FDA approves Gilotrif® (afatinib) as new oral treatment option for patients with squamous cell carcinoma of the lung

On April 15, 2016, Boehringer Ingelheim reported that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif (afatinib) tablets for the treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy (Press release, Boehringer Ingelheim, APR 15, 2016, View Source [SID:1234511360]). The U.S. approval follows the recent marketing authorization of Gilotrif in this patient population by the European Commission. Gilotrif, an oral, once-daily EGFR-directed therapy, is currently approved in the U.S. for the first-line treatment of specific types of EGFR mutation-positive NSCLC.

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"We are pleased to bring a proven therapy to patients suffering from advanced squamous cell carcinoma of the lung who have progressed despite chemotherapy," said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "This approval is further evidence of Boehringer Ingelheim’s strong commitment to bringing new treatment options to the lung cancer community."

Squamous cell carcinoma (SqCC) of the lung is associated with a poor prognosis, limited survival and symptoms like cough and dyspnea. The median overall survival (OS) after diagnosis of advanced SqCC is around one year.

LUX-Lung 8 clinical trial investigator Shirish Gadgeel, MD, leader of the Thoracic Oncology Multidisciplinary Team at the Karmanos Cancer Center, Detroit, commented: "The overall survival data and significant delay in lung cancer progression seen in the global head-to-head Phase III trial demonstrated that Gilotrif is an effective new treatment option in this patient population."

The sNDA was based on results of the head-to-head LUX-Lung 8 trial in patients with SqCC of the lung whose tumors progressed after first-line chemotherapy. Gilotrif, compared to erlotinib, demonstrated:

Significant delay in progression of lung cancer (PFS, progression-free survival, primary endpoint), reducing the risk of cancer progression by 18%
Significant improvement in overall survival (OS, key secondary endpoint), reducing the risk of death by 19%
Significantly improved disease control rate (51% vs 40%; P=0.002)

The most common adverse reactions observed with Gilotrif (reported in at least 20% of study patients) were diarrhea (75%), rash or acne (70%), stomatitis (mouth sores) (30%), decreased appetite (25%), and nausea (21%).

LUX-Lung 8 (NCT01523587) is part of the Gilotrif LUX-Lung program – the largest collection of clinical trials of any EGFR tyrosine kinase inhibitor (TKI), with over 3,760 patients across eight studies conducted around the world. The comprehensive LUX-Lung program includes two pivotal studies in the first-line setting for EGFR mutation-positive patients, LUX-Lung 3 and LUX-Lung 6, which compared Gilotrif to chemotherapy regimens. In addition, the program included two head-to-head studies (LUX-Lung 7 and LUX-Lung 8) of Gilotrif versus first-generation EGFR TKIs gefitinib and erlotinib, respectively. The LUX-Lung program has involved over 680 sites in 40 countries, reflecting the strong partnership between Boehringer Ingelheim and the lung cancer specialist community.

INDICATIONS AND USAGE

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 indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF (afatinib) TABLETS

WARNINGS AND PRECAUTIONS

Diarrhea

GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume 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

GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
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. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.

Interstitial Lung Disease

Interstitial Lung Disease (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. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.

Hepatic Toxicity

Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% 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 has been reported in patients taking GILOTRIF.
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.

Embryo-Fetal Toxicity

GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.

ADVERSE REACTIONS

Adverse Reactions observed in clinical trials were as follows:

First-line treatment of EGFR mutation-positive, metastatic non-small cell lung cancer (NSCLC)

In GILOTRIF-treated patients (n=229) the most common adverse reactions (≥20% all grades & vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/acneiform dermatitis (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%). Other clinically important adverse reactions observed in patients treated with GILOTRIF include: decreased appetite (29%), nausea (25%), and vomiting (23%).
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%).

Previously Treated Metastatic Squamous NSCLC

In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), nausea (21% vs 16%). Other clinically important laboratory abnormalities observed in patients treated with GILOTRIF include: increased alanine aminotransferase (ALT) (10%), increased aspartate aminotransferase (AST) (7%), and increased bilirubin (3%).
Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%); vomiting (4.8%); and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).

Postmarketing Experience

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

E ffect of P-glycoprotein (P-gp) Inhibitors and Inducers

Concomitant use 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 use 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

Lactation

Because of the potential for serious adverse reactions in nursing infants from GILOTRIF, lactating women should not breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.

Females and Males of Reproductive Potential

GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.

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 2016

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

10-K/A [Amend] – Annual report [Section 13 and 15(d), not S-K Item 405]

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Proceedings of the 2015 National Toxicology Program Satellite Symposium.

The 2015 Annual National Toxicology Program Satellite Symposium, entitled &amp;quot;Pathology Potpourri&amp;quot; was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to present and discuss diagnostic pathology challenges or nomenclature issues. Because of the combined meeting, both laboratory and domestic animal cases were presented. This article presents summaries of the speakers’ talks, including challenging diagnostic cases or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included hepatocellular lesions, a proposed harmonized diagnostic approach to rat cardiomyopathy, crop milk in a bird, avian feeding accoutrement, heat exchanger in a tuna, metastasis of a tobacco carcinogen-induced pulmonary carcinoma, neurocytoma in a rat, pituicytoma in a rat, rodent mammary gland whole mounts, dog and rat alveolar macrophage ultrastructure, dog and rat pulmonary phospholipidosis, alveolar macrophage aggregation in a dog, degenerating yeast in a cat liver aspirate, myeloid leukemia in lymph node aspirates from a dog,Trypanosoma cruziin a dog, solanum toxicity in a cow, bovine astrovirus, malignant microglial tumor, and nomenclature challenges from the Special Senses International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Group.
© The Author(s) 2016.

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A PHASE I DOSE ESCALATION STUDY EVALUATING THE SAFETY TOLERABILITY AND PHARMACOKINETICS OF CUDC-427, A POTENT, ORAL, MONOVALENT IAP ANTAGONIST, IN PATIENTS WITH REFRACTORY SOLID TUMORS.

To determine the dose-limiting toxicities, adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins.
Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily14-days on/7 days-off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMCs), and monocyte chemoattractant protein-1 (MCP-1) levels.
Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (Grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1; and five patients experienced AEs related to CUDC-427 that led to discontinuation and included Grade 3 pruritis, and fatigue, and Grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg po daily × 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses (CR) in one patient with ovarian cancer and one patient with MALT lymphoma.
CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6-producing lung carcinoma cells.

Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6-producing human lung cancer xenograft model.
Nude mice were subcutaneously inoculated with cells of the IL-6-producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined.
LC-06-JCK-bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non-tumor-bearing (NTB) mice. LC-06-JCK-bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK-bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK-bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK-bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and ferritin, with increased values of MCV and MCH.
Our results suggest that overproduction of hepcidin by IL-6 signaling might be a major factor that leads to functionally iron-deficient cancer-related anemia in the LC-06-JCK model. We demonstrated that inhibition of the IL-6 signaling pathway by MR16-1 treatment resulted in significant recovery of iron-deficiency anemia and alleviation of cancer-related symptoms. These results indicate that IL-6 signaling might be one possible target pathway to treat cancer-related anemia disorders.

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