New Data For Boehringer Ingelheim Corporation's Gilotrif® (Afatinib) Shows A Significant Improvement In Overall Survival In Lung Cancer Patients Whose Tumors Have The Most Common EGFR Mutation

New data for Boehringer Ingelheim's Gilotrif® (afatinib) shows a significant improvement in overall survival in lung cancer patients whose tumors have the most common EGFR mutation

RIDGEFIELD, Conn., May 14, 2014 /PRNewswire/ -- Boehringer Ingelheim today announced new overall survival data of two Phase III clinical trials (LUX-Lung 3 and LUX-Lung 6). Patients with advanced non-small cell lung cancer (NSCLC) whose tumors have the most common epidermal growth factor receptor (EGFR) mutation (exon 19 deletion) lived longer if treated with first-line afatinib compared to chemotherapy. An oral presentation at the 50^th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 2^nd (3:00 - 6:00 PM CDT, E Hall D2; Abstract #8004 scheduled for 4:00 - 4:12 PM) will discuss these data in more depth, providing further insights into their impact on clinical practice and patient care. Data from six other abstracts involving afatinib and other compounds in Boehringer Ingelheim's oncology portfolio will also be presented or published at ASCO in Chicago, May 30-June 3.

Overall survival results
In the pooled analysis from two of the largest trials in this patient population, afatinib prolonged survival of lung cancer patients whose tumors have common EGFR mutations compared with standard chemotherapy by a median of 3 months (27.3 to 24.3 months) and significantly reduced the risk of death by 19% (HR=0.81, p=0.037). The most pronounced reduction in risk of death was 41% (HR=0.59, CI 0.45, 0.77) in patients whose tumors have the most common EGFR mutation (exon 19 deletion of the EGFR gene); for patients with the exon 21 (L8585R) mutation there was no impact on overall survival (HR=1.25, CI 0.92, 1.71). Exon 19 deletions occur with a frequency of approximately 48% in EGFR-mutant lung tumors. See abstract (#8004) for full details.

The analysis of the delay in tumor growth (progression-free survival) and adverse events associated with afatinib in comparison with standard chemotherapy were consistent with previously published results of the primary data from these two trials.

"Our lung cancer patients urgently need more treatments that can improve overall survival," said Lecia V. Sequist, M.D., MPH, medical oncologist at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School. "These results provide encouraging perspective about overall survival when patients whose tumors have the most common EGFR mutation are treated with afatinib."

The LUX-Lung 3 Phase III clinical trial compared afatinib with chemotherapy (pemetrexed/cisplatin) as a first-line treatment in patients with advanced NSCLC with EGFR mutations. The LUX-Lung 6 Phase III clinical trial evaluated afatinib versus chemotherapy (gemcitabine/cisplatin) as a first-line treatment for Asian patients with advanced NSCLC with EGFR mutations.

Investigation of afatinib treatment beyond disease progression
Results from another Phase III study in NSCLC patients (LUX-Lung 5) also presented at ASCO met its primary endpoint by showing an improvement in progression-free survival (PFS) when continuing treatment with afatinib in combination with chemotherapy after the tumor started to grow on afatinib alone (treatment beyond progression). This Phase III study compared afatinib and paclitaxel versus investigator's choice of chemotherapy alone in patients with late-stage NSCLC whose disease has progressed after afatinib alone and have also failed several treatments, including chemotherapy, erlotinib or gefitinib.

Those patients who continued afatinib treatment, with the addition of chemotherapy, after progressing on afatinib alone, had a further delay in tumor growth compared to the group who stopped afatinib treatment and received chemotherapy only (tumor growth was delayed by 5.6 months and 2.8 months respectively, p=0.003). This corresponded to a 40% reduction in risk of disease progression (HR=0.60). The most common adverse events in patients treated with afatinib and chemotherapy versus chemotherapy were diarrhea (53.8% vs. 6.7%), hair loss or alopecia (32.6% vs. 15%) and weakness or asthenia (27.3% vs. 28.3%). See abstract (#8019) for full details.

Berthold Greifenberg, M.D., vice president, ClinicalDevelopment and Medical Affairs, Oncology, Boehringer Ingelheim Pharmaceuticals, Inc. commented: "These findings provide additional insights into afatinib's potential in patients with advanced lung cancer and across different stages of treatment. We now know that lung cancer represents an array of diseases, and we are proud to be conducting research on afatinib in a variety of treatment settings that may ultimately expand treatment options for patients with this devastating disease."

About Metastatic NSCLC and Common EGFR Mutations
In some people, genetic mutations lead to the constant activation of the EGFR protein, which is associated with uncontrolled cell division and the development and progression of NSCLC. Among patients diagnosed with NSCLC (the most common form of lung cancer), it is estimated that between 10 and 15% of Caucasians and approximately 40% of Asians have EGFR mutations which in 90% of cases are one of the two most common EGFR mutations (exon 19 deletions or exon 21 L858R).

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 interimoverall 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.

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