Head-to-head study demonstrating Gilotrif® (afatinib) significantly improved clinical outcomes compared to Iressa® (gefitinib) in EGFR mutation-positive advanced non-small cell lung cancer published in The Lancet Oncology

- LUX-Lung 7 trial showed afatinib significantly reduced the risk of lung cancer progression and treatment failure as well as increased overall response rate compared to gefitinib without compromising overall health-related quality of life, safety and tolerability

- Results provide oncologists who treat patients with EGFR mutation-positive lung cancer with important information for clinical practice

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Boehringer Ingelheim Pharmaceuticals, Inc.

Apr 13, 2016, 08:00 ET

RIDGEFIELD, Conn., April 13, 2016 /PRNewswire/ -- Results from LUX-Lung 7, a global head-to-head Phase IIb trial comparing treatment with Gilotrif^® (afatinib) to Iressa^® (gefitinib) in patients whose tumors harbor the most common EGFR mutations, were published in The Lancet Oncology.

LUX-Lung 7 lead investigator and lead author Professor Keunchil Park, director of Innovative Cancer Medicine Institute (ICMI) at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea commented, "This key finding from this study suggests a significant difference in efficacy between afatinib and gefitinib across multiple endpoints and pre-defined patient subgroups."

Results from the LUX-Lung 7 trial showed that afatinib significantly reduced the risk of lung cancer progression by 27% versus gefitinib. The improvement in progression free survival (PFS) became more pronounced over time. After two years of treatment, more than twice as many patients on afatinib were alive and progression free than those on gefitinib (after 18 months; 27% vs 15% and after 24 months; 18% vs 8%).

In addition, patients on afatinib had a significantly longer time on treatment, and risk of treatment failure was reduced by 27% versus gefitinib. Significantly more patients had an objective tumor response (ORR; a clinically meaningful decrease in tumor size) with afatinib when compared to gefitinib (70% vs 56%), with a median duration of response of 10.1 months and 8.4 months, respectively. Data for the co-primary endpoint of overall survival (OS) are not yet mature and will be presented in the future.

Both afatinib and gefitinib demonstrated similar improvements in patient-reported outcome measures in the LUX-Lung 7 trial with no significant differences in health-related quality of life with afatinib compared to gefitinib treatment. Treatment with both afatinib and gefitinib was generally tolerable, leading to an equal rate of treatment-related discontinuation in both arms (6%). Adverse events (AEs) observed in the trial were consistent with the known safety profiles of both treatments.

The overall frequency of serious AEs was 44.4% for afatinib and 37.1% for gefitinib. The most common grade ≥3 related AEs with afatinib were: diarrhea (13%) and rash/acne (9%), and with gefitinib: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase (9%) and rash/acne (3%). Drug-related interstitial lung disease was reported for four patients on gefitinib and no patients on afatinib. Dose modification of afatinib was available in patients who met a set criteria in order to better manage AEs. As gefitinib is only available in one dose formulation, no dose reduction was administered.

LUX-Lung 7 is the second head-to-head trial of afatinib versus a first-generation EGFR tyrosine-kinase inhibitor (TKI). The first, LUX-Lung 8, compared afatinib to erlotinib in squamous cell carcinoma of the lung.

"We are pleased with The Lancet Oncology publication of the LUX-Lung 7 trial results and believe the results will inform treatment practice in EGFR-mutated NSCLC," said Tarek Sahmoud, MD, PhD, vice president, Oncology Clinical Development and Medical Affairs, Boehringer Ingelheim. "LUX-Lung 7 builds on our clinical experience in head-to-head trials with afatinib and demonstrates our commitment to better understanding afatinib's place in the treatment paradigm."

About the LUX-Lung 7 trial
LUX-Lung 7 (NCT01466660) is the first global, head-to-head trial comparing second- and first-generation EGFR-directed therapies (afatinib and gefitinib respectively) for patients with EGFR mutation-positive NSCLC who received no prior treatment. The Phase IIb trial included 319 patients with advanced stage NSCLC harboring common EGFR mutations (del19 or L858R). The trial's co-primary endpoints were PFS by independent review, time to treatment failure and OS; and the secondary endpoints included ORR, disease control rate, tumor shrinkage, patient-reported outcomes and safety.

Results: compared to gefitinib, afatinib significantly improved:

PFS (HR=0.73; 95% CI, 0.57‒0.95; p=0.0165; median: 11.0 months [afatinib] versus 10.9 months [gefitinib])
Time to treatment failure (HR=0.73; 95% CI, 0.58‒0.92; p=0.0073; median: 13.7 months [afatinib] versus 11.5 months [gefitinib])
ORR (70% vs 56%, p=0.0083)

Currently available Lux-Lung 7 data have limitations. At time of publication, an analysis of all three co-primary endpoint was not possible.

Afatinib is approved in more than 60 countries for the first-line treatment of distinct types of EGFR mutation-positive NSCLC (under the brand names: GIOTRIF^® / GILOTRIF^®). Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumor growth when compared to standard chemotherapy. In addition, afatinib is the first treatment to have shown an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy. A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (exon 19 deletions; del19) compared to chemotherapy.

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.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF^® (afatinib) TABLETS

WARNINGS AND PRECAUTIONS

Diarrhea

Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal trial, diarrhea occurred in 96% of patients treated with GILOTRIF, of which 15% was Grade 3 in severity and occurred within the first six weeks.
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 at a reduced dose.
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 until loose stools cease for 12 hours.

Bullous and Exfoliative Skin Disorders

In the pivotal trial, 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 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 patients receiving GILOTRIF in clinical trials. 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 trial, 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 the pivotal trial, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF. Across all clinical trials 0.18% were fatal.
Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Treatment should be discontinued in patients who develop severe hepatic impairment while taking GILOTRIF.

Keratitis

Keratitis was reported in 2.2% of patients in the pivotal trial, with Grade 3 in 0.4% of patients.
Withhold GILOTRIF during evaluation of patients with suspected keratitis. 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.

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%), nausea (25% vs 68%), vomiting (23% vs 47%), 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%) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%).
Pancreatitis has been reported during post-marketing use of GILOTRIF. The frequency and causal relationship of pancreatitis to GILOTRIF has not been established.

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 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 Sep 2015

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 Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

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