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Iressa (Gefitinib), Oral Tyrosine Kinase Inhibitor, Approved for First-Line Therapy for Patients with Metastatic NSCLC and EGFR Mutation

March 2016, Vol 9, Seventh Annual Payers' Guide - Payers' Guide

Lung cancer is one of the most common types of cancer in the United States—second only to breast cancer.1 An estimated 221,200 new cases of lung cancer were diagnosed in 2015 alone, representing 13.3% of all new cancer cases.1 Lung cancer is the leading cause of cancer mortality in men and women, accounting for 27% of all cancer deaths and claiming more lives than breast, colon, prostate, and ovarian cancers combined.1,2 From 2007 to 2011, there was a slight decline in lung cancer incidence and deaths.3

Approximately 85% to 90% of all lung cancers are non–small-cell lung cancer (NSCLC), which comprises several major subtypes, including squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma.4,5 Adenocarcinomas account for 40% of all lung cancer cases, and squamous-cell carcinomas for approximately 25% to 30%.4 Other, less common types of NSCLC include carcinoid tumor, pleomorphic, salivary gland carcinoma, and unclassified carcinoma.5

As with other cancers, the earlier lung cancer is detected and treated, the more favorable the prognosis.4 Nevertheless, approximately 22% of cases of lung cancers have already spread regionally (to regional lymph nodes) at diagnosis, and 57% have metastasized to a distant site in the body.1 The 5-year relative survival rate for patients with regional metastases is 27.4% compared with only 4.2% for patients with distant metastases.1

The treatment of metastastic NSCLC typically includes chemotherapy, targeted therapy, immunotherapy, or a combination of these options.6 The majority of targeted therapies are small-molecule compounds that are designed for targets inside the cell, or monoclonal antibodies that are designed for targets outside of the cell.6

Scientific advances in cell biology and gene expression have fostered the development of new targeted therapies and changed the landscape of NSCLC treatment.7 Several predictive biomarkers indicating the therapeutic efficacy of a specific drug or drug class in specific NSCLC molecular targets have emerged.7 These biomarkers include the sensitizing epidermal growth factor receptor (EGFR) mutations (eg, exon 19 deletion or exon 21, L858R mutation) and the anaplastic lymphoma kinase (ALK) fusion gene, among others.7

Several clinical guidelines recommend testing for EGFR mutations and ALK gene rearrangements for select patients with NSCLC.7,8
Current therapies approved by the US Food and Drug Administration (FDA) for NSCLC include the 2 immune checkpoint inhibitors nivolumab and pembroliz­umab, as well as the targeted therapies bevacizumab, ramucirumab, afatinib, erlotinib, osimertinib, necitumumab, alectinib, ceritinib, and crizotinib.9,10

Molecular profiling and the evolving development of targeted treatments are transforming the therapeutic options available for patients with NSCLC. Accordingly, 2015 was a banner year for novel therapies approved by the FDA for NSCLC.

Iressa a New First-Line Therapy for Metastatic NSCLC with EGFR Mutation

On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca), an oral tyrosine kinase inhibitor, for the first-line treatment for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L848R substitution mutations, as detected by the therascreen EGFR RGQ PCR Kit, which was approved by the FDA on the same day.11,12 The test identifies EGFR mutations, and is used to select candidates for gefitinib treatment.11

Exon 19 deletions and exon 21 L858R substitution gene mutations are the most common types of EGFR mutations.11 Tumors that express these EGFR mutations have been linked to tumor-cell growth and metastasis in NSCLC.12 Gefitinib targets EGFR exon 19 deletions and exon 21 L858R mutations.12 Gefitinib is not indicated for patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 L858R substitution mutations.12

Although gefitinib had received FDA approval in 2003 for the treatment of advanced NSCLC, the drug was voluntarily withdrawn from the market in April 2012 for lack of evidence confirming the drug’s clinical benefit.11,13 The new FDA approval in 2015 is based on the evidence of clinical benefit with gefitinib in patients with untreated EGFR mutation–positive NSCLC; gefitinib received an orphan drug designation for this indication.11,12

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “Iressa offers another effective first-line therapy option for selected lung cancer patients. This approval provides further support for a highly targeted approach to treating cancer.”11

Mechanism of Action

Gefitinib is a tyrosine kinase inhibitor that blocks proteins that are involved in the proliferation of cancerous cells with EGFR exon 19 deletion and exon 21 L858R substitution mutations—2 EGFR-activating mutations that contribute to tumor-cell growth, angiogenic factors, and metastasis.12

Dosing and Administration

The recommended dosage of gefitinib is 250 mg once daily taken orally with or without food until disease progression or until unacceptable toxicity. If a dose is missed, it should not be taken within 12 hours of the missed dose.12

Gefitinib is available as a 250-mg tablet for oral administration.12

Clinical Studies
The IFUM Clinical Trial

The FDA approval of gefitinib was based on data from the IRESSA Follow-Up Measure (IFUM) clinical trial, a multicenter, single-arm, open-label study that included 106 patients (median age, 65 years) with untreated metastatic NSCLC containing EGFR exon 19 deletions or exon 21 L858R substitution mutations.12,14 The median duration of treatment with gefitinib was 8 months.12

The primary efficacy end point was the objective response rate. The secondary end points included duration of response, progression-free survival, overall survival, and safety and tolerability.12,14

Treatment with gefitinib demonstrated a 70% objective response rate based on an investigator assessment, and a 50% objective response rate based on a blinded independent central review (Table).12,14 Patients with EGFR exon 19 deletion mutations had similar
response rates as those with exon 21 L858R substitution mutations.12,14


The IPASS Study: NSCLC plus EGFR Mutation

The results from the IFUM clinical trial were supported by an exploratory analysis of a subset population of patients in the Iressa Pan-Asia Study (IPASS). IPASS was a randomized, multicenter, open-label study of 186 patients with EGFR mutation–positive NSCLC.12,15-18 Patients were randomized to receive gefitinib 250 mg or carboplatin plus paclitaxel.12

Patients who received gefitinib had a median progression-free survival of 10.9 months compared with 7.4 months in the carboplatin plus paclitaxel arm (hazard ratio, 0.54; 95% confidence interval [CI], 0.38-0.79).12,17 The objective response rate was 67% (95% CI, 56-77) with gefitinib versus 41% with carboplatin plus paclitaxel (95% CI, 31-51). The median duration of response was 9.6 months with gefitinib versus 5.5 months with carboplatin plus paclitaxel.12,17

Adverse Events

Adverse reactions with gefitinib therapy were evaluated in a randomized, double-blind, placebo-controlled clinical trial involving patients who received gefitinib 250 mg daily for a median duration of 2.9 months. The most common (≥10%) adverse reactions of all grades (and greater than placebo) associated with gefitinib therapy included skin reactions (47%), diarrhea (29%), and vomiting (14%).12,19

The most common (≥2% and more than with placebo) grade 3 or 4 adverse reactions reported with gefitinib were diarrhea (3%), decreased appetite (2.3%), and skin reactions (2%).

Approximately 5% of patients receiving gefitinib discontinued treatment because of an adverse reaction. The most frequent adverse reactions that led to the discontinuation of gefitinib were nausea (0.5%), vomiting (0.5%), and diarrhea (0.4%).12

Drug Interactions

Cytochrome (CY) P3A4 inducers. The dose of gefitinib should be increased to 500 mg daily for patients taking strong CYP3A4 inducers; the 250-mg dose can be resumed 7 days after the strong CYP3A4 inducer is discontinued.12

CYP3A4 inhibitors. Adverse reactions should be monitored in patients taking strong CYP3A4 inhibitors concomitantly with gefitinib.12

Drugs affecting gastric pH. Gefitinib should not be administered concomitantly with proton pump inhibitors, if possible.12

Hemorrhage in patients taking warfarin. Patients taking warfarin concomitantly with gefitinib should be monitored for changes in the prothrombin time or the international normalized ratio.12

Warnings and Precautions

Interstitial lung disease. Interstitial lung disease has been reported with gefitinib therapy. Gefitinib should be withheld if respiratory symptoms worsen, and discontinued if interstitial lung disease is confirmed.12

Hepatotoxicity. Periodic liver function testing should be performed in patients taking gefitinib. Gefitinib should be withheld in patients with grade ≥2 liver test abnormalities. Gefitinib should be discontinued in patients with severe hepatic impairment.12

Gastrointestinal perforation. Gefitinib should be permanently discontinued if gastrointestinal perforation occurs.12

Diarrhea. Gefitinib should be withheld for grade ≥3 diarrhea.12

Ocular disorders. Gefitinib should be withheld if patients show symptoms of severe or worsening ocular disorders, including keratitis. Gefitinib should be discontinued if persistent ulcerative keratitis occurs.12

Bullous and exfoliative skin disorders. Treatment with gefitinib should be interrupted or discontinued in patients with severe bullous, blistering, or exfoliating conditions, including erythema multiforme and dermatitis bullous.12

Embryo-fetal toxicity. Gefitinib may cause fetal harm when administered to a pregnant woman.12

Use in Specific Populations

Pregnancy. Gefitinib may cause fetal harm when administered to a pregnant woman.12 Women of reproductive potential should be advised to use contraception during treatment with gefitinib, and for at least 2 weeks after completing treatment with gefitinib.12

Lactation. It has not been determined whether gefitinib is excreted in human milk.12 Women should be advised to discontinue breast-feeding during treatment with gefitinib.12

Pediatric use. The safety and effectiveness of gefitinib in pediatric patients have not been determined.12

Geriatric use. No overall differences in the safety of gefitinib were observed between patients aged >65 years and younger patients.12 The data are insufficient to determine whether the efficacy of gefitinib is different in these 2 age-groups.12

Renal impairment. Clinical trials were not conducted in patients with severe renal impairment.12

Hepatic impairment. Patients with moderate or severe hepatic impairment who are receiving gefitinib should be monitored for adverse reactions.12


The FDA approval of the oral tyrosine kinase inhibitor gefitinib provides an important targeted treatment option for patients with NSCLC that harbors EGFR mutation. In this subset of patients with EGFR mutations, gefitinib showed important and significant clinical benefits, including an objective response rate of 70%, an 8.3-month median duration of response, and an objective response rate of 50%, with a 6-month median duration of response.


1. National Cancer Institute. SEER stat fact sheets: lung and bronchus cancer. Accessed February 2, 2016.
2. Mayo Clinic staff. Diseases and conditions: lung cancer. September 25, 2015. Accessed February 3, 2016.
3. American Cancer Society. Cancer facts and figures 2015. 2015. Accessed February 3, 2016.
4. American Cancer Society. Lung cancer (non-small cell). Revised February 8, 2016. Accessed February 23, 2016.
5. National Cancer Institute. Non-small cell lung cancer treatment (PDQ®). Updated May 12, 2015. Accessed February 4, 2016.
6. National Cancer Institute. Targeted cancer therapies. Accessed February 4, 2016.
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): non-small cell lung cancer. Version 4.2016. January 12, 2016. Accessed February 3, 2016.
8. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. J Clin Oncol. 2014;32:3673-3679.
9. American Cancer Society. Lung cancer (non-small cell): immunotherapy for non-small cell lung cancer. Revised February 8, 2016. non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-immunotherapy. Accessed February 23, 2016.
10. American Cancer Society. Lung cancer (non-small cell): targeted therapy drugs for non-small cell lung cancer. Revised February 8, 2016. ed-therapies. Accessed February 23, 2016.
11. US Food and Drug Administration. FDA approves targeted therapy for first-line treatment of patients with a type of metastatic lung cancer: companion test also approved to identify appropriate patients. Press release. July 13, 2015. Accessed January 13, 2016.
12. Iressa (gefitinib) tablets [prescribing information]. Wilmington, DE: AstraZeneca; July 2015.
13. US Food and Drug Administration, HHS. AstraZeneca Pharmaceuticals LP; withdrawal of approval of a New Drug Application for Iressa. Notice. Fed Regist. 2012; 77:24723-24724.
14. Douillard J-Y, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55-62.
15. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.
16. Fukuoka M, Wu Y-L, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-2874.
17. Mok T, Saijo N, Thongprasert S, et al. Efficacy by blind independent central review (BICR): post hoc analyses of the phase III, multicentre, randomised IPASS study of 1st-line gefitinib (G) vs carboplatin/paclitaxel (C/P) in Asian patients (pts) with EGFR mutation-positive advanced NSCLC. Ann Oncol. 2015;26(suppl 9). Abstract 426PD.
18. US Food and Drug Administration. Drugs: gefitinib (Iressa). Updated July 13, 2015. Accessed January 13, 2016.
19. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-1537.

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Last modified: August 30, 2021