Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE13.
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 receptor mutations, and/or amplification, and/or receptor ligand overexpression contributes to the malignant phenotype. Mutation in EGFR defines a distinct molecular subtype of lung cancer.

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 tumours with common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical settings. Limited non-clinical and/or clinical activity was observed in NSCLC tumours with insertion mutations in exon 20.

The acquisition of a secondary T790M 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. Other potential mechanisms of resistance to afatinib have been suggested preclinically and MET gene amplification has been observed clinically.

Clinical efficacy and safety

GIOTRIF in patients with Non-Small Cell Lung Cancer (NSCLC) with EGFR mutations 
LUX-Lung 3
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, multicentre, open-label trial. Patients 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 were randomised (2:1) to receive GIOTRIF 40 mg once daily or up to 6 cycles of pemetrexed/cisplatin. Among the patients randomised, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. 89% of patients had common EGFR mutations (Del 19 or L858R).

The primary endpoint was progression free survival (PFS) by independent review; the secondary endpoints included overall survival and objective response rate. At the time of the analysis, 14 Nov 2013, 176 patients (76.5%) in the afatinib arm and 70 patients (60.9%) in the chemotherapy arm experienced an event contributing to the PFS analysis, i.e. disease progression as determined by central independent review or death. The efficacy results are provided in Figure 1, Tables 6 and 7.



Giotrif                                                                       Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                    December 2019 LUX-Lung 6
The efficacy and safety of GIOTRIF in Asian patients with Stage IIIB/IV EGFR mutation-positive locally advanced or metastatic adenocarcinoma of the lung was evaluated in a randomised, multicentre, open-label trial. Similar to LUX-Lung 3, patients with previously untreated NSCLC were screened for EGFR mutations using TheraScreen®: EGFR29 Mutation Kit (Qiagen Manchester Ltd). Among randomized patients, 65% were female, the median age was 58 years and all patients were of Asian ethnicity. Patients with common EGFR mutations accounted for 89% of the study population.

The primary endpoint was PFS as assessed by central independent review; secondary endpoints included OS and ORR.
Both trials demonstrated significant improvement in PFS of EGFR mutation positive patients treated with GIOTRIF compared to chemotherapy. The efficacy results are summarized in Figure 1 (LUX-Lung 3) and Tables 6 and 7 (LUX-Lung 3 and 6). Table 7 shows outcomes in the subgroups of patients with two common EGFR mutations – Del 19 and L858R.

Figure 1: Kaplan-Meier curve for PFS by independent review by treatment group in trial LUX-Lung 3 (Overall Population)



Giotrif                                                                          Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                       December 2019 Table 6: Efficacy results of GIOTRIF vs. pemetrexed/cisplatin (LUX-Lung 3) gemcitabine/cisplatin (LUX-Lung 6) (Independent review)

LUX-Lung 3                     LUX-Lung 6
GIOTRIF     Pemetrexed/       GIOTRIF      Gemcitabine/
Cisplatin                       Cisplatin
(N=230)      (N=115)          (N=242)       (N=122)
Progression-free survival            11.2         6.9              11.0           5.6 Months (median)
Hazard Ratio (HR)                           0.58                                0.28 (95%CI)                                 (0.43-0.78)                         (0.20-0.39) p-value1                                   0.0002                            <0.0001 1-year PFS Rate                   48.1%            22.0%            46.7%               2.1% Objective Response Rate
(CR+PR)2                          56.5%            22.6%            67.8%             23.0% Odds Ratio (OR)                             4.80                                7.57 (95%CI)                                 (2.89-8.08)                        (4.52-12.68) 1 p-value                                   <0.0001                            <0.0001 Overall Survival (OS)              28.2             28.2             23.1               23.5 Months (median)
Hazard Ratio (HR)                           0.88                                0.93 (95%CI)                                 (0.66-1.17)                         (0.72-1.22) p-value1                                   0.3850                             0.6137 1 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logistic regression
2
CR=complete response; PR=partial response



Giotrif                                                                           Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                        December 2019 Table 7: PFS and OS efficacy results of GIOTRIF vs pemetrexed/cisplatin (LUX-Lung 3) gemcitabine/cisplatin (LUX-Lung 6) in the pre-defined EGFR mutation subgroups Del 19 and L858R (Independent review)

LUX-Lung 3                       LUX-Lung 6
GIOTRIF     Pemetrexed/         GIOTRIF      Gemcitabine/
Del19                                           Cisplatin                         Cisplatin (N=112)      (N=57)             (N=124)        (N=62)
Progression-free survival             13.8         5.6                13.1           5.6 Months (median)
Hazard Ratio (HR)                                 0.26                          0.20 (95%CI)                                       (0.17-0.42)                   (0.13-0.33) p-value1                                       <0.0001                       <0.0001 Overall Survival (OS)                  33.3                 21.1     31.4                 18.4 Months (median)
Hazard Ratio (HR)                             0.54                             0.64 (95%CI)                                   (0.36-0.79)                      (0.44-0.94) p-value1                                    0.0015                           0.0229 GIOTRIF       Pemetrexed/       GIOTRIF        Gemcitabine/
L858R                                              Cisplatin                        Cisplatin (N=91)          (N=47)          (N=92)           (N=46)
Progression-free survival           10.8             8.1             9.6              5.6 Months (median)
Hazard Ratio (HR)                           0.75                               0.31 (95%CI)                                 (0.48-1.19)                        (0.19-0.52) p-value1                                  0.2191                            <0.0001 Overall Survival (OS)              27.6             40.3            19.6                 24.3 Months (median)
Hazard Ratio (HR)                           1.30                               1.22 (95%CI)                                 (0.80-2.11)                        (0.81-1.83) p-value1                                  0.2919                             0.3432 1 p-value for PFS/OS based on stratified log-rank test

In the pre-defined subgroup of common mutations (combined Del 19 and L858R) for GIOTRIF and chemotherapy, the median PFS was 13.6 months vs. 6.9 months (HR 0.48; 95% CI 0.35-0.66; p<0.0001; N=307) in LUX-Lung 3, and 11.0 months vs. 5.6 months (HR 0.24; 95% CI 0.17-0.35; p<0.0001; N=324) in LUX-Lung 6, respectively.
PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 8). Mean scores over time for overall quality of life, global health status and physical, role, cognitive, social and emotional functioning were significantly better for GIOTRIF.



Giotrif                                                                            Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                         December 2019 Table 8: Symptom outcomes for GIOTRIF vs. chemotherapy in trials LUX-Lung 3 and LUX-Lung 6 (EORTC QLQ-C30 & QLQ-LC13)


LUX-Lung 3
Cough               Dyspnoea                    Pain a
% of patients improved               67% vs. 60%;          65% vs. 50%;             60% vs. 48%; p=0.2133              p=0.0078                 p=0.0427
Delay of median time to               27.0 vs. 8.0          10.4 vs. 2.9             4.2 vs. 3.1 deterioration (months) a,b         HR 0.60; p=0.0062     HR 0.68; p=0.0129        HR 0.83; p=0.1882 
LUX-Lung 6

Cough                   Dyspnoea              Pain
% of patients improved a             76% vs. 55%;             71% vs. 48%;       65% vs. 47%; p=0.0003                  p<0.0001           p=0.0017
Delay of median time to             31.1 vs. 10.3              7.7 vs. 1.7        6.9 vs. 3.4 deterioration (months) a,b       HR 0.46; p=0.0001         HR 0.53; p<0.0001 HR 0.70; p=0.0220 a values presented for GIOTRIF vs. chemotherapy, p-value based on logistic regression b p-value for time to deterioration based on stratified log-rank test

LUX-Lung 2
LUX-Lung 2 was a single arm Phase II trial in 129 EGFR TKI-naïve patients with stage IIIB or IV lung adenocarcinoma with EGFR mutations. Patients were enrolled in the first-line (N=61) or second-line setting (N=68) (i.e. after failure of 1 prior chemotherapy regimen). In 61 patients treated in the first-line setting, confirmed ORR was 65.6% and DCR was 86.9% according to independent review. The median PFS was 12.0 months by independent review. Efficacy was similarly high in the group of patients who had received prior chemotherapy (N=68; ORR 57.4%; median PFS by independent review 8 months). The updated median OS for first- and second-line was 31.7 months and 23.6 months, respectively.


LUX-Lung 7
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 categorised 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 9.



Giotrif                                                                           Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                        December 2019 Table 9: Efficacy results of GIOTRIF vs. gefitinib (LUX-Lung 7) based on primary analysis as of August 2015.

GIOTRIF            Gefitinib              Hazard Ratio/
(N=160)           (N=159)                 Odds Ratio
(95%CI) p-value2
Median PFS (months), Overall                   11.0                10.9                   HR 0.73 Trial Population                                                                        (0.57-0.95) 0.0165
18-months PFS rate                             27%                 15%  24-months PFS rate                             18%                 8%
Median OS (months)1, Overall                   27.9                24.5                    HR 0.86 Trial Population                                                                         (0.66, 1.12) 0.2580
Alive at 18-months                             71%                 67% Alive at 24-months                             61%                 51% Objective Response Rate                        70%                 56%                    OR 1.87 (CR+PR)3                                                                                (1.12, 2.99) 0.0083
1
OS results based on primary OS analysis as of April 2016 at event rates of 109 (68.1%) and 117 (73.6%) in the GIOTRIF and gefitinib arms, respectively
2 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on stratified logistic regression
3
CR=complete response; PR=partial response

The 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-naïve 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 with 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.

In 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

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. Randomization was stratified by race (Eastern Asian vs non Eastern Asian). The primary endpoint was PFS; OS was the key secondary endpoint. Other secondary endpoints included ORR, DCR, change in tumour size and HRQOL.
Among 795 patients randomized, the majority were males (84%), white (73%), current or former smokers (95%) with baseline performance status ECOG 1 (67%) and ECOG 0 (33%).

Giotrif                                                                              Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                           December 2019 Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLC compared to erlotinib. The efficacy results at the time of the primary analysis of OS including all randomized patients are summarized in Figure 2 and Table 10.

Table 10: Efficacy results for GIOTRIF vs erlotinib in LUX-Lung 8, based on primary analysis of OS, including all randomized patients

GIOTRIF              Erlotinib            Hazard Ratio/              p-value2 Odds Ratio
(N=398)             (n=397)                (95%CI)
PFS
Months (median)                      2.63                 1.94                 HR 0.81                 0.0103 (0.69, 0.96)
OS
Months (median)                      7.92                 6.77                 HR 0.81                 0.0077 (0.69, 0.95)

Alive at 12 months                  36.4%                 28.2%
Alive at 18 months                  22.0%                 14.4%
Objective Response                   5.5%                  2.8%                OR 2.06                 0.0551 Rate (CR+PR)1                                                                (0.98, 4.32) Duration of response                 7.29                 3.71
Months (median)
1
CR=complete response; PR=partial response
2 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logistic regression 
The overall survival hazard ratio in patients < 65 years of age was 0.68 (95% CI 0.55, 0.85) and in patients 65 years of age and older it was 0.95 (95% CI 0.76, 1.19).

Figure 2: Kaplan-Meier Curve for OS by treatment group in LUX Lung 8



PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to 
Giotrif                                                                          Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                       December 2019 deterioration (see Table 11).

Table 11: Symptom outcomes for GIOTRIF vs. erlotinib in trial LUX-Lung 8 (EORTC QLQ-C30 & QLQ-LC13)

Cough                      Dyspnoea                    Pain
% of patients                   43% vs. 35%;                 51% vs. 44%;             40% vs. 39%; improveda, c                      p=0.0294                     p=0.0605                 p=0.7752 Delay of time to                 4.5 vs. 3.7                  2.6 vs. 1.9              2.5 vs. 2.4 deterioration                 HR 0.89; p=0.2562            HR 0.79; p=0.0078        HR 0.99; p=0.8690 (months)b, c a values presented for GIOTRIF vs. erlotinib, p-value based on logistic regression b p-value for time to deterioration based on stratified log-rank test c p-values were not adjusted for multiplicity

Efficacy in EGFR-negative tumours has not been established.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

Absorption
Following oral administration of GIOTRIF, Cmax of afatinib were observed approximately 2 to 5 hours post dose. Cmax and AUC0-∞ values increased slightly more than proportionally 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 to 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 sections 4.2 and 4.5).

Distribution
In vitro binding of afatinib to human plasma proteins is approximately 95%. Afatinib binds to proteins both non-covalently (traditional protein binding) and covalently.

Biotransformation
Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins were the major circulating metabolites of afatinib.

Elimination
In humans, excretion of afatinib is primarily via the faeces. 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. Afatinib is eliminated with an effective half-life of approximately 37 hours. Thus, steady state plasma concentrations of afatinib were achieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold (AUC0-∞) and 2.11-fold (Cmax). In patients treated with afatinib for more than 6 months a terminal half-life of 344 h was estimated.

Special populations

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 Giotrif                                                                            Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                         December 2019 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” below and section 4.2). 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” below). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see section 4.2). The pharmacokinetics of afatinib have not been studied in subjects with severe (Child Pugh C) hepatic dysfunction (see section 4.4).

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 was considered necessary for any of the following covariates tested.

Age
No significant impact of age (range: 28 years - 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
Race had no effect on the pharmacokinetics of afatinib based on a population pharmacokinetic analysis, including patients of Asian, White, and Black racial groups. Data on Black racial groups was limited.

Renal impairment
Exposure to afatinib moderately increased with lowering of the creatinine clearance (CrCL, calculated according to Cockcroft Gault), i.e. for a patient with a CrCL of 60 mL/min 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 mL/min 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. There was limited data available for moderate and severe hepatic impairment.

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 phosphatase levels and total protein. The individual effect sizes of these covariates were considered not clinically relevant. Smoking history, alcohol consumption (limited data), or presence of liver metastases had no significant impact on the pharmacokinetics of afatinib.


Giotrif                                                                             Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                          December 2019 Other information on drug-drug interactions

Interactions with drug uptake transport systems
In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATB1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered unlikely.

Interactions with Cytochrome P450 (CYP) enzymes
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. Afatinib is not an inhibitor or an inducer of CYP enzymes. Therefore, this medicinal product is unlikely to interact with other medicines that modulate or are metabolised by CYP enzymes.

Effect of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibition on afatinib In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are considered unlikely.