Boehringer Ingelheim Corporation's Afatinib Meets Primary Endpoint In Phase 3 Study Of Head And Neck Cancer

RIDGEFIELD, Conn., Sept. 29, 2014 /PRNewswire/ -- Phase III data from Boehringer Ingelheim's LUX-Lung 8 trial, the first study to evaluate the superiority of afatinib versus erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung, demonstrated superior improvement in progression-free survival (PFS) with afatinib compared to erlotinib. The results (abstract #1222O) are being presented today at the European Society for Medical Oncology (ESMO) 2014 Congress (September 26-30).

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, with SCC representing approximately 30% of NSCLC cases. Afatinib, a once-daily kinase inhibitor that irreversibly binds and inhibits ErbB1, ErbB2 and ErbB4 receptors, is not approved for SCC of the lung; its safety and efficacy have not been established in this population.

LUX-Lung 8 demonstrated that afatinib significantly reduced the risk of disease progression by 18% when compared to erlotinib and delayed tumor growth (PFS by independent review: 2.4 vs. 1.9 months; HR=0.82; p=0.043). Overall survival (OS: length of time patients live for), the key secondary endpoint, is not yet mature and will therefore be assessed at a later stage in the trial and reported at a future medical congress.

Treatment with afatinib showed improvement in the secondary endpoint of disease control rate (DCR: the percentage of patients who achieved complete response, partial response and stable disease) compared to erlotinib (DCR: 45.7% vs. 36.8%; p=0.020). Objective response rate (ORR: percentage of patients who achieved a partial or complete response to therapy) was 4.8% in the afatinib arm versus 3.0% in the erlotinib arm (p=0.233). In addition to the efficacy measures, patient-reported outcomes were assessed. More patients reported an improvement in their global health status/quality of life (p=0.026) and cough (p=0.01) with afatinib versus erlotinib; no difference was observed with pain (p=1.0) and dyspnea (p=0.298) between groups. There was no significant difference in the time to deterioration across these four measures.

Lead investigator Glen D. Goss, M.D., director of Clinical and Translational Research, the Ottawa Hospital Cancer Center, University of Ottawa, Canada, commented: "The results of LUX-Lung 8 demonstrate the progression-free survival benefit for afatinib over erlotinib in advanced squamous cell carcinoma of the lung, a disease with a poor prognosis for which there are currently limited treatment options. We are awaiting with interest the results of the overall survival data."

The overall rate of severe (>/= grade 3) adverse events was comparable between both therapies. Incidence of severe adverse events was 50.2% in patients treated with afatinib compared to 49.1% with erlotinib. A higher incidence of severe diarrhea and stomatitis was observed in patients treated with afatinib compared to erlotinib (severe diarrhea: 9% vs. 2%; stomatitis: 3% vs. 0%), while there was a higher incidence of severe rash/acne observed with erlotinib compared to afatinib (9% vs. 6%).

"We are pleased to be presenting the results of the LUX-Lung 8 study, which demonstrated that treatment with afatinib significantly improved progression-free survival compared to erlotinib in advanced squamous cell carcinoma of the lung," said Berthold Greifenberg, M.D., vice president, Clinical Development and Medical Affairs, Oncology, Boehringer Ingelheim Pharmaceuticals, Inc. "These data demonstrate our commitment to further evaluate afatinib's potential in treating patients with lung cancer, a disease made up of a number of distinct subtypes."

About LUX-Lung 8 trial
LUX-Lung 8 [ClinicalTrials.gov Identifier: NCT01523587] is the largest prospective head-to-head trial to evaluate the superiority of afatinib versus erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung. In the randomized, open-label Phase III trial, 795 patients with stage IIIB/IV SCC of the lung were randomized 1:1 to receive afatinib or erlotinib until disease progression. The planned primary analysis was based on 414 PFS events by independent review in the first 669 patients randomized (afatinib: 335, erlotinib: 334) while recruitment was ongoing.

See abstract #1222O for details. (A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8), 27.09.2014, 16:00 17:45 CET, Madrid).

A second head-to-head trial, LUX-Lung 7, is currently evaluating afatinib versus gefitinib as a first-line treatment in EGFR mutation positive non-small cell lung cancer patients.

About Gilotrif® (afatinib) tablets
GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.

GILOTRIF is an oral, once-daily kinase inhibitor that is designed to irreversibly bind and inhibit the following receptors: EGFR (ErbB1), HER2 (ErbB2) and ErbB4.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Diarrhea

• Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.
• For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.

Bullous and Exfoliative Skin Disorders

• Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.

Interstitial Lung Disease (ILD)

• ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade >/=3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.

Hepatic Toxicity

• In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.

Keratitis

• Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Embryofetal Toxicity

• GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF.

Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer

• An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving GILOTRIF in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of GILOTRIF and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. GILOTRIF combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer.

ADVERSE REACTIONS

• In GILOTRIF-treated patients (n=229) the most common adverse reactions in the pivotal study (>/=20% all grades & vs. pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs. 23%), rash/dermatitis acneiform (90% vs. 11%), stomatitis (71% vs. 15%), paronychia (58% vs. 0%), dry skin (31% vs. 2%), decreased appetite (29% vs. 55%), pruritus (21% vs. 1%).
• Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
• More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).

DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers

• Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) with GILOTRIF can decrease exposure to afatinib.

USE IN SPECIFIC POPULATIONS
Nursing Mothers

• It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Renal Impairment

• GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated.

Hepatic Impairment

• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI Apr 2014

For full prescribing information, including patient information, please click here. You can also visit www.gilotrif.com or contact Boehringer Ingelheim's Medical and Technical Information (MTI) Unit at 1-800-542-6257.

About Boehringer Ingelheim in Oncology
Building on scientific expertise and excellence in the fields of pulmonary and cardiovascular medicine, metabolic disease, neurology, virology and immunology, Boehringer Ingelheim has embarked on a major research program to discover and develop innovative cancer treatments. Working in close collaboration with the international scientific community and a number of the world's leading cancer centers, Boehringer Ingelheim's commitment to oncology is underpinned by using advances in science to develop a range of targeted therapies for various solid tumors and hematological cancers. The current focus of late-stage research includes compounds in three areas: signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition. The company is also evaluating a robust and growing pipeline of early-stage oncology compounds in areas including growth/survival signaling, immunotherapy and epigenetics.

For information about participating in a Boehringer Ingelheim clinical trial, please visit www.bicancertrials.com or call 1.866.725.7110.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

For more information, please visit us.boehringer-ingelheim.com

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