1.What is GIOTRIF®(afatinib*)?

2.How does GIOTRIF®(afatinib*) work?

3.Data overview

4.Clinical potential

1. WHAT IS GIOTRIF® * (AFATINIB*)?

Afatinib* (GIOTRIF® ) is an irreversible ErbB Family Blocker approved in over 40 countries worldwide including the EU, US, Japan, Taiwan, Canada and Mexico. It is indicated for the treatment of patients with distinct types of Epidermal Growth Factor Receptor (EGFR) mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), a specific type of lung cancer. It is an oral, once daily targeted therapy.

2. HOW DOES GIOTRIF® (AFATINIB*) WORK?

The ErbB Family of receptors consists of four related enzymes called tyrosine kinases: EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.1 These receptors are often over expressed (i.e. too many are produced) or mutated in many cancers (including lung, breast, head and neck, and colorectal cancers), and are involved in fundamental processes which allow tumour cells to grow and multiply.2

Afatinib* irreversibly blocks EGFR (ErbB1) as well as other members of the ErbB Family that are known to play a critical role in the growth and spread of the most widespread cancers and cancers associated with high mortality (death).

The irreversible binding of afatinib* is unlike other compounds which are reversible in that it aims to provide a sustained, selective and complete ErbB Family Blockade. Afatinib’s* unique mechanism of action could potentially lead to a greater overall effect on the tumour, preventing tumour cell growth and spread across a broad range of cancers, compared to other treatments which offer single, reversible, receptor blocking.3,4

Signal Transduction

Signal Transduction

 

The signalling of ErbB3 is blocked indirectly through blocking of transphosphorylation Source: Hynes NE, et al. Nat Rev Cancer 2005;5:341-54.

3. DATA OVERVIEW

The LUX-Lung clinical trial programme is investigating afatinib* in a number of patient populations with advanced NSCLC. There are currently eight studies in the LUX-Lung clinical trial programme, including investigating the use of afatinib* in patients who have EGFR mutations and those with recurrent disease.

Two pivotal Phase III studies, LUX-Lung 35,6 and LUX-Lung 67,8 represent the largest and most robust clinical trial programme in EGFR mutation-positive NSCLC to date.

A further study, LUX-Lung 59 , is the first prospective trial looking at the advantage of continuing treatment with afatinib, in combination with chemotherapy, after the tumour started to grow on afatinib alone (treatment beyond progression).

Efficacy and Safety Profile

LUX-Lung 3 and LUX-Lung 6 are multicentre, randomised, open-label, Phase III trials of afatinib* versus chemotherapy (pemetrexed/cisplatin and gemcitabine/ cisplatin respectively) as first-line treatment for patients with advanced and metastatic NSCLC with an EGFR mutation.5,6,7,8 

LUX-Lung 35,6

(Afatinib* vs pemetrexed/cisplatin)

LUX-Lung 67,8

(Afatinib* vs gemcitabine/cisplatin) 
Progression-Free Survival6,8 (PFS – time patient is alive without their tumour starting to grow) 
  • 11.1 months vs. 6.9 months for all patients with EGFR mutations by independent review
  • 13.6 months vs. 6.9 months for patients with the most common mutations (~90% of all patients, del19 and L858R) by independent review 
  • 11.0 months vs. 5.6 months for all patients with EGFR mutations by independent review 
  • Based on investigator review patients lived for well over a year before their tumour started to grow again, versus just under half a year for those on standard chemotherapy (PFS of 13.7 months vs. 5.6 months) 
  • In addition, 47% of afatinib-treated patients are alive and progression-free after 1 year of treatment compared to only 2% on chemotherapy
  • The delay in tumour growth compares well in both trials, substantiating the efficacy of afatinib and the robustness of the data
Objective Response6,7(Tumour Shrinkage) 
  •  One in two patients (56%) taking afatinib experienced tumour shrinkage compared to one in four (23%) in the chemotherapy arm, by independent review 
  • In 67% of patients taking afatinib the tumour shrunk significantly in size compared to 23% in the chemotherapy arm, by independent review
  • Tumour shrinkage translated into improvements in disease-related symptoms
Disease Related Symptoms5,8
  • More patients across both studies taking afatinib experienced improvement of symptoms such as dyspnoea (shortness of breath), cough and chest pain. Afatinib treatment also delayed the onset of these symptoms
Quality of Life (Measured by patient questionnaires)5,8
  • Afatinib patients in LUX-Lung 3 and LUX-Lung 6 reported to have a significantly better quality of life (for example, at work and during household activities) than those on chemotherapy 
Grade ≥3 Adverse Events (AEs)6,7
  • The most common drug-related AEs observed in the afatinib treatment arm were diarrhoea, rash and paronychia (infection of the skin next to the nail)
  • The most common drug-related AEs observed in the chemotherapy arm were nausea/vomiting, decreased appetite, and fatigue
  • There was a low discontinuation rate associated with treatment-related AEs in the trial (8% discontinuation rate for afatinib; 12% for chemotherapy)
  • 1% of patients in the afatinib arm discontinued treatment due to diarrhoea 
  • The most common drug-related AEs associated with afatinib were diarrhoea, rash/acne and stomatitis/mucositis (inflammation of mouth and throat)
  • The most common AEs associated with chemotherapy were neutropenia (an abnormally low level of neutrophils, a type of white blood cell), vomiting and leukopenia (a decrease in the number of white blood cells)
  • The discontinuation rate due to AEs was 6% of patients on the afatinib arm and 40% of patients on the chemotherapy arm
  • Only 2% discontinued due to rash/acne and none for diarrhoea 
Overall survival (OS)10 
  • Statistically significant improvement in overall survival, in patients with common mutations (del19/L858R ), with afatinib compared to chemotherapy (median 27.3 vs. 24.4 months) in the posthoc analysis combining LUX-Lung 3 and LUX-Lung 6.
  • One year overall survival benefit (median 33.3 vs. 21.1 months) in patients with the del19 mutation compared to chemotherapy 
  • More than one year overall survival benefit (median 31.4 vs. 18.4 months) in patients with the del19 mutation compared to chemotherapy
  • In the overall patient population, there was no significant overall survival benefit of afatinib compared with chemotherapy (28.16 vs. 28.22 months for LUX-Lung 3 and 23.1 vs. 23.5 months for LUX-Lung 6)

Overall survival data presented at ASCO in 2014: Overall survival results from a post-hoc analysis10 combining the data of of the LUX-Lung 3 and LUX-Lung 6 studies demonstrated that afatinib significantly prolonged survival of lung cancer patients with common EGFR mutations (del19/L585R) compared with standard chemotherapy by a median of 3 months (27.3 to 24.3 months), significantly reducing the risk of death by 19%. The most pronounced reduction in risk of death by 41%, was noted for patients with the most frequent type of EGFR mutation (deletion in exon 19 of the EGFR gene; del19).

Data on prespecified subgroups from the individual trials LUX-Lung 3 and LUX-Lung 6 showed for afatinib a prolongation of survival in lung cancer patients with the most common type of EGFR mutation (del19) compared with standard chemotherapy by a median of more than 12 months in both the trials (LUX-Lung 3; 33.3 months compared to 21.1 months, LUX-Lung 6; 31.4 months compared to 18.4 months).

The conclusions of this analysis further substantiate earlier published results on delay in tumour growth (progression-free survival), better control of lung cancer symptoms and adverse events associated with afatinib in comparison with standard chemotherapy.

LUX-Lung 5 is a randomised, open label Phase III trial comparing afatinib with chemotherapy versus chemotherapy alone in patients with late-stage lung cancer after failure of several treatments, including chemotherapy, erlotinib or gefitinib, and afatinib alone (treatment beyond progression).

Those patients who continued afatinib* treatment, with the addition of chemotherapy, after progressing on afatinib alone, had a further delay in tumour growth compared to the group who stopped afatinib treatment, and received chemotherapy only (tumour growth was delayed by 5.6 months and 2.8 months respectively). This corresponded to a 40% reduction in risk of disease progression. 

LUX-Lung 59

(afatinib* vs pemetrexed/cisplatin)
Progression-Free Survival (PFS – time patient is alive without their tumour starting to grow) 
  • 5.6 months vs. 2.8 months 
Objective Response (Tumour Shrinkage)
  • Almost a third of patient patients (32.1%) taking afatinib experienced tumour shrinkage compared to 13.2% in the chemotherapy arm
  • Tumour shrinkage translated into improvements in disease-related symptoms 
Overall survival (OS)
  • OS was similar in both arms 12.2 vs 12.2 months
Adverse Events (AEs) 
  • The most common drug-related AEs observed in the afatinib* treatment arm were diarrhoea, alopecia (hair loss) asthenia (a condition in which the body lacks or has lost strength either as a whole or in any of its parts 

Tolerability

The side effects of afatinib* are predictable, generally manageable and reversible. In studies to date, drug-related adverse events were largely related to the gastrointestinal tract (diarrhoea) and skin disorders (rash), which is in line with EGFR tyrosine-kinase inhibition.5-16

4. CLINICAL POTENTIAL

The irreversible binding properties of afatinib* and its selective and irreversible ErbB Family Blockade, may provide benefits and broaden potential indications in many cancers. Phase III trials in squamous head and neck cancer (HNSCC) indications and investigations in other tumour types are ongoing.

The positive results from the Phase III LUX-Lung trials showcase the growing evidence of the superiority of afatinib* over standard of care chemotherapy. The consistent results substantiate the robust efficacy and safety profile of afatinib*, and reinforce confidence in the data.

The study programme evaluating afatinib* in a number of indications will provide more clinical data to further establish the benefits of this compound demonstrated in earlier studies. 

Footnotes

*Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the US under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Afatinib is under regulatory review by health authorities in other countries worldwide

Reference

  1. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-54.
  2. Hynes NE, MacDonald G. ErbB receptors and signalling pathways in cancer. Curr Opin Cell Biol 2009; 21:177- 84.
  3. Reid A, Vidal L, Shaw H, do Bono J.Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). Eur J Cancer 2007;43:481-9.
  4. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012;343:342-50.
  5. Yang J, Hirsh V, Schuler M, et al. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2013;DOI: 10.1200/JCO.2012.46.1764.
  6. Sequist L, Yang J, Yamamoto N, et al. Phase III Study of afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2013;DOI: 10.1200/JCO.2012.44.2806.
  7. Wu, Y., MD. LUX-Lung 6: A randomized, open-label, Phase III study of afatinib (A) vs. gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts.) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung. (Abstract #8016) at American Society of Clinical Oncology, Chicago, June 2, 2013.
  8. Geater, SL, MD. LUX-Lung 6: Patient reported outcomes (PROs) from a randomized open-label, Phase III study in 1st-line advanced NSCLC patients (pts.) harbouring epidermal growth factor receptor (EGFR) mutations. Poster (Abstract #8061) at American Society of Clinical Oncology, Chicago, June 1, 2013.
  9. Schuler M, Chih-Hsin Yang J et al. Continuation of afatinib beyond progression: Results of a randomized, openlabel, Phase III trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC) progressed on erlotinib/gefitinib and afatinib: LUX-Lung 5. (Abstract #8019) at 2014 American Society of Clinical Oncology, 50th ASCO Annual Meeting, 30 May–3 June 2014, Chicago, IL, USA.
  10. Yang J, Sequist L et al. Overall survival (OS) In patients with advanced non-small cell lung cancer (NSCLC) harbouring common (Del19/L858R) Epidermal Growth Factor Receptor mutations (EGFR mut):pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6] comparing afatinib with chemotherapy. (Abstract #8004) at 2014 American Society of Clinical Oncology, 50th ASCO Annual Meeting, 30 May–3 June 2014, Chicago, IL, USA.
  11. Plummer R, Vidal L, Li L, et al. Phase I study of BIBW2992, an oral irreversible dual EGFR/HER2 inhibitor, showing activity in tumours with mutated EGFR. Eur J Cancer Suppl 2006;4(12):173-4 (Abstract 573).
  12. Agus DB, Terlizzi E, Stopfer P, et al. A Phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumors. J Clin Oncol 2006;24(18,Suppl):Abstract 2074
  13. Mom CH, Eskens FA, Gietema JA, et al. Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of Epidermal Growth Factor Receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule. J Clin Oncol 2006;24(18,Suppl):Abstract 3025.
  14. Shaw H, Plummer R, Vidal l, et al. phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours. J Clin Oncol 006;24(18,Suppl):Abstract 3027.
  15. Eskens FA, Mom CH, Planting AS, et al. A Phase I dose escalation study of BIBW 2992, an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR-1) and 2 (HER 2) in a 2 week on 2 week off schedule in patients with advanced solid tumors. Poster A235 presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, USA, 14-18 November 2005.
  16. Marshall JL, Lewis NL, Amelsberg A, et al. A Phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors. Poster B161 presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, USA, 14-18 November 2005. .