions (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%)

†In a prespecified subgroup analysis of patients with del19 mutation for the secondary endpoint of OS.

LUX-LUNG 3: EXPLORATORY ASIAN PATIENT SUBGROUP DATA

In an exploratory analysis of an Asian patient subgroup of LUX-Lung 39

  • 46% relative reduction in risk of progression or death with GILOTRIF vs pemetrexed-cisplatin in Asian patients (n=249)(HR, 0.54 [95% CI, 0.38-0.76])

  • 32% reduction in risk of progression or death vs pemetrexed-cisplatin in non-Asian patients (n=96)(HR, 0.68 [95% CI, 0.39-1.19])

  • Subgroup analyses were exploratory

LUX-LUNG 3: PREPLANNED EXPLORATORY ANALYSIS OF JAPANESE PATIENTS

OS and PFS results with GILOTRIF vs pemetrexed-cisplatin in preplanned exploratory analysis of Japanese patients in LUX-Lung 316

Limitations: This is a subgroup analysis with smaller patient numbers and, therefore, is not powered to identify potential differences between treatment groups.

lux lung 3 exploratory analysis median os with Gilotrif
lux lung 3 exploratory analysis median pfs with Gilotrif

90% of Japanese patients treated with GILOTRIF in LUX-Lung 3 received subsequent anticancer therapy16

OS and PFS in Japanese patients with del19 mutation16

  • Median OS in Japanese patients with del19 mutation: 46.9 months with GILOTRIF (n=23) vs 31.5 months with pemetrexed-cisplatin (n=16; HR, 0.34 [95% CI: 0.13-0.87])

  • Median PFS in Japanese patients with del19 mutation: 16.4 months with GILOTRIF (n=23) vs 3.1 months with pemetrexed-cisplatin (n=16; HR, 0.16 [95% CI: 0.06-0.39])

LUX-Lung 31,16:

  • A randomized (2:1), multicenter, open-label trial in patients with EGFR M+ metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer [AJCC, 6th edition]) NSCLC

    Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen® EGFR RGQ PCR Kit

  • GILOTRIF 40 mg orally once daily (n=230) vs IV pemetrexed (500 mg/m2)-cisplatin (75 mg/m2) once every 21 days for up to 6 cycles (n=115)
  • Randomization was stratified according to EGFR mutation category (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian)
  • Primary endpoint was PFS, as assessed by an IRC; secondary endpoints included OS
  • A preplanned subgroup analysis of Japanese patients (n=83) in LUX-Lung 3 was performed to confirm if the efficacy and safety of GILOTRIF in Japanese patients were consistent with the overall population
  • All efficacy analyses were performed in an intent-to-treat manner and included all randomized patients

Limitations to the preplanned analysis: this is a subgroup analysis with smaller patient numbers and, therefore, is not powered to identify potential differences between treatment groups.

LUX-Lung 3: Median OS in Japanese patients16

Limitations: This is an exploratory subgroup analysis of a secondary endpoint with smaller patient numbers and is not powered to identify potential differences between treatment groups.

chart LL3 Median OS curve
BRAIN METASTASES

Data on brain metastases in first-line afatinib vs chemotherapy in EGFR M+ mNSCLC patients6,15§

  • LUX-Lung 3 and LUX-Lung 6 trial programs included patients with and without brain metastases at baseline15*

  • LUX-Lung 3: PFS in patients with and without brain metastases GILOTRIF versus chemotherapy15

    In patients with brain metastases, median PFS was 11.1 months for GILOTRIF (n=20) vs 5.4 months for pemetrexed-cisplatin (n=15) (HR, 0.54; 95% CI, 0.23-1.25)

    In patients without brain metastases, median PFS was 13.8 months for GILOTRIF (n=166) vs 8.1 months for pemetrexed-cisplatin (n=82) (HR, 0.48; 95% CI, 0.34-0.69)

In an exploratory pooled post-hoc analysis of LUX-Lung 3 and 6, the incidence of CNS progression was 6.3% in patients without baseline brain metastases6*

Competing risk analysis for progression in patients without baseline brain metastases6

chart brain mets
 FrequencyPercentCumulative FrequencyCumulative Percent
CNS PD226.3226.3
Censored5916.88123.1
Non-CNS PD or death27077351100

Limitations of the analysis: Data censored in 59 of 351 patients (17%). LUX-Lung 3 and 6 were not powered nor error controlled to assess CNS response. Treatment effects observed in this exploratory analysis cannot be regarded as statistically significant. The analysis described here was exploratory.6

T790M PREVALENCE

Many patients with a del19 mutation, up to 70%, may go on to develop a T790M mutation after treatment with first- or second-generation EGFR TKIs13

Pooled analysis of 7 studies on the prevalence of the T790M mutation13

graph analysis of 7 studies on T790M mutation prevalence
GIOTAG REAL-WORLD DATA

GIOTAG STUDY: OVERALL SURVIVAL

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 therapy14

  • 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.

Watch a short video for an overview of the GioTag study

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

  • GioTag is a real-world, global, multicenter, observational study of 203 adult patients with EGFR M+ mNSCLC (del19/L858R). Data were collected via manual medical chart review (n=77) or from electronic health records (n=126).2,3,35

  • Primary outcome of the study was time on treatment, defined as time from first dose of afatinib to that of last dose of osimertinib or death2,3,35

  • Although OS was not a primary outcome of the study, it was measured and included as part of the statistical analysis plan. OS analysis was exploratory and was defined as time from start of afatinib to death.2,3,35

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

GioTag median OS chart

Median time on treatment35

median time on treatment chart

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.

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

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 OS was not a primary outcome of the study, it was measured and included as a part of the statistical analysis plan

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

Review Real World Evidence

CI=confidence interval; EGFR M+=epidermal growth factor receptor mutation-positive; HR=hazard ratio; IRC=independent central review; IV=intravenous; K-M=Kaplan-Meier; NSCLC=non-small cell lung cancer; OS=overall survival; PFS=progression-free survival; TKI=tyrosine kinase inhibitor; CNS=central nervous system; PD=progressive disease.

§LUX-Lung 3 Study Design was a randomized, multicenter, open-label trial with GILOTRIF 40 mg orally once daily (n=230) vs up to 6 cycles of pemetrexed-cisplatin (n=115) as first-line therapy in patients with EGFR M+ mNSCLC; primary endpoint was PFS; key secondary endpoint was OS. LUX-Lung 6 was a randomized, multicenter study comparing treatment with GILOTRIF 40 mg to 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 6 cycles. Limitations of the post-hoc analysis data: Further data on the impact of GILOTRIF on brain metastases are required.1

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.

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NCCN=National Comprehensive Cancer Network® (NCCN®).