Superiority of afatinib* over comparator chemotherapy for patients with EGFR mutation-positive advanced lung cancer is reinforced by second Phase III study

Data from Boehringer Ingelheim’s LUX-Lung 6 trial, presented at the official American Society of Clinical Oncology (ASCO) Annual Conference, demonstrate that patients treated with the novel, investigational compound afatinib* lived for almost one year before their tumour started to grow again, compared to less than half a year for those on standard chemotherapy (gemcitabine/cisplatin). 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 chemotherapies2 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/cisplatin3
• LUX-Lung 6: PFS = 11.0 vs. 5.6 months – afatinib* vs. gemcitabine/cisplatin1

(These are data from primary analyses based on independent review.)

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.9This novel mode of action may lead to a distinct therapeutic benefit10 and is further being investigated in the comprehensive LUX-Lung trial programme.

About the LUX-Lung 6 trial

LUX-Lung 6 is the largest (n = 364), prospective, registration trial to date in patients with advanced EGFR mutation positive lung cancer. It is a multicentre, randomised, open-label Phase III trial, which evaluated the efficacy and safety of afatinib* versus chemotherapy (cisplatin/gemcitabine) as first-line treatment for patients with advanced and metastatic NSCLC harbouring an EGFR mutation.1

In the study, 364 patients from China, the Republic of Korea and Thailand (Stage IIIB/IV, performance status 0–1, chemo-naïve) were randomised 2:1 to oral daily afatinib* 40 mg (n=242) or intravenous cisplatin/gemcitabine (75mg/m2 on day 1 / 1000 mg/m2 on day1 and day8 every 21 days up to 6 cycles, n=122). The primary endpoint was progression-free survival by central independent review.1

Cisplatin/gemcitabine is commonly used for the treatment of first-line NSCLC patients in China, the Republic of Korea and Thailand.

About the LUX-Lung 3 trial

LUX-Lung 3 is a large, randomised, open-label, Phase III registration study comparing afatinib* to two chemotherapy agents, pemetrexed and cisplatin, as first-line treatment for patients with stage IIIb or IV NSCLC harbouring an EGFR mutation. The study included 345 patients with EGFR mutation positive NSCLC globally.3 LUX-Lung 3 is the first study in patients with EGFR mutation positive NSCLC to use pemetrexed/cisplatin as a comparator.

The most common grade 3 drug-related adverse events observed in the afatinib* treatment arm were diarrhoea (14%), rash (16%), and paronychia (11%). The most common drug-related grade 3 adverse events observed in the chemotherapy arm (pemetrexed/cisplatin) were neutropenia (15%), fatigue (13%), and leucopenia (8%). There was a low discontinuation rate associated with treatment-related adverse events in the trial (8% discontinuation rate for afatinib*; 12% for chemotherapy). One percent of patients in the afatinib* arm discontinued due to drug-related diarrhoea.3

About Afatinib*

Afatinib* is an irreversible ErbB Family Blocker which irreversibly blocks EGFR (ErbB1) as well as the other relevant members of the ErbB Family that are known to play a critical role in the growth and spread of the most pervasive cancers and cancers associated with high mortality (lung, breast, and head & neck cancers). Afatinib* is currently in Phase III clinical development in NSCLC and head & neck cancer.

Afatinib* has been submitted to the FDA, EMA, regulatory authorities in Asia and other countries for treatment of EGFR mutation-positive locally advanced and metastatic NSCLC patients. Afatinib* received priority review and orphan drug status in the US.

About Lung Cancer

Lung cancer is the most common and most deadly form of cancer in the world: it accounts for 1.6 million new cancer cases annually. Because of its poor prognosis, 1.38 million deaths each year are attributable to lung cancer.6 Overall, lung cancer is the cause of 18% of all cancer deaths.6 13% of all new cases of cancer are lung cancers11 and smoking is attributed as the main cause.

About Boehringer Ingelheim in Oncology

Building on scientific expertise and research excellence in the fields of pulmonary and cardiovascular medicine, metabolic disease, neurology, virology and immunology, Boehringer Ingelheim has embarked on a major research programme to develop innovative cancer drugs. Working in close collaboration with the international scientific community and a number of the world’s leading cancer centres, Boehringer Ingelheim’s commitment to oncology is underpinned by using advances in science to develop a range of targeted therapies for various solid tumours and haematological cancers.

The current focus of research includes compounds in three areas: angiogenesis inhibition, signal transduction inhibition and cell-cycle kinase inhibition. Nintedanib* is an oral triple angiokinase inhibitor that blocks three growth factor receptors simultaneously: vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR alpha and beta), and fibroblast growth factor receptors (FGFR 1-3). Phase III results for nintedanib* in lung cancer patients with advanced adenocarcinoma are due to be presented at the ASCO 2013 Annual Meeting on June 3rd 2013. Patients with advanced adenocarcinoma have a very poor prognosis12 and once they have failed on initial chemotherapy they currently have very limited treatment options.13 Nintedanib* is also currently in Phase III clinical development in ovarian cancer. In the area of cell-cycle kinase inhibition, Boehringer Ingelheim is developing an inhibitor of polo-like kinase 1 (Plk1), volasertib*, a protein that is involved in the processes of cell division. The compound is in Phase III development for acute myeloid leukaemia.

Boehringer Ingelheim’s oncology pipeline is evolving and demonstrates the company’s continued commitment to advance the disease area.

* Afatinib, nintedanib and volasertib are investigational compounds and are not yet approved. Their safety and efficacy have not been fully establised.

References

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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.
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