GIOTRIF® (afatinib) frequently asked questions

General questions

What is GIOTRIF®’s (afatinib’s) mechanism of action?

GIOTRIF® (afatinib) is a tyrosine kinase inhibitor that acts as a highly selective irreversible ErbB family blocker.1,2 This provides potent signal blockade of mutated EGFR and silences aberrant ErbB network activity, a key driver in the growth and spread of EGFR M+ NSCLC.1–3

What are the approved indications for the use of GIOTRIF® (afatinib)?

Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®. Registration conditions differ internationally; please refer to locally approved prescribing information.

 


Side effects & contraindications

What are the side effects of GIOTRIF® (afatinib) and how can they be managed?

The most frequent adverse reactions associated with GIOTRIF® (afatinib) use are diarrhoea, skin related adverse events, stomatitis and paronychia.4 Read the full summary of ADRs to understand all those that have occurred during NSCLC trials and post marketing experience with GIOTRIF® (afatinib). Overall, dose reductions have led to a lower frequency of common adverse reactions.4

Find information on how to manage some of the more common side ADRs associated with GIOTRIF® (afatinib) use at the links below:

What are the contraindications for GIOTRIF® (afatinib) use?

GIOTRIF® (afatinib) is contraindicated in any patients hypersensitive to afatinib or any of the following excipients:4

  • Lactose monohydrate
  • Cellulose, microcrystalline (E460)
  • Silica, colloidal anhydrous (E551)
  • Crospovidone (type A)
  • Magnesium stearate (E470b)
  • Hypromellose (E464)
  • Macrogol 400
  • Titanium dioxide (E171)
  • Talc (E553b)
  • Polysorbate 80 (E433)
  • Indigo carmine aluminium hydroxide (E132)

Can GIOTRIF® (afatinib) be used during pregnancy?

Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm. As a precautionary measure, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with GIOTRIF® (afatinib). Adequate contraceptive methods should be used during therapy and for at least one month after the last dose.4

If used during pregnancy, or if the patient becomes pregnant while or after receiving GIORTIF® (afatinib), she should be informed of the potential hazard to the foetus.4

How should GIOTRIF® (afatinib) be used in special populations?

Patients with renal impairment4

Exposure to GIOTRIF® (afatinib) has been found to be increased in patients with moderate (eGFR 30–59 mL/min/1.73m2) or severe (eGFR 15–29 mL/min/1.73m2) renal impairment. Adjustments to starting dose are not necessary; however, patients with severe renal impairment should be monitored and have their dose adjusted if not tolerated. GIOTRIF® (afatinib) treatment is not recommended in patients with eGFR <15 mL/min/1.73m2 or on dialysis.

Patients with hepatic impairment4

Exposure to GIOTRIF® (afatinib) is not significantly altered in patients with mild or moderate hepatic impairment and adjustment to starting dose are not necessary. GIOTRIF® (afatinib) has not been studied in patients with severe (Child Pugh C) hepatic impairment and treatment is not recommended in this population.

Female gender and lower body weight4

Higher exposure to GIOTRIF® (afatinib) has been observed in female patients and patients with lower body weight, which could result in a higher risk of developing adverse reactions, in particular diarrhoea, rash/acne and stomatitis. Closer monitoring is recommended in these patients.

Paediatric population4

There is no relevant use for GIOTRIF® (afatinib) in the paediatric population and treatment of children or adolescents is not recommended.

What are the potentially clinically relevant interactions between GIOTRIF® (afatinib) and other drugs?

P-gp inhibitors and BCRP inhibitors4

In vitro studies have demonstrated that GIOTRIF® (afatinib) is a substrate of P-gp and BCRP. It is therefore recommended that strong P-gp inhibitors (including, but not limited to, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tracrolimus, nelfinavir, saquinavir, and amiodarone) are administered using staggered dosing, preferably 6 hours or 12 hours apart from GIOTRIF®.

P-gp inducers4

Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John’s wort) may decrease exposure to GIOTRIF® (afatinib).

BCRP substrates4

In vitro studies have indicated that GIOTRIF® (afatinib) is a substrate of the transporter BCRP and as such may increase the bioavailability of orally administered BCRP substrates (including, but not limited to, rosuvastatin and sulfasalazine).

 


Dosing and administration questions

What is the recommended dosing for GIOTRIF® (afatinib)?

GIOTRIF® (afatinib) is available at a dose of 20, 30, 40 and 50 mg once daily. The recommended starting dose for GIOTRIF® (afatinib) is 40 mg once daily.4

GIOTRIF® (afatinib) allows for the flexibility of individualised dosing and dose modification can be an important strategy to help manage adverse reactions.4 Dose modification has been shown to reduce the incidence of adverse drug reactions without impacting on drug effectiveness in real-world clinical practice, replicating results seen in clinical trials.4–6

What is the maximum daily dose of GIOTRIF® (afatinib)?

A dose escalation to a maximum of 50 mg once daily may be considered in patients who tolerate a 40 mg once daily starting dose.4

In case of suspected overdose, GIOTRIF® (afatinib) should be withheld and supportive care initiated. If indicated, elimination of unabsorbed GIOTRIF® (afatinib) may be achieved by emesis or gastric lavage.4

What if a dose of GIOTRIF® (afatinib) is missed?

If a dose is missed, it should be taken within the same day as soon as the patient remembers, unless the next scheduled dose is due within 8 hours, whereupon the missed dose must be skipped.4

Can you initiate patients on a modified GIOTRIF® (afatinib) dose?

GIOTRIF® (afatinib) allows for the flexibility of individualised dosing; however, it is recommended that all those patients that are eligible to receive GIOTRIF® (afatinib) receive a starting dose of 40 mg once daily.4

 


Efficacy questions

How does GIOTRIF® (afatinib) compare to other EGFR targeted therapies?

Two of the pivotal trials for GIOTRIF® (afatinib) were head-to-head trials against EGFR targeted therapies:

  • In LUX-Lung 7, GIOTRIF® (afatinib) demonstrated superior PFS and TTF* vs. gefitinib as 1st-line therapy for patients with EGFR M+ advanced NSCLC, with a comparable incidence and severity of all-cause adverse events7,8
  • In LUX Lung 8, GIOTRIF® (afatinib) demonstrated superior PFS and OS vs. erlotinib in adults with stage IIIB or IV squamous cell carcinoma of the lung, who had progressed after at least 4 rounds of platinum-based chemotherapy, with a comparable incidence and severity of all-cause adverse events9

In a real world evidence study that analysed three large claims databases in the USA, adult EGFR M+ NSCLC patients prescribed with 1st-line GIOTRIF® (afatinib) monotherapy demonstrated an extended duration spent on treatment over patients prescribed with erlotinib.10 When compared with erlotinib, GIOTRIF® (afatinib) also exhibited a reduced risk of therapy discontinuation.10     

Explore the clinical trial data and real-world evidence for GIOTRIF® (afatinib).

Is GIOTRIF® (afatinib) effective in patients with uncommon EGFR mutations?

Several clinical trials for GIOTRIF® (afatinib) have permitted patients with uncommon EGFR NSCLC mutations and a post hoc pooled analysis of prospectively collected data from LUX-Lung 2, 3 and 6 demonstrated GIOTRIF® (afatinib) efficacy in patients harboring certain uncommon mutations.**11–14

What is the resistance profile for GIOTRIF® (afatinib)?

Most patients that receive GIOTRIF® (afatinib) 1st-line for the treatment of EGFR M+ NSCLC will develop a T790M resistance mutation, with rates of 50–70%.15–17

Other, less common, reported putative mechanisms of GIOTRIF® (afatinib) resistance have included Met amplification, NRAS amplification, PIK3CA mutation and PIK3CA amplification.18,19

Is GIOTRIF® (afatinib) efficacious in Del19 patient populations?

GIOTRIF® (afatinib) has been found to be to be highly efficacious in patients with a Del19 activating mutation across a number of clinical trials.7,11,12 LUX-Lung 3 demonstrated a median OS of 33.3 months in Del19 patients treated with 1st-line GIOTRIF® (afatinib), compared to 21.1 months when treated using pemetrexed and cisplatin chemotherapies (pre-specified analysis).20 In LUX-Lung 6, Del19 patients treated with GIOTRIF® (afatinib) achieved a median OS of 31.4 months vs. 18.4 months in patients on gemcitabine and cisplatin therapies (pre-specified analysis).20

An exploratory combined analysis of LUX-Lung 3 and LUX-Lung 6 found that, in countries with universal reimbursement policies, GIOTRIF® (afatinib) patients with a Del19 mutation achieved an OS of 41.5 months (95% CI: 33.0–not estimable, n=76).20,21

Explore the clinical trial data and real-world evidence for GIOTRIF® (afatinib) to learn more about its established efficacy and safety profile.

What are the data for GIOTRIF® (afatinib) use in patients with brain metastases?

GIOTRIF® (afatinib) in 1st-line has been shown to delay CNS progression and onset of brain metastases and has also demonstrated efficacy in patients with brain metastases in real-world practice.22–24

 


*Co-primary endpoints were PFS, TTF, and OS. OS for GIOTRIF® (afatinib) compared with gefitinib was not statistically significant (median 27.9 vs. 24.5 months, respectively; HR=0.86; 95% CI: 0.66–1.09; p=0.1950). An overall trend in favour of GIOTRIF® (afatinib) was observed across all age groups and EGFR mutation subgroups.7,8

**Uncommon mutations consisted of patients with all point mutations or duplications in exons 18–21 (Leu861GIn, Gly719Ser, Gly719Ala, Gly719Cys, Ser768lle and other rare mutations), but not de novo Thr790Met mutations and exon 20 insertions.13

Main countries contributing: Japan, Taiwan, South Korea, Germany, France, Australia, UK, Belgium, Ireland.21

ADR=adverse drug reactions, BCRP=breast cancer resistance protein, CNS=central nervous system, eGFR=estimated glomerular filtration rate, EGFR M+=epidermal growth factor receptor mutation positive, NSCLC=non-small-cell lung cancer, OS=overall survival, P-gp=P-glycoprotein 1, PFS=progression free survival, TTF=time to treatment failure

 


References

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Solca F, et al. J Pharmacol Exp Ther 2012;343(2):342–350.
2
Li D, et al. Oncogene 2008;27(34):4702–4711.
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Engelman JA and Cantley LC. Clin Cancer Res. 2006;14(12):4372–4376.
4
GIOTRIF® (afatinib), Summary of Product Characteristics, 2018.
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Yang JC, et al. Ann Oncol 2016;27(11):2103–2110.
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Halmos B, et al. Lung Cancer 2018;127:103–111.
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Park K, et al. Lancet Oncol 2016;17(5):577–589.
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Paz-Ares L, et al. Ann Oncol 2017;28(2):270–277.
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Soria JC, et al. Lancet Oncol 2015;16(8):897–907.
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Lim J, et al. Future Oncol 2019 [Epub ahead of print]
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Yang JC, et al. Lancet Oncol 2012;13(5):539–548.
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Sequist LV, et al. J Clin Oncol 2013;31(27):3327–3334.
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Wu YL, et al. Lancet Oncol 2014;15(2):213–222.
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Yang JC, et al. Lancet Oncol 2015;16:830–838.
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Hochmair M et al. Poster #73255 presented at: International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer; Yokohama, Japan; 15-18 October 2017.
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Yang JC et al. J Clin Oncol. 2017;35(12):1288–1296.
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Wu SG et al. Oncotarget. 2016;7:12404–12413.
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Iwama E, et al. Cancer Sci 2018;109(12):3921–3933.
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Campo M, et al. J Thorac Oncol 2016;11(11):2022–22026.
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Yang JCH, et al. Lancet Oncol 2015;16:141–151.
21
Yang JCH, et al. Lancet Oncol 2015;16:141–151. supplementary material.
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Girard N. Future Oncol 2018;14(11):1117–1132.
23
Wu Y-L, et al. Poster presented at the World Conference on Lung Cancer (WCLC); Toronto, Canada, 23–26 September 2018 (Poster P1.01-98).
24
Kim Y, et al. J Thorac Oncol 2017;12:S2209.