Giotrif Adverse Reactions

The safety evaluation of Afatinib dimaleate (Giotrif) is based on the data from clinical trials and post-marketing experience.
NSCLC: Controlled studies: In the pivotal LUX-Lung 3 (1200.32) trial a total of 229 EGFR TKI naïve patients were treated with Afatinib dimaleate (Giotrif) with a starting dose of 40 mg once daily. A total of 111 patients were treated with pemetrexed/cisplatin. The overall incidence of Adverse Drug Reactions (ADRs) in patients treated with once daily Afatinib dimaleate (Giotrif) 40 mg was similar to pemetrexed/cisplatin (100% vs. 96%). The incidence of diarrhoea (95% vs. 15%) and rash/acne (89% vs. 6%) ADRs was higher in the Afatinib dimaleate (Giotrif)-treated patients than in those patients treated with pemetrexed/cisplatin, respectively. Dose reductions due to adverse events occurred in 57% of Afatinib dimaleate (Giotrif)-treated patients.
Overall dose reduction led to a lower frequency of common adverse events (e.g. after first dose reduction, frequency for diarrhoea regardless of causality decreased from 96% to 52%).
Discontinuation of therapy due to ADRs was lower in patients who received once daily Afatinib dimaleate (Giotrif) 40 mg compared with pemetrexed/cisplatin (8% vs. 12%). In patients treated with Afatinib dimaleate (Giotrif), discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0%, respectively.
In the LUX-Lung 6 (1200.34) trial a total of 239 EGFR TKI naïve patients were treated with Afatinib dimaleate (Giotrif) with a starting dose of 40 mg once daily. A total of 113 patients were treated with gemcitabine/cisplatin. The overall incidence of ADRs in patients treated with Afatinib dimaleate (Giotrif) was similar to gemcitabine/cisplatin (98.7% vs. 99.1%). The incidences of diarrhoea (88.7% vs. 10.6%) and rash/acne (81.2% vs. 8.8%) ADRs were higher in the Afatinib dimaleate (Giotrif) treated patients than in patients treated with gemcitabine/cisplatin. Dose reductions due to adverse events occurred in 33.1% of Afatinib dimaleate (Giotrif)-treated patients and in 26.5% of gemcitabine/cisplatin-treated patients.
Discontinuations of study medication due to ADRs were less frequent in patients who received Afatinib dimaleate (Giotrif) compared with gemcitabine/cisplatin (6.3% vs. 39.8%). In patients treated with Afatinib dimaleate (Giotrif), the incidences of discontinuations due to the ADRs diarrhoea and rash/acne were 0% and 2.5% respectively.
In the supportive placebo-controlled LUX-Lung 1 (1200.23) trial a total of 390 EGFR TKI pre-treated patients were randomised to Afatinib dimaleate (Giotrif) and were treated with a starting dose of 50 mg once daily. A total of 195 patients received placebo. The overall incidence of ADRs in patients treated with once daily Afatinib dimaleate (Giotrif) 50 mg was higher than placebo (95% vs. 38%). The incidence of diarrhoea (85% vs. 6%) and rash/acne (77% vs. 13%) ADRs were higher in the Afatinib dimaleate (Giotrif)-treated patients. Dose reductions due to adverse events occurred in 38% of Afatinib dimaleate (Giotrif)-treated patients. Overall dose reduction led to a lower frequency of common adverse events (e.g. after first dose reduction, frequency for diarrhoea regardless of causality decreased from 87% to 49%).
Discontinuation of therapy due to ADRs was higher in patients who received once daily Afatinib dimaleate (Giotrif) 50 mg compared with those who received placebo (8% vs. < 1%). In patients treated with Afatinib dimaleate (Giotrif), discontinuation due to diarrhoea and rash/acne was 3.6% and 1.8%, respectively.
In the pivotal LUX-Lung 8 (1200.125) trial a total of 392 patients with Squamous NSCLC were treated with Afatinib dimaleate (Giotrif) with a starting dose of 40 mg once daily and a total of 395 patients were treated with 150 mg erlotinib once daily. After the first treatment cycle (28 days) the dose of Afatinib dimaleate (Giotrif) was escalated to 50 mg in 39 (10%). The overall incidence of ADRs in patients treated with Afatinib dimaleate (Giotrif) or erlotinib was 93% vs. 81% respectively. The incidence of diarrhoea ADRs was higher in the Afatinib dimaleate (Giotrif)-treated patients compared to erlotinib (70% vs. 33%), while incidence of rash/acne was similar in both groups (67% vs. 67%). Dose reductions due to adverse events occurred in 27% of Afatinib dimaleate (Giotrif)-treated patients. Treatment was discontinued due to ADRs in 11% of patients treated with Afatinib dimaleate (Giotrif), and in 5% of erlotinib treated patients.
All NSCLC studies with daily doses of 40 mg or 50 mg Afatinib dimaleate (Giotrif): The safety of Afatinib dimaleate (Giotrif) monotherapy at starting doses of 40 mg or 50 mg once daily was assessed in pooled analyses of NSCLC trials in patients with or enriched for EGFR mutations. The predominant type of histology in this patient population was adenocarcinoma of the lung. The types of ADRs were generally associated with the EGFR inhibitory mode of action of afatinib and the profile of ADRs was consistent between the trials LUX-Lung 3 and LUX-Lung 1, respectively. CTCAE Grade 1 or 2 ADRs occurred in 58.8% and 53.1% of patients treated with Afatinib dimaleate (Giotrif) 40 mg and 50 mg, respectively. CTCAE Grade 3 or 4 ADRs occurred in 38% and 41% of patients treated with Afatinib dimaleate (Giotrif) 40 mg and 50 mg, respectively. For both doses in the 2 different patient populations, the majority of ADRs were of CTCAE Grade 1 or 2. ADRs were manageable as described in Dosage & Administration and Precautions which was reflected in low treatment discontinuation rates due to ADRs for both starting doses (7% and 11.7%).
A summary of common ADRs of diarrhoea and rash/acne in EGFR mutation positive or enriched population with NSCLC treated with Afatinib dimaleate (Giotrif) monotherapy is provided in Table 9. (See Table 9.)

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In the patients receiving a 40 mg starting dose 1 patient (0.2%) experienced Grade 4 rash/acne. In the patients receiving a 50 mg starting dose 1 patient (0.1%) experienced Grade 4 rash/acne and 3 (0.2%) experienced Grade 4 diarrhoea.
The safety of Afatinib dimaleate (Giotrif) monotherapy in patients with squamous cell carcinoma of the lung receiving 40 mg starting dose was assessed in trial LUX-Lung 8. The most frequent ADRs were associated with the EGFR inhibitory mode of action of Afatinib dimaleate (Giotrif) and were consistent with trials LUX-Lung 3 and LUX-Lung 1 in patients with adenocarcinoma of the lung. The majority of patients with ADRs (65%) had Grade 1 or 2 events. The ADR of CTCAE grade 3 / 4 diarrhoea occurred in 9.9% / 0.5% of patients. The rate of drug-related CTCAE grade 3 rash was 5.9%. ADRs led to discontinuation of treatment for 11% of patients. Discontinuation of treatment due to ADRs diarrhoea and rash/acne regardless of severity grade occurred in 3.8% and 2.0% of patients.
List of adverse reactions: ADRs classified by SOC and MedDRA preferred terms reported from any Afatinib dimaleate (Giotrif) dosing group per population of all NSCLC trials with daily starting doses of 40 mg and 50 mg Afatinib dimaleate (Giotrif) are shown in the Table 10. (See Table 10.)

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