By: Jenny Park, PharmD Candidate c/o 2015

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On July 12, 2013, the FDA approved afatinib (Gilotrif^TM) as a new first-line treatment for patients with late-stage non-small cell lung cancer (NSCLC), a type of carcinoma where specific types of epidermal growth factor receptor (EGFR) gene mutations are expressed.¹ The drug afatinib irreversibly blocks EGFR, also known as ErbB-1, as well as other members of the ErbB family that play a role in the growth and proliferation of pervasive cancers with a high mortality rate. These are cell surface receptors that are involved in cellular functions such as mitosis. In some patients, mutations cause the constant activation of the EGFR protein; therefore, the binding of afatinib will provide a sustained and selective method of blockage.²

Afatinib was an orphan drug that originated in the United States and was provided an expedited review. The drug approval was based upon the LUX-Lung 3 trial, which compared afatinib to chemotherapy with a combination of pemetrexed (Almita^®) and cisplatin (Patlinol^®) in a randomized, phase III study. Being a multi-national trial in 25 countries across Asia, Australia, Europe, North America, and South America, this was the largest global trial in EGFR mutation lung cancer treatment.³

There are several subtypes of lung cancer, with NSCLC being the most common subtype. Approximately 85% to 90% of lung cancers are NSCLC, which is also further broken down into three categories: squamous cell (epidermoid) carcinoma, adenocarcinoma, and large cell (undifferentiated) carcinoma.⁴ EGFR gene mutations are present in about 10% of NSCLC, with the majority of these gene mutations expressing EGFR exon 19 deletions or exon 21 L858R substitutions.² The pathogenesis of EGFR depends highly on cell surface receptors that control intracellular transduction pathways.⁵ When EGFR is activated, it increases cellular tumor growth and proliferation. It is also the target of tyrosine kinase inhibitors.⁶ It has been shown in clinical studies that 20% of NSCLC tumors are EGFR based and that about 85% of patients respond to tyrosine kinase inhibitor treatment.⁷

The LUX-Lung 3 trial was a two-armed, randomized, parallel comparison with 229 patients in the afatinib arm and 111 patients in the chemotherapy arm with the majority of patients (89.3%) having stage IV NSCLC.³ The patients that were chosen for the trial underwent a biomarker testing for the presence of the common EGFR mutation. Patients were given either 40 mg of afatinib once daily or a combination of pemetrexed (Almita^® powder) and cisplatin (Platinol^® solution) infusion over two hours. The primary endpoint of the study highlighted a progression free survival (PFS) according to the evaluation criteria for tumors. Other key secondary endpoints were overall survival and disease control. For afatinib, patients received continuous daily dosing as long as they did not develop disease progression. For pemetrexed/ cisplatin, patients received a maximum of 6 treatment courses unless they developed disease progression.³ Results showed that a course of treatment with afatinib showed a significantly higher PFS than chemotherapy treatment. The median progression free survival was 11.14 months for afatinib versus 6.90 months for the chemotherapy (95% CI 0.425, 0.784; p = 0.0004).³ After a full year, 46.5% of the control patients in the afatinib arm and 22.0% in that of the chemotherapy arm were still alive and progression free (95% CI 0.367, 0.649; p <0.0001).  The proportion of patients that were alive and progression free on afatinib more than doubled at month 12 and month 18 compared to those on a standard chemotherapy treatment regimen. Not only was there significant PFS, there was also a higher tumor response rate, higher disease control rate, and greater disease-related symptom relief as well. There was a significant delay in disease progression, which resulted in a 4.24 month gain in a median PFS for all patients and a 6.70 month gain in patients with EGFR mutations such as deletions in exon 19 and L858R mutation in exon 21 which are the most common.⁸ The results of the testing were very encouraging, demonstrating a potentially viable alternative to standard chemotherapy treatments of today. As Prof. Klaus Dugi, Corporate SVP of Medicine, Boehringer Inhelheim states, “We are delighted to announce the first approval of Afatinib, offering a new personalized treatment approach for patients with EGFR mutation positive NSCLC.”⁸

SOURCES:

1. FDA approves a new treatment for a type of late stage lung cancer. FDA Web Site.  http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm360499.htm. Updated July 12, 2013. Accessed August 23, 2013.
2.  U.S. FDA approves Gilotrif™ (afatinib) as first-line treatment for lung cancer patients with EGFR mutations. Boehringer Ingelheim Web Site.  http://www.boehringer- ingelheim.com/news/news_releases/press_releases/2013/15_july_2013_oncology.html. Accessed August 24, 2013.
3.  LUX-lung 3 trial. Boehringer Ingelheim Web Site. http://trials.boehringer-ingelheim.com/trial_results/clinical_trials_overview/clinical_trial_result.c=n.i=12.html.  Accessed August 24, 2013.
4.  Lung cancer non small cell. MedlinePlus Web Site. http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Updated August 24, 2011.  Accessed August 24, 2013.
5. Lilenbaum R. Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor.  UpToDate Web Site. http://www.uptodate.com/contents/systemic-therapy-for-advanced-non-small-cell-lung-cancer-with-an-activating-mutation-in-the-epidermal-growth-factor-receptor?source=see_link. Updated November 4, 2013. Accessed August 24, 2013.
6. Sequist LV, Neal JW. Personalized, genotype directed therapy for advanced non-small cell lung cancer. UpToDate Web Site. http://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer?source=preview&anchor=H3902134&selectedTitle=2~150#H3902134.  Updated October 11, 2013. Accessed August 24, 2013.
7. EGFR mutation analysis in non-small cell lung cancer. Integrated Oncology Web Site. https://www.labcorp.com/wps/portal/!ut/p/c1/04_SB8K8xLLM9MSSzPy8xBz9CP0os3h_U2cv30B_IwN_f3MDA88APyM_byN_Q3cfU30_j_zcVP2CbEdFAOwTccM!/dl2/d1/L0lDU0lKSWdrbUEhIS9JRFJBQUlpQ2dBek15cXchL1lCSkoxTkExTkk1MC01RncvN19PNUNKTVFPMjBPTzcwMElQTjJOSzJPMUdENi9JX19fXzE!/?WCM_PORTLET=PC_7_O5CJMQO20OO700IPN2NK2O1GD6_WCM&WCM_GLOBAL_CONTEXT=/wps/wcm/connect/IntOncologyLib/integratedoncology/home/our+services/oncology+testing/egfr-mutation-analysis-nsclc.  Accessed August 24, 2013.
8. FDA approves GILOTRIF™ (afatinib) as first-line treatment for metastatic non-small cell lung cancer with common EGFR mutations. Boehringer Ingelheim Web Site. July 12, 2013. http://www.multivu.com/mnr/62238-boehringer-ingelheim-usda-approval-gilotrif-non-small-cell-lung-cancer. Accessed August 27, 2013.

Published by Rho Chi Post