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Pharmacology: Pharmacodynamics: Mechanism of action: Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.
Pharmacodynamic effects: Aberrant ErbB signalling triggered by, for instance, EGFR mutations and/or amplification, HER2 amplification or mutation and/or ErbB ligand or receptor overexpression contributes to the malignant phenotype in subsets of patients across multiple cancer types.
In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signalling resulting in tumour growth inhibition or tumour regression. NSCLC models with either L858R or Del 19 EGFR mutations are particularly sensitive to afatinib treatment.
The acquisition of a secondary T790 mutation is a major mechanism of acquired resistance to afatinib and gene dosage of the T790M - containing allele correlates with the degree of resistance in vitro. The T790M mutation is found in approximately 50% of patients' tumours upon disease progression on afatinib, for which T790M targeted EGFR TKIs may be considered as a next line treatment option.
Cardiac Electrophysiology: GIOTRIF at doses of 50 mg daily did not result in significant prolongation of the QTcF interval after single and multiple administrations in patients with relapsed or refractory solid tumours. There were no cardiac safety findings of clinical concern. This suggests that GIOTRIF does not have a relevant effect on the QTcF interval.
Clinical trials: GIOTRIF in Non-Small Cell Lung Cancer (NSCLC): The efficacy and safety of GIOTRIF as second line treatment of patients with NSCLC of squamous histology was investigated in an open-label active controlled trial LUX-Lung 8.
GIOTRIF in EGFR mutation positive patients naïve to EGFR TKI treatment: LUX-Lung 3 (1200.32): In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-positive locally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a global, randomised, multicenter, open-label trial (LUX-Lung 3). Patients naïve to prior systemic treatment for their advanced or metastatic disease were screened for the presence of 29 different EGFR mutations using a polymerase chain reaction (PCR) based method (TheraScreen: EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients (N=345) were randomised (2:1) to receive GIOTRIF 40 mg orally once daily (N=230) or up to 6 cycles pemetrexed/cisplatin (N=115). Randomisation was stratified according to EGFR mutation status (L858R; Del 19; other) and race (Asian; non-Asian). Dose escalation of GIOTRIF to 50 mg was allowed after the first treatment cycle (21 days) if patients had no or limited drug-related adverse events (i.e. absence of diarrhoea, skin rash, stomatitis, and/or other drug related events above CTCAE Grade 1), were compliant, and had no prior dose reduction.
Among the patients randomized, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 72% were Asian and 26% were Caucasian. The majority of patients had a tumour sample with an EGFR mutation categorized as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.
The primary endpoint of PFS (independent review, 221 events) showed a statistically significant improvement in PFS for patients treated with GIOTRIF compared with patients treated with chemotherapy (median PFS 11.1 vs. 6.9 months). When comparing the pre-specified subgroup of common (L858R or Del 19) EGFR mutations, the difference in PFS was further pronounced (median PFS: 13.6 vs 6.9 months). The percentages of patients being alive and progression-free (PFS rate) at 12 months were 46.5% in patients treated with GIOTRIF and 22% in patients treated with chemotherapy for the overall trial population, and 51.1% vs. 21.4% in the subgroup of common mutations.
The Kaplan-Meier curves of the primary PFS analysis are shown in Figure 1, and efficacy results are summarised in Table 1. At the time of primary PFS analysis, a total of 45 (20%) patients treated with GIOTRIF and 3 (3%) patients treated with chemotherapy were known to be alive and progression-free and thus censored in Figure 1. (See Figure 1 and Table 1.)
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Click on icon to see table/diagram/imageIn the pre-defined EGFR mutation subgroups, the median OS with first-line GIOTRIF vs chemotherapy was 33.3 months vs 21.1 months (HR=0.54, (95% CI 0.36-0.79), p=0.0015) in patients with Del19 (n=169) and 27.6 months vs 40.3 months (HR=1.30, (95% CI: 0.80-2.11), p=0.2919) in patients with L858R (n=138).
PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 2). Mean scores over time for overall quality of life, global health status and physical, role, and cognitive functioning were significantly better for GIOTRIF. (See Table 2.)
Click on icon to see table/diagram/imageLUX-Lung 7 (1200.123): LUX-Lung 7 is a randomised, global, open label Phase IIb trial investigating the efficacy and safety of GIOTRIF in patients with locally advanced or metastatic lung adenocarcinoma (stage IIIB or IV) with EGFR mutations in the first-line setting. Patients were screened for the presence of activating EGFR mutations (Del 19 and/or L858R) using the TheraScreen EGFR RGQ PCR Kit, Qiagen Manchester Ltd. Patients (N=319) were randomised (1:1) to receive GIOTRIF 40 mg orally once daily (N=160) or gefitinib 250 mg orally once daily (N=159). Randomisation was stratified according to EGFR mutation status (Del 19; L858R) and presence of brain metastases (yes; no).
Among the patients randomised, 62% were female, the median age was 63 years, 16% of patients had brain metastases, the baseline ECOG performance status was 0 (31%) or 1 (69%), 57% were Asian and 43% were non-Asian. Patients had a tumour sample with an EGFR mutation categorized as either exon 19 deletion (58%) or exon 21 L858R substitutions (42%).
The co-primary endpoints include PFS by independent review and OS. Secondary endpoints include ORR and DCR. GIOTRIF significantly improved PFS and ORR in EGFR mutation positive patients compared to gefitinib. The efficacy results are summarized in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageThe PFS hazard ratio for patients with DEL 19 mutations and L858R mutations was 0.76 (95% CI [0.55, 1.06]; p=0.1071), and 0.71 (95% CI [0.47, 1.06]; p=0.0856) respectively for afatinib vs gefitinib.
Analysis of GIOTRIF's efficacy in EGFR TKI naïve patients with tumours harbouring uncommon EGFR Mutations (LUX-Lung 2, -3 and -6): In three clinical trials of GIOTRIF with prospective tumour genotyping (Phase 3 trials LUX-Lung 3 and -6), and single arm Phase 2 trial LUX-Lung 2), an analysis was conducted of data from a total of 75 TKI-naive patients with advanced (stage IIIb-IV) lung adenocarcinomas harbouring uncommon EGFR mutations, which were defined as all mutations other than Del 19 and L858R mutations. Patients were treated GIOTRIF 40 mg (all three trials) or 50 mg (LUX-Lung 2) orally once daily.
In patients with tumours harbouring either G719X (N=18), L861Q (N=16), or S768I substitution mutation (N=8), the confirmed ORR was 72.2%, 56.3%, 75.0%, respectively, and the median duration of response was 13.2 months, 12.9 months and 26.3 months, respectively (see table 4).
Click on icon to see table/diagram/imageIn patients with tumours harbouring exon 20 insertions (N=23) the confirmed ORR was 8.7% and the median duration of response was 7.1 months. In patients with tumours harbouring de-novo T790M mutations (N=14) the confirmed ORR was 14.3% and the median duration of response was 8.3 months.
GIOTRIF in patients with NSCLC of squamous histology: LUX-Lung 8 (1200.125): The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced NSCLC of squamous histology was investigated in a randomized open-label global Phase III trial LUX-Lung 8. Patients who received at least 4 cycles of platinum-based therapy in the first line setting were subsequently randomized 1:1 to daily GIOTRIF 40 mg or erlotinib 150 mg until progression. Dose escalation of GIOTRIF to 50 mg was allowed after first cycle (28 days) on treatment in case of no or limited drug related adverse events (i.e. absence of diarrhoea, skin rash, stomatitis, and/or other drug related events above CTCAE Grade 1), compliant dosing and no prior dose reduction. Randomization was stratified by race (Eastern Asian vs non Eastern Asian). The primary endpoint was PFS (analysed when at least 372 events were reported by independent review); OS was the key secondary endpoint (analysed at first 632 deaths). Other secondary endpoints included ORR, DCR, change in tumour size and HRQOL.
Among 795 patients randomized, the majority were males (83.8%), white (72.8%), current or former smokers (91.6%) with baseline performance status ECOG 1 (66.8%).
Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLC compared to erlotinib. In the primary PFS analysis median PFS was 2.43 months in the GIOTRIF group and 1.94 month on erlotinib (HR=0.82, 95% CI (0.676, 0.998), p=0.0427). The final PFS analysis including all randomized patients confirmed earlier results (Table 5). The primary analysis of OS demonstrated significant reduction in the risk of death for patients treated with GIOTRIF compared with erlotinib (HR=0.81 95% CI (0.69, 0.95), p=0.0077) with significantly higher proportions of GIOTRIF-treated patients alive at the landmark points throughout the period of observation such as 12 and 18 months post randomization.
The rates of objective tumour response and stabilization of disease were higher with GIOTRIF. The median duration of response was 7.29 months on GIOTRIF and 3.71 on erlotinib. (See Table 5 and Figure 2.)
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Click on icon to see table/diagram/imagePFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 6.)
Click on icon to see table/diagram/imagePharmacokinetics: Absorption and distribution: Following oral administration of GIOTRIF, maximum concentrations (Cmax) of afatinib are observed approximately 2 to 5 hours post dose. Mean Cmax and AUC0-∞ values increased slightly more than proportional in the dose range from 20 mg to 50 mg GIOTRIF. Systemic exposure to afatinib is decreased by 50% (Cmax) and 39% (AUC0-∞), when administered with a high-fat meal compared with administration in the fasted state. Based on population pharmacokinetic data derived from clinical trials in various tumour types, an average decrease of 26% in AUCτ,ss was observed when food was consumed within 3 hours before or 1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking GIOTRIF (see Dosage & Administration and Interactions). After administration of GIOTRIF, the mean relative bioavailability was 92% (adjusted gMean ratio of AUC0-∞) when compared to an oral solution.
In vitro binding of afatinib to human plasma proteins is approximately 95%.
Metabolism and excretion: Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins are the major circulating metabolites of afatinib.
Following administration of an oral solution of 15 mg afatinib, 85.4% of the dose was recovered in the faeces and 4.3% in urine. The parent compound afatinib accounted for 88% of the recovered dose. The apparent terminal half-life is 37 hours. Steady state plasma concentrations of afatinib are achieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold (AUC) and 2.11-fold (Cmax).
Renal impairment: Less than 5% of a single dose of afatinib is excreted via the kidneys. Exposure to afatinib in subjects with renal impairment was compared to healthy volunteers following a single dose of 40 mg GIOTRIF. Subjects with moderate renal impairment (n=8; eGFR 30-59 mL/min/1.73m2, according to the Modification of Diet in Renal Disease [MDRD] formula) had an exposure of 101% (Cmax) and 122% (AUC0-tz) in comparison to their healthy controls. Subjects with severe renal impairment (n=8; eGFR 15-29 mL/min/1.73m2, according to the MDRD formula) had an exposure of 122% (Cmax) and 150% (AUC0-tz) in comparison to their healthy controls. Based on this trial and population pharmacokinetic analysis of data derived from clinical trials in various tumour types, it is concluded, that adjustments to the starting dose in patients with mild (eGFR 60-89 mL/min/1.73m2), moderate (eGFR 30-59 mL/min/1.73m2), or severe (eGFR 15-29 mL/min/1.73m2) renal impairment are not necessary, but patients with severe impairment should be monitored (see Population pharmacokinetic analysis in special populations as follows and Dosage & Administration). GIOTRIF has not been studied in patients with eGFR <15 mL/min/1.73m2 or on dialysis.
Hepatic impairment: Afatinib is eliminated mainly by biliary/faecal excretion. Subjects with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had similar exposure in comparison to healthy volunteers following a single dose of 50 mg GIOTRIF. This is consistent with population pharmacokinetic data derived from clinical trials in various tumour types (see Population pharmacokinetic analysis in special populations as follows). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see Dosage & Administration). The pharmacokinetics of afatinib had not been studied in subjects with severe (Child Pugh C) hepatic dysfunction (see Precautions).
Population pharmacokinetic analysis in special populations: A population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC) receiving GIOTRIF monotherapy. No starting dose adjustment is considered necessary for any of the following covariates tested.
Age: No significant impact of age (range: 28 to 87 years) on the pharmacokinetics of afatinib could be observed.
Body weight: Plasma exposure (AUCτ,ss) was increased by 26% for a 42 kg patient (2.5th percentile) and decreased by 22% for a 95 kg patient (97.5th percentile) relative to a patient weighing 62 kg (median body weight of patients in the overall patient population).
Gender: Female patients had a 15% higher plasma exposure (AUCτ,ss, body weight corrected) than male patients.
Race: There was no statistically significant difference in afatinib pharmacokinetics between Asian and Caucasian patients.
Renal impairment: Exposure to GIOTRIF moderately increased with lowering the creatinine clearance (CrCL), i.e. for a patient with a CrCL of 60 or 30 mL/min exposure (AUCτ,ss) to afatinib increased by 13% and 42%, respectively, and decreased by 6% and 20% for a patient with CrCL of 90 or 120 mL/min, respectively, compared to a patient with the CrCL of 79 mL/min (median CrCL of patients in the overall patient population analysed).
Hepatic impairment: Patients with mild and moderate hepatic impairment as identified by abnormal liver tests did not correlate with any significant change in afatinib exposure.
Other patient characteristics/intrinsic factors: Other patient characteristics/intrinsic factors found with a significant impact on afatinib exposure were: ECOG performance score, lactate dehydrogenase levels, alkaline phospatase levels and total protein. The individual effect sizes of these covariates were considered not clinically relevant.
Smoking history, alcohol consumption, or presence of liver metastases had no significant impact on the pharmacokinetics of afatinib.
Pharmacokinetic Drug Interactions: Drug transporters: P-glycoprotein (P-gp): Effect of P-gp inhibitors and inducers on afatinib: Two trials were conducted to assess the effect of ritonavir, a potent inhibitor of P-gp, on the pharmacokinetics of afatinib. In one trial, the relative bioavailability of afatinib was investigated when ritonavir (200 mg b.i.d. for 3 days) was given either simultaneously or 6 hours after a single dose of 40 mg GIOTRIF. The relative bioavailability of afatinib was 119% (AUC0-∞) and 104% (Cmax) when administered simultaneously with ritonavir and 111% (AUC0-∞) and 105% (Cmax) when ritonavir was administered 6 hours after GIOTRIF. In a second trial, when ritonavir (200 mg b.i.d. for 3 days) was administered 1 hour before a single dose of 20 mg GIOTRIF, exposure to afatinib increased by 48% (AUC0-∞) and 39% (Cmax) (see Dosage & Administration, Precautions and Interactions).
Pre-treatment with rifampicin (600 mg q.d. for 7 days), a potent inducer of P-gp, decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of 40 mg GIOTRIF (see Precautions and Interactions).
Effect of afatinib on P-gp Substrates: Based on in vitro data, afatinib is a moderate inhibitor of P-gp. It is considered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations of other P-gp substrates.
Breast cancer resistance protein (BCRP): In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP.
Drug Uptake Transport Systems: In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered unlikely.
Drug metabolising enzymes: Cytochrome P450 (CYP) enzymes: Effect of CYP enzymes inducers and inhibitors on afatinib: In vitro data indicated that drug-drug interactions with afatinib due to inhibition or induction of CYP enzymes by concomitant medicines are considered unlikely. In humans it was found that enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3 and the CYP3A4-dependent N-demethylation was too low to be quantitatively detected.
Effect of afatinib on CYP enzymes: Afatinib is not an inhibitor or an inducer of CYP enzymes. Therefore, GIOTRIF is unlikely to affect the metabolism of other medicines that are dependent on CYP enzymes.
UDP-glucuronosyltransferase 1A1 (UGT1A1): In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are considered unlikely.
Toxicology: Oral administration of single doses to mice and rats indicated a low acute toxic potential of afatinib. In oral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs the main effects were identified in the skin (dermal changes, epithelial atrophy and folliculitis in rats), the gastrointestinal tract (diarrhoea, erosions in the stomach, epithelial atrophy in rats and minipigs) and the kidneys (papillary necrosis in rats). Depending on the finding, these changes occurred at exposures below, in the range of or above clinically relevant levels. Additionally, in various organs pharmacodynamically mediated atrophy of epithelia was observed in both species.
Reproduction toxicity: Based on the mechanism of action, GIOTRIF has the potential to cause foetal harm. The embryo-foetal development studies performed on afatinib revealed no indication of teratogenicity up to dose levels including maternal death. Changes identified were restricted to skeletal alterations consisting of incomplete ossifications/unossified elements (rat) and abortions at maternally toxic dose, reduced foetal weights as well as mainly visceral and dermal variations (rabbit). The respective total systemic exposure (AUC) was either slightly above (2.2 times in rats) or below (0.3 times in rabbits) compared with levels in patients.
Radiolabelled afatinib administered orally to rats on Day 11 of lactation was excreted into milk of the dams. The average concentrations in milk at time points 1 h and 6 h post dose were approximately 80- and 150-fold above the respective concentration in plasma.
A fertility study in male and female rats by the oral route up to the maximum tolerated dose revealed no significant impact on fertility. The total systemic exposure (AUC0-24) that could be achieved in male and female rats was in the range or less than that observed in patients (1.3 times and 0.51 times, respectively). A study in rats by the oral route up to the maximum tolerated doses revealed no significant impact on pre-/postnatal development. Effects were limited to lower birth weight and body weight gain of offspring but without materially affecting the attainment of developmental landmarks, sexual maturation or performance with behavioural assessments. The highest total systemic exposure (AUC0-24) that could be achieved in female rats was less than that observed in patients (0.23 times).
Phototoxicity: An in vitro 3T3 phototoxicity test with afatinib was performed. It was concluded that GIOTRIF may have phototoxicity potential.
Carcinogenicity: Carcinogenicity studies have not been conducted with afatinib.
A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. However, no mutagenic or genotoxic potential could be identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as the in vivo bone marrow micronucleus assay, the in vivo Comet assay and an in vivo 4-week oral mutation study in the Muta Mouse.
