Superiority of afatinib over comparator chemotherapy

Tumour assessment was based on independent review of the data showing progression-free survival (PFS) of 11.0 months for afatinib* and PFS of 5.6 months for chemotherapy.(1) In addition, 47% of afatinib*-treated patients were alive and progression-free after one year of treatment compared to only 2% on chemotherapy.

LUX-Lung 6 is the second Phase III trial after LUX-Lung 3 to show superiority of afatinib* over standard chemotherapies(2) in patients with EGFR (ErbB1) mutation-positive non-small cell lung cancer (NSCLC). The consistent results in two large prospective trials in this patient population substantiate the robust efficacy of afatinib*.(1,3)

“LUX-Lung 6 and LUX-Lung 3 together represent the largest clinical trial programme in EGFR mutation-positive NSCLC patients,” said Professor James Chih-Hsin Yang, Director of the Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan. “The results of both trials have shown us that afatinib* could offer lung cancer patients with EGFR mutations a significant delay in tumour growth, and a better quality of life, compared to current standard of care chemotherapies.”

The delay in tumour growth compares well in both registration studies, underlining the robustness of the data.

LUX-Lung 3: PFS = 11.1 vs. 6.9 months – afatinib* vs. pemetrexed/cisplatin(3)

LUX-Lung 6: PFS = 11.0 vs. 5.6 months – afatinib* vs. gemcitabine/cisplatin(1)

Consistent with LUX-Lung 3, afatinib* treatment led to significant and sustained tumour shrinkage compared to chemotherapy (gemcitabine/ cisplatin) in LUX-Lung 6. Specifically, in approximately two thirds of patients (66.9%) taking afatinib*, the tumour shrank (objective response) significantly in size compared to 23% in the chemotherapy arm (gemcitabine/cisplatin), by independent review.(1) Tumour shrinkage with afatinib* translated into improvements in life-restricting, disease-related symptoms such as cough, pain and shortness of breath (dyspnoea) as measured by standard lung cancer questionnaires.(4)

In addition, afatinib*-treated patients also reported to have a significantly better quality of life (e.g. at work and during household activities) than those on gemcitabine/cisplatin (as measured by standard lung cancer questionnaires).(4) These quality of life results are also consistent with data from the LUX-Lung programme, including the LUX-Lung 3 clinical trial results presented at last year’s ASCO.

“We are extremely encouraged by the clinical evidence base for afatinib* so far, and the results of the LUX-Lung 6 trial reaffirm our belief in this compound as a highly effective first-line treatment option for patients with lung cancer harbouring EGFR mutations,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “The LUX-Lung clinical trials form part of our extensive oncology development programme aimed at improving the lives of people affected by cancer, through the advance of innovative treatments such as afatinib*.”

The most common Grade 3 adverse events (AEs) associated with afatinib* in LUX-Lung 6 were rash (14.2%), diarrhoea (5.4%) and stomatitis/mucositis (inflammation of the mouth and throat) (5.4%).(1) These side effects are as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible.

The most common AEs associated with chemotherapy were neutropenia (an abnormally low level of neutrophils, a type of white blood cell) (17.7%), vomiting (15.9%) and leukopenia (a decrease in the number of white blood cells) (13.3%). The discontinuation rate due to AEs related to treatment was 5.9% of patients on the afatinib* arm and 39.8% of patients on the chemotherapy arm. Importantly, only 2% of patients on afatinib* decided to discontinue due to rash and none for diarrhoea.(1)

NSCLC comprises over 85% of the 391,000 new cases of lung cancer diagnosed annually in Europe. Because of its poor prognosis, approximately 340,000 deaths each year in Europe are attributed to lung cancer, making it the most common cause of cancer death.(5,6) In Asia, lung cancer accounts for more than 14% of all cancers and over 18% of all cancer deaths, however incidence varies by region.

The highest rates are found in Eastern Asia; each year over half a million new lung cancer cases are diagnosed in China, over 86,000 in Japan and over 9,000 in Taiwan.(7) Early testing for tumour EGFR mutation status of lung cancer patients is critical in improving patient outcomes. Between 10-15% of Caucasian and 40% of Asian NSCLC patients have tumours harbouring EGFR mutations.(8)

Afatinib* is an irreversible ErbB Family Blocker, thus it differs from currently available targeted therapies in that it irreversibly and completely inhibits ErbB receptor signal transduction, blocking the key pathways that help tumour cells grow, migrate and metabolise.(9) This novel mode of action may lead to a distinct therapeutic benefit(10) and is further being investigated in the comprehensive LUX-Lung trial programme.

1. Wu YL, Zhou C, Hu CP, et al. 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.
2. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–51.
3. Yang JC, Shuler M, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol 2012;30(18,Suppl):abstract LBA 7500.
4. Geater SL, Zhou C, Hu CP, et al. LUX-Lung 6: patient reported outcomes (PROs) from a randomized open-label, phase III study in 1st-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. Poster (Abstract #8061) at American Society of Clinical Oncology, Chicago, June 1, 2013.
5. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765-81.
6. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
7. International Agency for Research on Cancer; Globocan 2008, Fast Stats, Asia
8. Quest Diagnostics – Lung Cancer Mutation Panel. [Online] Available at: http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=TS_LungCancerMutation_Panel.htm [Last Accessed May2013]
9. 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.
10. 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.