EGFR-TKIs Gefitinib Research Articles

Overview of Gefitinib in Non-small Cell Lung Cancer: An Asian Perspective

Clinical experience with the EGFR-TKI gefitinib in Asian patients with NSCLC will be reviewed, both in patients who have previously failed chemotherapy and in the first-line setting (gefitinib is currently not licensed for first-line treatment). Tolerability and specific adverse events in patients of Asian origin will be discussed. Differing objective response rates between patients of Asian and non-Asian origin when treated with gefitinib (and standard cytotoxics) will also be discussed along with EGFR mutations and drug resistance. Reports of Phase II/III clinical experience with gefitinib 250 mg/day in Asia were identified by searching in Medline and ASCO databases for publications between 1993 and 2008. Defined search criteria included (gefitinib OR Iressa OR ZD1839) AND NSCLC AND (Asia OR Japan OR China OR Taiwan OR Korea) or 'Clinical trial' type, with additional searches, including AND 'interstitial lung disease (ILD)' or 'EGFR mutation'. Numerous Phase II/III trials including patients of Asian origin with previously treated advanced NSCLC report a consistent clinical benefit of gefitinib. Gefitinib is generally well tolerated by patients with NSCLC although the incidence of ILD in Japanese patients must be noted. Studies analyzing EGFR mutations indicate that these mutations occur at a much higher rate in patients of Asian origin than in non-Asian patients. Data from several studies indicate that EGFR mutation-positive patients of Asian origin have better efficacy outcomes with first-line gefitinib when compared with those who are EGFR mutation-negative. Research is ongoing to evaluate the role of tailoring patients' treatment according to their genetic phenotype.

Preliminary cost-consequence analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as 2nd line therapy in advanced non-small cell lung cancer

8110 Background: The INTEREST trial is the first to demonstrate non-inferiority of EGFR TKI gefitinib compared to standard second-line chemotherapy (docetaxel) in NSCLC,with better quality of life in gefitinib-treated patients. Methods: A cost-consequence analysis of direct medical costs was undertaken, given non-inferiority of the two study arms, from the perspective of the Canadian public health system. Direct medical costs (2007 CAD$)were applied to resources (e.g study treatment, toxicity management) obtained from INTEREST trial data in the public domain. Mean overall cost per patient on each treatment arm was calculated from the start of treatment until first progression. Incremental costs over best supportive care (BSC), based on an analysis of the TAX317 trial, are also calculated. Results: The mean total cost per patient treated with gefitinib was $10,840 and $8,613 for docetaxel, resulting in an incremental cost of gefitinib treatment over docetaxel of $2,227. Drug costs are the major driver, $10,515 for gefitinib (6.5 cycles) versus $6,942 for docetaxel (4.4 cycles). Limited data on toxicity management, (e.g. febrile neutropenia, anemia, rash), are available, and cost estimates are $325 for gefitinib and $1,671 for docetaxel-treated patients. Additional hospitalization data were not available and therefore not included in these estimates. Based on published cost data for BSC, the incremental cost of gefitinib over BSC is estimated at $12,916 with available data, with an incremental cost effectiveness ratio of $37,988/life-year gained. Conclusion: Gefitinib second-line has similar efficacy compared to docetaxel with better quality of life. While drug costs for gefitinib are greater, costs for toxicity management are substantially less, and underestimated in this analysis. Gefitinib second-line is an attractive and affordable alternative for patients with advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, sanofi-aventis

Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors.

PD-145 Long-term survival of NSCLC patients with EGFR mutationstreated with EGFR TKIs gefitinib or erlotinib

PD-145 Long-term survival of NSCLC patients with EGFR mutationstreated with EGFR TKIs gefitinib or erlotinib

Efficacy and safety of gefitinib in chemo-naive patients with non-small cell lung cancer (NSCLC) in an expanded access program (EAP)

7094 Background: Patients (pts) with advanced NSCLC who cannot tolerate or refuse chemotherapy (CT) have few or no treatment options. The EGFR-TKI gefitinib (Iressa) has antitumor activity and favorable tolerability in pts with recurrent advanced NSCLC. A global EAP made gefitinib available to >37,000 pts with NSCLC who had failed standard treatment or were ineligible for or refused cytotoxic CT. Methods: Retrospective chart review of 1671 pts enrolled at 11 sites in the US EAP identified 198 pts (89 men, 109 women, median age 72.7 y [range 37.8–89.9 y]) who had not received prior CT for advanced NSCLC. Pts received 250 mg/d gefitinib until treatment failure or undue toxicity. Outcomes analyzed included clinical response, survival, and adverse events (AEs). Results: Reasons for enrollment were disease progression (57.6%), CT intolerance (22.2%), significant comorbidity (21.7%), and CT refusal (21%). Predominant (66%) histology was adenocarcinoma, 16.2% with bronchioloalveolar subtype: 186 pts (93.9%) had stage III/IV disease, 3 (1.5%) were stage I/II, and 9 (4.5%) had no staging data recorded. Fifty-six (28.3%) patients had ECOG performance status (PS) ≥2. Although PS was not recorded for 69 (34.8%) pts, at enrollment 60% were nonambulatory, 15.2% required oxygen, and 4% were in a hospice. Median survival was 6 months (95% CI, 5–8 mo); estimated 1-year survival rate was 29.7% (95% CI, 22.1–37.3%). In 142 (72.2%) pts with ≥1 imaging study postenrollment, complete, partial, and stable response rates were 0.7%, 5.6%, and 40.6%, respectively. Most common AEs were diarrhea (31.3%), rash (31.3%), asthenia (15.7%), anorexia (11.6%), and nausea (11.1%). Mean treatment duration was 4.7 months (range 0.1–26 mo). Post-EAP treatment data were available for 157 (79.3%) pts: 36 (22.9%) of this group went on to further treatment, 25 received CT, and 11 received radiation therapy. Conclusions: Oral gefitinib was well tolerated and effective in this unselected population of chemo-naive pts with NSCLC who were unsuitable for or refused CT. Median and 1-year survival were significantly better than with best supportive care alone and similar to CT, with substantially less toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Ligand Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Genta, Ligand, Pfizer AstraZeneca Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly

Phase II trial of docetaxel and gefitinib as first-line therapy for elderly patients with advanced non-small cell lung cancer (ANSCLC)

7342 Background: Currently chemotherapy with two cytotoxic drugs is considered standard treatment for ANSCLC. We hypothesized that doublet therapy with a cytotoxic drug (docetaxel) and an EGFRTKI (gefitinib) will yield a more favorable toxicity profile but without compromising efficacy. We report here the preliminary data from an on going phase II trial combining docetaxel and gefitinib in elderly (≥ 70 years) patients with ANSCLC. Methods: Previously untreated patients were eligible. Docetaxel was administered at a dose of 75mg/m2 on day 1. Gefitinib was administered orally daily at a dose of 250 mg starting on day 1. Treatment was repeated every 21 days. The RECIST criteria were used to measure response.Functional status was assessed using the Lawton and Brodys Instrumental Activities of Daily Living(IADL). The Cumulative Illness Rating Scale adapted to Geriatric patients (CIRS-G) was used to assess comorbidities. Results: From August 2003 to November 2003 12 patients have been enrolled on this trial. Eleven patients are assessable for toxicity and 10 patients are assessable for response. Patients characteristics are the following M/F = 9/3; Median age 74 years (range 70 to 82 years); ECOG PS 0/1= 4/8 and Stage IV/IIIB = 11/1. Preliminary response rate is 50% out of 10 evaluable patients; CR=0, PR=5(50%). SD=3 (30%), PD=2(20%). Most common treatment related non-hematologic adverse events were fatigue, rash and diarrhea all of which grade 1 or 2. Most common hematologic adverse events were grade II neutropenia and grade II anemia. Serious adverse events include 4 hospitalizations; 1 each for DVT, non-neutropenic staphylococcal pneumonia and non-neutropenic bacterial pneumonia and COPD exacerbation. No episode of febrile neutropenia has been reported to date. Three deaths have occurred so far two from progressive disease and one from bacterial pneumonia. Conclusions: Preliminary analysis suggests that the combination of docetaxel and gefitinib appears be promising with a favorable toxicity profile in a population of elderly patients with ANSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis; AstraZeneca

Phase II trial of docetaxel and gefitinib as first-line therapy for elderly patients with advanced non-small cell lung cancer (ANSCLC)

7342 Background: Currently chemotherapy with two cytotoxic drugs is considered standard treatment for ANSCLC. We hypothesized that doublet therapy with a cytotoxic drug (docetaxel) and an EGFRTKI (gefitinib) will yield a more favorable toxicity profile but without compromising efficacy. We report here the preliminary data from an on going phase II trial combining docetaxel and gefitinib in elderly (≥ 70 years) patients with ANSCLC. Methods: Previously untreated patients were eligible. Docetaxel was administered at a dose of 75mg/m2 on day 1. Gefitinib was administered orally daily at a dose of 250 mg starting on day 1. Treatment was repeated every 21 days. The RECIST criteria were used to measure response.Functional status was assessed using the Lawton and Brodys Instrumental Activities of Daily Living(IADL). The Cumulative Illness Rating Scale adapted to Geriatric patients (CIRS-G) was used to assess comorbidities. Results: From August 2003 to November 2003 12 patients have been enrolled on this trial. Eleven patients are assessable for toxicity and 10 patients are assessable for response. Patients characteristics are the following M/F = 9/3; Median age 74 years (range 70 to 82 years); ECOG PS 0/1= 4/8 and Stage IV/IIIB = 11/1. Preliminary response rate is 50% out of 10 evaluable patients; CR=0, PR=5(50%). SD=3 (30%), PD=2(20%). Most common treatment related non-hematologic adverse events were fatigue, rash and diarrhea all of which grade 1 or 2. Most common hematologic adverse events were grade II neutropenia and grade II anemia. Serious adverse events include 4 hospitalizations; 1 each for DVT, non-neutropenic staphylococcal pneumonia and non-neutropenic bacterial pneumonia and COPD exacerbation. No episode of febrile neutropenia has been reported to date. Three deaths have occurred so far two from progressive disease and one from bacterial pneumonia. Conclusions: Preliminary analysis suggests that the combination of docetaxel and gefitinib appears be promising with a favorable toxicity profile in a population of elderly patients with ANSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis; AstraZeneca

Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer.

Molecular blockade of EGFR with either an EGFR MAb or an EGFR TKI enhances the radiosensitivity of human SCCs. In the present study, we investigated whether treatment with the EGFR TKI gefitinib (Iressa, ZD1839) improves the response to radiotherapy in the OSCC cell lines HSC2 and HSC3. We examined potential mechanisms that may contribute to the enhanced radiation response induced by gefitinib. Growth inhibition was observed in vitro with radiation or gefitinib. A cooperative antiproliferative effect was obtained when cancer cells were treated with radiation followed by gefitinib. Cells treated with a combination of radiation and gefitinib arrested in G(1) and G(2)-M phases, with a decrease in the S-phase population. While radiation alone did not significantly affect MEK1/2 and p38 MAPK autophosphorylation, the combination of gefitinib and radiation completely inhibited the downstream signaling of EGFR. Results from DNA damage repair analysis in cultured OSCC cells demonstrated that gefitinib had a strong inhibitory effect on DNA-PKc pathways after radiation. Tumor xenograft studies demonstrated that the combination of gefitinib and radiation caused growth inhibition and tumor regression of well-established OSCC tumors in athymic mice; tumor volume was reduced from 1,008.2 to 231.4 mm(3) in HSC2 cells (p < 0.01) and from 284.2 to 12.4 mm(3) in HSC3 cells (p < 0.01). Immunohistochemical analysis of OSCC xenografts revealed that gefitinib caused a striking decrease in tumor cell proliferation when combined with radiotherapy. Overall, we conclude that gefitinib enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.