Pharmacotherapeutic group: Other antineoplastic agents - protein kinase inhibitors.
ATC code: L01EB03.
Pharmacology: Mode 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.
Pharmacodynamics: 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 nonclinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signalling resulting in tumour growth inhibition or tumour regression. Anti-tumour activity of afatinib was demonstrated in HER2 overexpressing models. Various ErbB pathways aberrations (e.g. EGFR overexpression or mutation) were also the most likely underlying cause for the activity of afatinib in Lung Cancer models. NSCLC models with either L858R or Del 19 EGFR mutations are particularly sensitive to afatinib treatment. 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.
Cardiac Electrophysiology: Afatinib dimaleate (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 Afatinib dimaleate (Giotrif) does not have a relevant effect on the QTcF interval.
Clinical trials: Afatinib dimaleate (Giotrif) in Non-Small Cell Lung Cancer (NSCLC): The efficacy and safety of Afatinib dimaleate (Giotrif) monotherapy in the treatment of NSCLC patients with EGFR mutations was demonstrated in 4 randomised, controlled trials (LUX-Lung 3; 1200.32, LUX-Lung 6; 1200.34, LUX-Lung 1; 1200.23 and LUX-Lung 7; 1200.123), a large Phase III trial (LUX- Lung 5; 1200.42) and a large single arm Phase II trial (LUX-Lung 2; 1200.22). LUX-Lung 3, LUX-Lung 6, LUX-Lung 7 and LUX-Lung 2 trials enrolled EGFR mutation positive patients who were EGFR TKI treatment naïve. LUX-Lung 1 and LUX-Lung 5 trials enrolled patients clinically enriched for EGFR mutations who had received and progressed upon prior EGFR TKI treatment (gefitinib or erlotinib). The trial populations in LUX-Lung 1 and 5 were expected to contain a large proportion of patients with T790M resistance mutation, which is detectable in approximately 50% of previously responsive NSCLC patients with resistance to erlotinib and/or gefitinib.
The efficacy and safety of Afatinib dimaleate (Giotrif) as second line treatment of patients with NSCLC of squamous histology was investigated in an open-label active controlled trial LUX- Lung 8.
Afatinib dimaleate (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 Afatinib dimaleate (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 Afatinib dimaleate (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 Afatinib dimaleate (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.
The primary endpoint of PFS (independent review, 221 events) showed a statistically significant improvement in PFS for patients treated with Afatinib dimaleate (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 Afatinib dimaleate (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-Meiers curve of the primary PFS analysis are shown in Figure 1 and efficacy results are summarised in Table 2. At the time of primary analysis a total of 45 (20%) patients treated with Afatinib dimaleate (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.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
The analysis of PFS based on investigator review yielded similar results (median PFS 11.1 vs. 6.7 months, HR=0.49, p<0.0001) as the analysis based on the independent review. The effect on PFS was consistent across major subgroups, including gender, age, race, ECOG status, and mutation type (L858R, Del 19) in both the independent and investigator reviews. Based on investigator review, ORR was 69.1% vs. 44.3% and DCR was 90.0% vs. 82.6% in Afatinib dimaleate (Giotrif)-treated patients compared with chemotherapy-treated patients. In the pre-defined sub-group of common EGFR mutations (Del 19, L858R) for Afatinib dimaleate (Giotrif) (N=203) and chemotherapy (N=104) the median OS was 31.6 months vs. 28.2 months (HR=0.78, 95% CI (0.58, 1.06), p=0.1090). In the pre-defined EGFR mutation subgroups, the median OS with first-line Afatinib dimaleate (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).
The PFS benefit of Afatinib dimaleate (Giotrif) was accompanied by improvement in disease-related symptoms, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). Afatinib dimaleate (Giotrif) significantly delayed the time to deterioration for the pre-specified symptoms of cough (HR 0.60; p=0.0072) and dyspnoea (HR 0.68; p=0.0145) by more than 7 months when compared with chemotherapy. Time to deterioration of pain was also longer with Afatinib dimaleate (Giotrif) but did not reach statistical significance (HR 0.83; p=0.1913).
Significantly more patients treated with Afatinib dimaleate (Giotrif) compared with chemotherapy had improvements for dyspnoea (64% vs. 50%; p=0.0103). A trend favouring Afatinib dimaleate (Giotrif) was observed for pain (59% vs. 48%; p=0.0513), with individual items of pain reaching significance ('Have pain': 56.0% vs. 40.0%; p=0.0095; 'Pain in chest': 51.0% vs. 37.0%; p=0.0184; 'Pain in arm or shoulder': 41.0% vs. 26.0%; p=0.0103). For cough, numerically more patients improved on Afatinib dimaleate (Giotrif) (67% vs. 60%; p=0.2444).
Mean scores over time for health-related quality of life (HRQoL) were measured using the EORTC QLQ-C30. Mean scores over time for overall quality of life and global health status were significantly better for Afatinib dimaleate (Giotrif) compared with chemotherapy. Mean scores were significantly better in 3 of the 5 functioning domains (physical, role, cognitive) and showed no difference in the emotional and social functioning domains.
LUX-Lung 6 (1200.34): The efficacy and safety of Afatinib dimaleate (Giotrif) in Asian patients with EGFR mutation-positive locally advanced or metastatic adenocarcinoma of the lung (stage IIIB/IV) was assessed in a randomised, multicenter, open-label trial (LUX-Lung 6). Similar to 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 PCR based method (TheraScreen: EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients (N=364) were randomised (2:1) to receive Afatinib dimaleate (Giotrif) 40 mg orally once daily (N=242) or up to 6 cycles gemcitabine/cisplatin (N=122). Randomisation was stratified according to EGFR mutation status (L858R; Del 19; other). Dose escalation of Afatinib dimaleate (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 randomized patients, 65% were female; the median age was 58 years and all patients were Asian. Patients with common (L858R or Del 19) EGFR mutations accounted for 89% of the study population.
The primary endpoint of PFS (central independent review, 221 events) showed a statistically significant improvement in PFS for patients treated with Afatinib dimaleate (Giotrif) compared with patients treated with chemotherapy (median PFS: 11.0 vs. 5.6 months). When comparing the prespecified subgroup of common (L858R or Del 19) EGFR mutations, the difference in median PFS remained constant (11.0 vs. 5.6 months). The percentages of patients being alive and progression-free (PFS rate) at 12 months were 46.7% in patients treated with Afatinib dimaleate (Giotrif) and 2.1% in patients treated with chemotherapy for the overall trial population, and 46.9% vs. 2.3% in the subgroup of common mutations.
The Kaplan-Meier curves of the primary PFS analysis are shown in Figure 2, and efficacy results are summarised in Table 3. At the time of primary PFS analysis, 48 (19.8%) patients treated with Afatinib dimaleate (Giotrif) and 8 (6.6%) patients treated with chemotherapy were known to be alive and progression-free. (See Figure 2 and
Table 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
The analysis of PFS based on investigator review yielded similar results (HR=0.26, CI= 95% 0.19 – 0.36; p<0.0001; median PFS: 13.7 vs. 5.6 months) as the analysis based on the independent review. The effect on PFS was consistent across major subgroups, including gender, age, race, ECOG status, and mutation type (L858R, Del 19) in both the independent and investigator reviews. Based on investigator review, ORR was 74.4% vs. 31.1% and DCR was 93.0% vs. 75.4% in Afatinib dimaleate (Giotrif)-treated patients compared with chemotherapy-treated patients. In the pre-defined subgroup of common EGFR mutations (Del 19, L858R) for Afatinib dimaleate (Giotrif) (N=216) and chemotherapy (N=108) the median OS was 23.6 months vs. 23.5 months (HR=0.83, 95% CI (0.62-1.09), p=0.1756). In the pre-defined EGFR mutation subgroups, the median OS with first-line Afatinib dimaleate (Giotrif) vs chemotherapy was 31.4 months vs 18.4 months (HR=0.64, (95% CI 0.44-0.94), p=0.0229) in patients with Del 19 (n=186) and 19.6 months vs 24.3 months (HR=1.22, (95% CI: 0.81-1.83), p=0.3432) in patients with L858R (n=138).
The PFS benefit of Afatinib dimaleate (Giotrif) was accompanied by improvement in disease-related symptoms, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). Afatinib dimaleate (Giotrif) statistically significantly delayed the time to deterioration for the pre-specified symptoms of cough (HR 0.453; 95% CI 0.299, 0.685; p = 0.0001), dyspnoea (HR 0.536; 95% CI 0.395, 0.727; p <0.0001), and pain (HR 0.703; 95% CI 0.514, 0.961; p = 0.0265) compared with chemotherapy. Significantly more patients treated with Afatinib dimaleate (Giotrif) compared with chemotherapy had improvements for cough (75.9% of patients vs. 55.4%; p=0.0003), dyspnoea (70.9% vs. 47.5%; p <0.0001), and pain (64.3% vs. 46.5%; p=0.0029).
Mean scores over time for health-related quality of life (HRQoL) were measured using the EORTC QLQ-C30. Mean scores over time for overall quality of life, global health status and physical, role, cognitive, social and emotional functioning were significantly favouring Afatinib dimaleate (Giotrif) over chemotherapy.
LUX-Lung 2 (1200.22): LUX-Lung 2 was an open label single arm Phase II trial which investigated the efficacy and safety of Afatinib dimaleate (Giotrif) in 129 EGFR TKI-naïve patients with locally advanced or metastatic lung adenocarcinoma (stage IIIB or IV) 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). Patients were centrally screened for EGFR mutations. Patients received either 40 mg (N=30) or 50 mg (N=99) of Afatinib dimaleate (Giotrif) once daily.
The primary endpoint was ORR. Secondary endpoints included PFS, DCR and OS.
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 and 15.6 months by investigator assessment. Median OS was not reached in the first-line population. Efficacy was similarly high in the group of patients who had received prior chemotherapy (N=68; ORR 57.4%; PFS by independent review 8 months and by investigator assessment 10.5 months; DCR 77.9%). Median OS in the second line patients was 23.3 months (95% CI 18.5-38).
LUX-Lung 7 (1200.123): LUX-Lung 7 is a randomized, global, open label Phase IIb trial investigating the efficacy and safety of Afatinib dimaleate (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 Afatinib dimaleate (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 randomized, 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 are PFS by independent review, time to treatment failure (TTF) and OS. Secondary endpoints include ORR and DCR. The risk of progression was significantly reduced for afatinib versus gefitinib (see Table 3) and ORR was 70% for afatinib and 56% for gefitinib. Primary analysis of OS will be conducted after the number of required events has occurred as per protocol. (See
Table 3.)
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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 Afatinib dimaleate (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 Afatinib dimaleate (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 with Afatinib dimaleate (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.)
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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.
Afatinib dimaleate (Giotrif) in patients who had received prior EGFR TKI treatment: LUX-Lung 1 (1200.23): The efficacy and safety of Afatinib dimaleate (Giotrif) in patients with locally advanced or metastatic NSCLC (stage IIIB or IV) who had previously received 1 or 2 lines of chemotherapy and progressed after treatment with an EGFR TKI (either gefitinib or erlotinib) were assessed in a global, double-blind, placebo controlled Phase IIb/III trial (LUX-Lung 1). The trial enrolled 585 patients who were randomised (2:1) to receive 50 mg Afatinib dimaleate (Giotrif) once daily plus best supportive care (BSC) (N=390) or placebo plus BSC (N=195). The trial population was clinically enriched for EGFR mutations by requiring patients to have had prior EGFR TKI therapy for at least 12 weeks.
The primary trial endpoint was OS. Secondary endpoints included PFS, ORR, DCR and Health Related Quality of Life (HRQoL) as measured by the EORTC QLQ-C30, QLQ-LC13 and EQ-5D questionnaires. PFS was evaluated by the investigator and an independent review committee. Among the 585 randomised patients 60% had 1 and 39% had 2 lines of prior chemotherapy for metastatic disease. 55 % of patients had received prior EGFR TKI therapy with erlotinib, 40% had received gefitinib and 5% received both. A total of 214 patients (36.5%) met the criteria of acquired resistance to erlotinib/gefitinib (i.e. CR/PR to erlotinib/gefitinib or SD ≥ 6 months on prior erlotinib/gefitinib, progression within the last 4 weeks on erlotinib/gefitinib and no intervening systemic prior to treatment with Afatinib dimaleate (Giotrif)).
Optional EGFR mutation testing was performed in 141 patients of whom 96 patients (68%) were tested positive suggesting a high mutation positivity rate in the overall trial population. Long duration of prior EGFR TKI treatment (≥ 48 weeks) and/or tumour response (CR/PR) to prior EGFR TKI were associated with a further increased probability of EGFR mutation positivity (subpopulation highly enriched for EGFR mutations; see Table 5). (See
Table 5.)
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Efficacy results are summarized in Table 6. The primary endpoint of OS did not show any statistical difference between patients treated with Afatinib dimaleate (Giotrif) and patients who received placebo (10.8 vs. 12.0 months). This result is most likely attributable to the unexpectedly long post- progression survival time in both treatment groups and extended duration and high frequency of subsequent anti-cancer therapies which showed an imbalance in favour of the placebo group. The secondary endpoint of PFS showed a statistically significant improvement in the median PFS between patients treated with Afatinib dimaleate (Giotrif) and patients who received placebo (3.3 vs. 1.1 months). The percentage of patients alive and without progression at 6 months was 26.1% for Afatinib dimaleate (Giotrif) and 6.0% for placebo. This difference was further pronounced when comparing the subpopulations highly clinically enriched for EGFR mutations (N=391) (PFS 4.4 vs. 1.0 month; 6-months PFS rate 29.9% vs. 3.7%). In the complementary subpopulation not meeting the criteria for high clinical enrichment (N=194) the difference between Afatinib dimaleate (Giotrif) vs. placebo was reduced (PFS 2.76 vs. 1.84 months, 6-months PFS rate 18.7% vs. 11.5%).
In an analysis of patients who met the criteria of acquired resistance (133 [34%] patients treated with Afatinib dimaleate (Giotrif), 81 [42%] of patients who received placebo), median PFS by independent review was 4.5 months (95% CI 2.73-4.73) for patients treated with Afatinib dimaleate (Giotrif) compared with 1.0 month (95% CI 0.95-1.71) for patients who received placebo. (See
Table 6.)
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The activity of Afatinib dimaleate (Giotrif) in this subgroup (in which the interval between end of previous EGFR TKI treatment and start of the trial treatment was ≤4 weeks) suggests that the effect of Afatinib dimaleate (Giotrif) is not merely a result of re-exposure to an EGFR targeting treatment.
PFS benefit was accompanied by improvement in disease-related symptoms, as measured by the EORTC QLQ-C30 and QLQ-LC13. Afatinib dimaleate (Giotrif) significantly delayed the time to deterioration for pre-specified symptoms of cough by more than 3 months (HR 0.60; p<0.001) when compared to placebo. Time to deterioration of dyspnoea (HR 0.84; p=0.1701) and pain (HR 0.88; p=0.2876) was also longer with Afatinib dimaleate (Giotrif), but did not reach statistical significance. Significantly more patients treated with Afatinib dimaleate (Giotrif) compared with placebo had improvements in cough (46% vs. 25%, p<0.0001), dyspnoea (51% vs. 36%; p=0.0006), and pain (50% vs. 32%; p<0.0001).
Mean scores over time for HRQoL were measured using the EORTC QLQ-C30. Mean scores over time for overall quality of life and global health status were significantly better for Afatinib dimaleate (Giotrif) compared with placebo. Mean scores were significantly better in 1 of the 5 functioning domains (physical) and favouring Afatinib dimaleate (Giotrif) in the domain of role, and showed no difference in 3 of the 5 domains (cognitive, emotional, and social functioning).
LUX-Lung 5 (1200.42): LUX-Lung 5 is a global, open label, randomised Phase III trial in an EGFR mutation enriched patient population similar to LUX-Lung 1. In Part A, patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥ 1 line of chemotherapy and progression following treatment with gefitinib or erlotinib for generally 12 weeks or longer received Afatinib dimaleate (Giotrif) 50 mg once daily until disease progression. After progression, in Part B, patients with clinical benefit (≥ 12 weeks) were eligible to continue Afatinib dimaleate (Giotrif) 40 mg plus paclitaxel or to receive investigator's choice chemotherapy.
Primary endpoint for Part A was PFS by investigator assessment. Secondary endpoints included ORR, DCR and OS.
An interim analysis of Part A was performed and confirmed the results of the LUX-Lung 1 trial. The median PFS in the overall trial population (N=1154) was 3.3 months, the 6-months PFS rate was 24.5%, ORR and DCR were 7.6% and 63.6%, respectively. Similar to LUX-Lung 1, the efficacy in the highly clinically enriched subgroup (N=598) was more pronounced with a median PFS of 4.2 months and ORR and DCR of 9.5% and 72.2%, respectively.
The number of patients with an OS event was 301 (26.1%). Median OS was 13.70 months.
Afatinib dimaleate (Giotrif) in patients with NSCLC of squamous histology: LUX-Lung 8 (1200.125): The efficacy and safety of Afatinib dimaleate (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 Afatinib dimaleate (Giotrif) 40 mg or erlotinib 150 mg until progression. Dose escalation of Afatinib dimaleate (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 Afatinib dimaleate (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 Afatinib dimaleate (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 7). The primary analysis of OS demonstrated significant reduction in the risk of death for patients treated with Afatinib dimaleate (Giotrif) compared with erlotinib (HR=0.81 95% CI (0.69, 0.95), p=0.0077) with significantly higher proportions of Afatinib dimaleate (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 Afatinib dimaleate (Giotrif). The median duration of response was 7.29 months on Afatinib dimaleate (Giotrif) and 3.71 on erlotinib. (See Tables 7 and Figure 3.)
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Click on icon to see table/diagram/image
The analyses of patient reported outcomes, based on the QLQ-C30 and QLQ-LC13 questionnaires favoured Afatinib dimaleate (Giotrif). Significantly more patients in the Afatinib dimaleate (Giotrif) group reported improvement in the global health status/quality of life compared to erlotinib (35.7% vs 28.3%, p=0.0406). Higher proportion of Afatinib dimaleate (Giotrif) patients had improvement in cough (43.4% vs 35.2%, p=0.0294) and dyspnoea (51.3% vs 44.1%, p=0.0605), while no difference was observed for pain (40.2% vs 39.2%, p=0.7752). Afatinib dimaleate (Giotrif) significantly delayed the time to deterioration of dyspnoea (HR 0.79, p=0.0078). Mean scores over time for cough, dyspnoea, and pain as well as for physical, role, cognitive, and emotional functioning were significantly better for Afatinib dimaleate (Giotrif) than for erlotinib.
Paediatric population: A Phase I/II open-label, dose escalation, multicentre trial evaluated the safety and efficacy of Afatinib dimaleate (Giotrif) in paediatric patients aged 2 to less than 18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology (1200.120). A total of 17 patients were treated in the dose finding part of the trial. In the maximum tolerated dose (MTD) expansion part of the trial, 39 patients selected by biomarkers for ErbB pathway deregulation received Afatinib dimaleate (Giotrif) at a dose of 18 mg/m2/day. This accounts for 80% of the adult MTD normalised for body surface area. The adverse reaction profile of Afatinib dimaleate (Giotrif) in paediatric patients was consistent with the safety profile seen in adults. In the MTD expansion part, no objective responses were observed in 38 patients, including 6 patients with refractory high grade glioma (HGG),
4 patients with diffuse intrinsic pontine glioma (DIPG), 8 patients with ependymoma and 20 patients with other histologies. One patient with
a neural-glial tumour of the brain with a CLIP2-EGFR gene fusion had a confirmed partial response.
Pharmacokinetics: Absorption and distribution: Following oral administration of Afatinib dimaleate (Giotrif), maximum concentrations (C
max) of afatinib are observed approximately 2 to 5 hours post dose. Mean C
max and AUC
0-∞ values increased slightly more than proportional in the dose range from 20 mg to 50 mg Afatinib dimaleate (Giotrif). Systemic exposure to afatinib is decreased by 50% (C
max) and 39% (AUC
0-∞), 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 AUC
τ,ss was observed when food was consumed within 3 hours before or 1 hour after taking Afatinib dimaleate (Giotrif). Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking Afatinib dimaleate (Giotrif) (see Dosage & Administration and Interactions). After administration of Afatinib dimaleate (Giotrif), the mean relative bioavailability was 92% (adjusted gMean ratio of AUC
0-∞) 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 (C
max).
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 Afatinib dimaleate (Giotrif). Subjects with moderate renal impairment (estimated glomerular filtration rate [eGFR] of 30 to 59 mL/min/
1.73m2 according to MDRD formula) had an exposure of 101% (C
max) and 122% (AUC
0-tz) in comparison to their healthy controls. Subjects with severe renal impairment (eGFR of 15 to 29 mL/min/
1.73m2 according to MDRD formula) had an exposure of 122% (C
max) and 150% (AUC
0-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). Afatinib dimaleate (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 Afatinib dimaleate (Giotrif). This is consistent with population pharmacokinetic data derived from clinical trials in various tumour types (see Pharmacokinetic analysis in target 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).
Pharmacokinetic analysis in target populations: A population pharmacokinetic analysis was performed in 927 cancer patients receiving Afatinib dimaleate (Giotrif) monotherapy. No starting dose adjustment is considered necessary for any of the following covariates tested.
Age: No significant impact of age (range: 28-87 years) on the pharmacokinetics of afatinib could be observed.
Body weight: Plasma exposure (AUC
τ,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 (AUC
τ,ss, body weight corrected) than male patients.
Race: There was no statistically significant difference in afatinib pharmacokinetics between Asian and Caucasian patients. Also no obvious difference in pharmacokinetics for American Indian/Alaska native or Black patients could be detected based on the limited data available in these populations (6 and 9 out of 927 patients included in the analysis, respectively).
Renal impairment: Exposure to Afatinib dimaleate (Giotrif) moderately increased with lowering the creatinine clearance (CrCL), i.e. for a patient with a CrCL of 60 or 30 mL/min exposure (AUC
τ,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 phosphatase 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.
Paediatric population: After administration of 80% of the adult dose per body surface area, the pharmacokinetic profile in paediatric patients aged 2 to less than 18 years was comparable to that observed in adults.
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 Afatinib dimaleate (Giotrif). The relative bioavailability of afatinib was 119% (AUC
0-∞) and 104% (C
max) when administered simultaneously with ritonavir and 111% (AUC
0-∞) and 105% (C
max) when ritonavir was administered 6 hours after Afatinib dimaleate (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 Afatinib dimaleate (Giotrif), exposure to afatinib increased by 48% (AUC
0-∞) and 39% (C
max) (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% (AUC
0-∞) and 22% (C
max) after administration of a single dose of 40 mg Afatinib dimaleate (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 Afatinib dimaleate (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, Afatinib dimaleate (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, Afatinib dimaleate (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 (AUC
0-24) 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 (AUC
0-24) 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 Afatinib dimaleate (Giotrif) may have phototoxicity potential.
Carcinogenicity: Carcinogenicity studies have not been conducted with Afatinib dimaleate (Giotrif).
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.
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