Afatinib 40 mg ( xovoltib) GILOTRIF

[Product Information]

Generic Name: Afatinib / Tovok

Product Brand Name: XOVOLTIB

[Afatinib Indications]

Afatinib (Tovok) is indicated for the first-line treatment of advanced non-small cell lung cancer (NSCLC) and for patients with advanced HER2-positive breast cancer.

[Afatinib Dosage and Administration]

The recommended dose of Afatinib (GILOTRIF) is 40 mg taken orally once daily until disease progression or until the patient is no longer able to tolerate the treatment. Afatinib (GILOTRIF) should be taken at least 1 hour before a meal or 2 hours after a meal.

[Afatinib Adverse Reactions]

The most common toxic side effects of Afatinib include diarrhea, rash, nausea, hypertension, anorexia, asymptomatic QT interval prolongation, and proteinuria. With increasing doses, adverse events such as hypophosphatemia, stomatitis, elevated transaminases, non-specific intestinal obstruction, thrombocytopenia, congestive heart failure, deep vein thrombosis, and pulmonary embolism may occur. The most common dose-limiting toxicities (DLTs) associated with Afatinib (Tovok) are diarrhea, hypertension, and rash.

[Afatinib Precautions]

(1) Diarrhea: Diarrhea may lead to dehydration and renal failure. Withhold GILOTRIF in cases of severe or prolonged diarrhea that does not respond to anti-diarrheal medications.

(2) Bullous and Exfoliative Skin Disorders: Severe bullous, blistering, and exfoliative skin lesions have occurred in 0.15% of patients treated with Afatinib. Discontinue the drug in the event of life-threatening skin reactions. Withhold GILOTRIF in cases of severe or prolonged skin reactions. (3) Interstitial Lung Disease (ILD): Occurs in 1.5% of patients. Withhold GILOTRIF in cases of acute onset or worsening of pulmonary symptoms. Discontinue GILOTRIF if ILD is diagnosed.

(4) Hepatotoxicity: Fatal hepatic injury occurred in 0.18% of patients. Monitor with periodic liver function tests. Withhold or discontinue GILOTRIF in cases of severe or worsening liver function abnormalities.

(5) Keratitis: Occurs in 0.8% of patients.

(6) Embryo-fetal Toxicity: May cause fetal harm. Advise women of the potential risk to the fetus and to use effective contraception.

[Afatinib: Pharmacodynamics and Pharmacokinetics]

Afatinib (Gilotrif) is an oral medication and an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. A randomized Phase IIb study demonstrated that, compared to placebo plus best supportive care, treatment with Afatinib plus best supportive care in patients with non-small cell lung cancer (NSCLC)—who had previously failed first- or second-line chemotherapy and EGFR-TKI therapy—did not improve overall survival; however, it significantly improved progression-free survival and increased both the objective response rate (ORR) and the 8-week disease control rate. Results from another study (LUX-LUNG 2) showed that the majority (61%) of patients harboring common EGFR mutation types experienced significant tumor shrinkage, delayed time to tumor progression, and prolonged survival following treatment with Afatinib. These results preliminarily confirm that Afatinib is a promising targeted therapy agent.

It is a second-generation, highly potent, dual, irreversible tyrosine kinase inhibitor. While Erlotinib and Gefitinib act as tyrosine kinase inhibitors that selectively inhibit EGFR, BIBW2992 (Afatinib) simultaneously inhibits both the EGFR and HER2 receptors. James Sr. and colleagues at Guy's Hospital, King's College London, conducted a study involving patients with various solid tumors. Phase I clinical trials demonstrated encouraging results in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations: 20% of patients achieved a sustained partial response (PR)—specifically two women and one man. Of these three patients, two exhibited a deletion in exon 19 of the EGFR gene; this specific mutation type is frequently observed in women, non-smokers, and patients with adenocarcinoma. BIBW2992, administered orally at a daily dose of 50 mg, was well tolerated. The Phase I clinical trials for BIBW2992 indicated that, even in NSCLC patients with EGFR mutations who had developed resistance to first-generation tyrosine kinase inhibitors, BIBW2992 still demonstrated potential for anti-tumor activity. This efficacy is attributed to its unique ability to exert irreversible dual inhibition against both EGFR and HER2. Given the exceptional data generated during preliminary clinical studies, the drug was granted expedited review status by the U.S. FDA on February 15, 2008. An international, multicenter Phase III clinical trial is currently poised to commence, investigating the use of BIBW2992 in NSCLC patients who have previously failed treatment with epidermal growth factor receptor (EGFR) inhibitors; this initiative holds the potential to offer a new therapeutic possibility for patients with NSCLC.

[Mechanism of Action of Afatinib]

Afatinib (Giotrif) is an irreversible inhibitor of the ErbB family of receptors; it functions by suppressing signal transduction and blocking the primary pathways associated with the growth and division of cancer cells. Since signal transduction via the ErbB family mechanism can be triggered by various homodimers and heterodimers, the simultaneous inhibition of multiple members of the ErbB family (such as EGFR, HER2, ErbB3, and ErbB4) proves more effective in disrupting downstream signaling pathways.

In cancer cells, the activity of the ErbB family is frequently dysregulated. When the factors governing cellular growth mechanisms are overexpressed or function abnormally, the risk of developing various solid tumors increases. Such receptor overexpression stimulates intracellular signal transduction to levels exceeding normal physiological thresholds, thereby driving uncontrolled tumor cell proliferation, migration, and metastasis, while simultaneously inhibiting apoptosis. The aforementioned abnormalities in cellular signal transduction can arise from various mechanisms, including: receptor mutations (e.g., EGFR mutations in lung tumors), receptor overexpression (e.g., HER2 overexpression in breast tumors), or ligand overexpression.

[Afatinib: Approval and Usage]

Based on the groundbreaking efficacy results achieved in clinical studies, Afatinib (Giotrif) was previously granted inclusion in the U.S. Food and Drug Administration's (FDA) Priority Review program. The FDA's Priority Review process provides an expedited pathway for the review of drugs that are safe, effective, address unmet medical needs (i.e., lack satisfactory alternative treatments), and offer significant improvements over currently marketed products, thereby accelerating the delivery of breakthrough therapies to patients in need.

On July 12, 2013, Afatinib was approved by the FDA for marketing as a novel first-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test method [1].

The European Medicines Agency (EMA) also approved Afatinib on July 25, 2013, for the treatment of patients with NSCLC driven by EGFR mutations.

The Taiwan Food and Drug Administration (TFDA), under the Department of Health of the Executive Yuan, had previously granted early approval for the marketing of Afatinib (marketed in Taiwan as Giotrif) on May 17, 2013.

[Afatinib: Key Research and Development]

Lung Cancer

The LUX-Lung clinical research program is currently investigating the efficacy of Afatinib (Giotrif) in patients with advanced or metastatic non-small cell lung cancer (NSCLC). Two pivotal Phase III studies—LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364)—constitute the largest, most robust, and most consistent clinical registration program to date for advanced non-small cell lung cancer (NSCLC) driven by EGFR mutations. In 2013, the results of the LUX-Lung 3 study were published in the *Journal of Clinical Oncology*, while the results of the LUX-Lung 6 study were presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO).

Data presented at the official ASCO Annual Meeting demonstrated that, following treatment with the novel investigational compound afatinib, patients experienced a delay of up to one year before their tumors resumed growth; in contrast, tumors recurred in patients receiving chemotherapy (gemcitabine/cisplatin) in less than six months. Data from independent tumor assessments revealed that the progression-free survival (PFS) for afatinib was 11 months—a superior outcome compared to the 5.6-month PFS observed with chemotherapy. Furthermore, nearly half (47%) of the patients treated with afatinib remained alive and free of disease progression one year into treatment, whereas only 2% of patients receiving chemotherapy maintained this status.

As part of the LUX-Lung clinical research program, eight studies are currently underway. These studies are designed to evaluate the efficacy of afatinib across various clinical settings involving advanced and metastatic NSCLC, including patients with EGFR mutations as well as those with persistent disease.

[Afatinib and Other Cancers]

Afatinib has also been selected for investigation across various tumor types, and advanced-stage clinical trials are currently being conducted for indications such as head and neck cancer. [Efficacy and Safety of Afatinib]

LUX-Lung 3 and LUX-Lung 6 were multicenter, randomized, open-label Phase III clinical trials designed to compare afatinib against chemotherapy (specifically pemetrexed/cisplatin and gemcitabine/cisplatin, respectively) as a first-line treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations.

These pivotal Phase III studies provided compelling evidence demonstrating that afatinib offers superior efficacy compared to conventional chemotherapy (pemetrexed/cisplatin and gemcitabine/cisplatin). Furthermore, the findings from both studies consistently validated the efficacy and safety profile of afatinib, thereby further bolstering confidence in the research outcomes.

Afatinib (Giotrif) is a drug developed by Boehringer Ingelheim. Although classified as a short-acting agent, it was the first drug approved for use in lung cancer patients who had previously failed treatment with EGFR inhibitors. Results from Phase Ib/III trials involving 585 patients with advanced NSCLC harboring EGFR or KRAS gene mutations showed that treatment with afatinib extended progression-free survival compared to placebo (3.3 months versus 1.1 months, respectively); however, overall survival rates were 10.8 months and 12 months, respectively—a seemingly contradictory result that has drawn skepticism from various quarters. Consequently, Boehringer Ingelheim is currently conducting two Phase III trials to further evaluate the efficacy of Giotrif in treating the specific subgroup of patients with EGFR mutations. [Afatinib – FDA Approval]

On July 12, 2013, the U.S. Food and Drug Administration (FDA) announced the approval of Gilotrif (afatinib) for the treatment of patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors harbor specific epidermal growth factor receptor (EGFR) gene mutations—specifically exon 19 deletions or exon 21 L858R substitutions—as detected by a companion diagnostic test (the *therascreen* EGFR RGQ PCR kit). Gilotrif is a tyrosine kinase inhibitor that works by blocking proteins that promote the growth and development of cancer cells.

The safety and efficacy of Gilotrif were established in a clinical study involving 345 patients with EGFR-mutated metastatic NSCLC. Subjects were randomized to receive either Gilotrif or up to six cycles of chemotherapy consisting of pemetrexed plus cisplatin. The results demonstrated that patients treated with Gilotrif experienced a progression-free survival period that was 4.2 months longer than that of patients receiving chemotherapy. There was no statistically significant difference in overall survival between the two groups.

Furthermore, compared to patients receiving standard chemotherapy regimens, patients treated with afatinib (Gilotrif) experienced improvements in both their lung cancer-related symptoms and their overall quality of life.

(Afatinib) – A New Drug for Lung Cancer

The research and development of oncology therapeutics has long been a focal point within the pharmaceutical industry. Each year, novel anti-cancer drugs emerge, bringing renewed hope to cancer patients worldwide.

At the annual meeting of the American Society of Clinical Oncology (ASCO), held from June 4 to 8, Boehringer Ingelheim presented updated data regarding its investigational next-generation compound, afatinib. These data indicated that, in the treatment of head and neck cancer, afatinib is at least as effective as cetuximab and demonstrates a comparable safety profile. Additionally, these data further reaffirmed the efficacy of afatinib in the treatment of non-small cell lung cancer characterized by EGFR mutations. Recurrent head and neck cancer carries a particularly poor prognosis; consequently, there is a critical need for effective therapeutic agents specifically tailored to patients with advanced-stage head and neck cancer. Research data indicates that afatinib can induce tumor shrinkage—referred to as "partial response"—in 22% of patients with head and neck cancer, whereas this figure stands at only 13% for those treated with cetuximab. These findings confirm that afatinib, an oral EGFR-targeted therapeutic agent, demonstrates favorable efficacy against head and neck cancer and holds promise as a highly potential treatment option. Furthermore, data from the LUX-Lung 2 study reveal that the majority of patients (61%) with non-small cell lung cancer (NSCLC) harboring common EGFR mutation types experienced significant tumor shrinkage following treatment with afatinib. Among patients treated with afatinib who possessed these common mutation types, the onset of tumor progression was delayed (with a median time of approximately 14 months), and survival duration was prolonged (with a median of 2 years). These study results once again validate the significant anti-tumor activity of afatinib in the treatment of NSCLC patients harboring EGFR mutations.

Afatinib is a new-generation small-molecule drug that targets the receptor tyrosine kinases of the epidermal growth factor receptor (EGFR/HER1) and human epidermal growth factor receptor 2 (HER2). It exerts its therapeutic effect by irreversibly binding to these corresponding receptors; this irreversible binding mechanism constitutes a unique feature of afatinib—a characteristic not shared by other currently available drugs in its class.

Afatinib is a potent, irreversible dual inhibitor of EGFR and HER2 tyrosine kinases developed by Boehringer Ingelheim; it is effective when administered orally. Studies conducted in tumor-bearing mice have demonstrated that this agent exerts a potent and sustained inhibitory effect on the growth of various tumors, including squamous cell carcinoma (A-431), breast cancer (MDA-MB-453), gastric cancer (NCL-N87), and ovarian cancer (SK-OV-3).

[Afatinib and Lung Cancer]

Lung cancer is the most common and most fatal form of cancer globally, with the number of newly diagnosed cases reaching 1.6 million annually. Due to the poor prognosis associated with lung cancer, the disease claims 1.38 million lives annually. Overall, lung cancer accounts for 18% of all cancer-related deaths. It represents approximately 13% of all newly diagnosed cancer cases, with smoking identified as its primary cause.

The incidence of lung cancer is higher in men than in women. Furthermore, lung cancer is not a monolithic disease; research indicates that it encompasses numerous distinct subtypes, each requiring specific treatment approaches. One particular subtype of lung cancer can be identified through testing for mutations in the EGFR (ErbB receptor family) gene. These patients constitute the demographic that demonstrated the greatest clinical benefit from treatment with afatinib (Giotrif) during clinical trials.