Trial Of Gefitinib Research Articles

Comparison of adverse events of erlotinib with those of gefitinib in Japanese patients with NSCLC.

7566 Background: Liver dysfunction, diarrhea, skin disorder, and interstitial pneumonia are known as adverse events of EGFR-TKI. However, clinical trials of gefitinib reported difference profiles in adverse events compared to those of erlotinib. The hypothesis is that there may be some differences in adverse event of gefitinib and erlotinib. Methods: We retrospectively analyzed mainly adverse events, patient backgrounds, treatment efficacy and treatment periods for patients treated erlotinib or gefitinib for 30 or more days. Results: Forty-six patients were received erlotinib therapy and 41 patients were received gefitinib therapy in 2007 to 2009 in our hospital. There were no significant differences in patient backgrounds except for EGFR mutations. Erlotinib was administered in more patients without mutations than gefitinib (p = 0.003). Skin disorders had significant differences of erlotinib and gefitinib with 96% and 73% in all grades, respectively (p < 0.001). Skin disorders in grade 2/3 of erlotinib and gefitinib were 54% and 15%, respectively (p < 0.001). On the contrary, liver dysfunctions of erlotinib and gefitinib were 30% and 73% in all grades, respectively (p < 0.001). Liver dysfunctions in grade 2/3 of erlotinib and gefitinib were 17% and 29% with no significant difference (p = 0.212). No significant difference was seen in patients between erlotinib and gefitinib in any grades of diarrhea. The patients with gefitinib had tendencies of longer overall survivals and progression free survivals than those with erlotinib (p = 0.084, p = 0.098). Conclusions: Erlotinib had higher rate of skin disorders and lower rate of liver dysfunctions than gefitinib. The patients who caused liver dysfunctions by gefitinib may have a decrease of liver damages when the treatment was changed to erlotinib. No significant financial relationships to disclose.

Randomized phase II trial of gefitinib or gemcitabine or docetaxel chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2 or 3 (IFCT-0301 study)

Background To compare 3 treatment strategies in chemotherapy naive patients with advanced NSCLC and a PS 2–3. Patients and Methods Patients were assigned to gefitinib 250 mg daily ( n = 43) or to gemcitabine (1250 mg/m 2 d 1, 8 q 21d) ( n = 42) or docetaxel (75 mg/m 2 d 1 q 21d) ( n = 42). Treatments were taken until progression or toxicity. The primary endpoint was progression-free survival. Secondary end points were response and overall survival. Results Disease control rates were 20.9%, 33.4% and 38.1%, respectively. Median PFS was 1.9 months in the gefitinib arm, 2.0 months in the gemcitabine arm and 2.0 months in the docetaxel arm (HR gemcitabine versus gefitinib: 0.74, 95%CI: [0.48; 1.16], HR docetaxel versus gefitinib: 0.67, 95%CI: [0.43; 1.05]). Median survival times were 2.2, 2.4 and 3.5 months, respectively (HR gemcitabine versus gefitinib: 0.76, 95%CI: [0.48; 1.20], HR docetaxel versus gefitinib: 0.69, 95%CI: [0.44; 1.09]). There were more grade 3–4 adverse events in the docetaxel arm when compared with either the gefitinib arm or the gemcitabine arm. Conclusion In unselected NSCLC patients with PS 2–3, gefitinib, gemcitabine and docetaxel achieved similar results. Docetaxel was associated with higher rates of adverse events.

Abstract 1655: Mechanism of the synergistic antiproliferative effect of gefitinib and interferon-alpha in sarcoma cell lines

Abstract A static 50% 5-year overall survival rate reflects inadequacy of currently available therapies and urgent need to develop treatment strategies for sarcoma. Single epidermal growth factor receptor (EGFR) inhibitor, gefitinib was reported in a phase II trial in synovial sarcoma with a low response rate and short sustained time. Identification of combinations with both a higher proportion of responders and potentially more sustained benefit is needed. One potential partner is interferon-alpha. We have shown in vitro that cell growth signals such as those from an activated EGFR increases resistance to interferon-alpha, and the combination of EGFR inhibitor and interferon-alpha has synergistic antitumor effect in some colon and bladder cancer cell lines. A recent phase II trial of gefitinib and pegylated interferon alfa 2b in previously-treated renal cell carcinoma has demonstrated significant and prolonged disease control benefit with acceptable toxicity. However the effect of the combination therapy in sarcoma is unreported. This study aimed to investigate the effect and mechanisms of this combination therapy in human sarcoma cell lines. Combination treatment using gefitinib and interferon-alpha was investigated in a panel of sarcoma cell lines (6 soft tissue sarcomas (STS) and 3 osteosarcomas (OS)) with synergy analysis based on the Chou-Talalay combination index. Mechanism studies examined a pair of synergistic and antagonistic liposarcoma cell lines using multiple techniques. All 9 cell lines expressed wild-type and/or activated EGFR and interferon-alpha receptors but no EGFR gene mutation was identified. Combination treatment of EGFR inhibition and interferon-alpha achieved synergistic antiproliferative effect (combination index (CI) &amp;lt;1 = synergism) in 6/9 sarcoma cell lines (CI for STS: GCT 0.1-0.3, SW684 0.3-0.7, and 778 0.1-0.7; for OS: MG63 0.3-0.7, U2OS 0.3-0.7, and SJSA 0.1-0.3), accompanied by apoptotic and necrotic cell death. The drug reduction index (DRI) at IC50 measures how much the dose of each drug may be reduced when drugs were combined at the IC50 effect level compared with the dose of drug alone. For the most synergistic GCT cell line, the DRI for gefitinib and interferon-alpha was 4.7 and &amp;gt;100. Characterisation of interferon-alpha and EGFR signaling interaction by both pathway inhibition and western blot detection of downstream factor expression discovered that interferon-alpha enhances gefitinib through affecting the ratio of the signal transducer and activator of transcription (STAT) family members (STAT1 up, STAT3 down) to favour tumor cell death. The activated Akt enhanced by interferon-alpha alone was significantly down regulated by combination therapy. EGFR inhibition combined with interferon-alpha is a worthwhile treatment to pursue in anti-sarcoma therapy. These results provide a rationale for the clinical evaluation of this treatment strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1655.

Personalized cancer therapy coming of age: clinical highlights in 2009 and future directions.

Brigette BY Ma Author for correspondence: LKS Specialist Clinic, Department of Clinical Oncology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Tel.: +852 2632 2118 Fax: +852 2648 7097 brigette@clo.cuhk.edu.hk and State Key Laboratory in Oncology in South China, Hong Kong SAR, China and Sir YK Pao Centre for Cancer, Hong Kong SAR, China and Hong Kong Cancer Institute, Hong Kong SAR, China and Chinese University of Hong Kong, Hong Kong SAR, China

A phase II trial of gefitinib as maintenance therapy after first-line chemotherapy for advanced non-small cell lung cancer in China

Objective To investigate the efficacy and safety of gefitinib as maintenance therapy for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after first-line chemotherapy in Chinese population.

Randomized Phase III Trial of Gefitinib versus Docetaxel in Non–Small Cell Lung Cancer Patients Who Have Previously Received Platinum-Based Chemotherapy

The ISTANA (IRESSA as Second-line Therapy in Advanced NSCLC-KoreA) study compared gefitinib with docetaxel in patients with advanced or metastatic non-small cell lung carcinoma (NSCLC) pretreated with platinum-based chemotherapy. We conducted a multicenter, randomized, open-label phase III trial of gefitinib (250 mg/d) versus docetaxel (75 mg/m(2) day 1 every 3 weeks) in patients with advanced or metastatic NSCLC treated with one previous platinum-based chemotherapy. The primary endpoint was progression-free survival. A total of 161 patients (male, 62%; never smoker, 41%; adenocarcinoma, 68%) were enrolled. Progression-free survival was longer for gefitinib compared with docetaxel (hazard ratio, 0.729; 90% confidence interval, 0.533-0.998; one-sided P = 0.0441). Gefitinib significantly improved objective response rate (28.1% versus 7.6%; two-sided P = 0.0007). In the final analysis of overall survival, the hazard ratio was 0.870 (95% confidence interval, 0.613-1.236; two-sided P = 0.4370). No significant differences were seen in the quality of life or symptom improvement rates between the two treatment groups. Gefitinib was well tolerated, was consistent with previous data and disease, and had fewer serious adverse events and fewer Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events than docetaxel. The incidence of interstitial lung disease-type events was 3.7% (n = 3) with gefitinib and 3.9% (n = 3) with docetaxel. The primary endpoint of progression-free survival was longer with gefitinib than docetaxel, and the secondary endpoints showed superior objective response rate, good tolerability, and similar quality of life improvement rates for gefitinib than docetaxel. Therefore, gefitinib is an important valid treatment option for second-line therapy for Korean NSCLC patients.

A Phase I/II Trial of Gefitinib Given Concurrently With Radiotherapy in Patients With Nonmetastatic Prostate Cancer

To estimate the safety and tolerability of daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy for patients with nonmetastatic prostate cancer. A total of 42 patients with T2-T3N0M0 tumors were treated in a nonrandomized single-center study. A prostate-specific antigen (PSA) level of <20 and a good performance status (WHO, 0-1) were required. Adjuvant or neoadjuvant hormone treatments were not allowed. A daily regimen of 250 mg of gefitinib was started 1 week before radiation therapy began and lasted for the duration of radiation therapy. A dose of 50.4 Gy (1.8 Gy/day) was administered to the tumor, prostate, and seminal vesicles, followed by a 22-Gy booster (2 Gy/day) for a total dose of 72.4 Gy. Correlative studies included analysis of epidermal growth factor receptor (EGFR), EGFRvIII, and phosphorylated EGFR in tumors and tumor necrosis factor, interleukin-1alpha (IL-1alpha), and IL-6 in serum. Maximum tolerated dose was not reached in phase I (12 patients), and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication. Dose-limiting toxicities were recorded for 16 (38.1%) patients, the most common of which was a grade 3 to 4 increase in transaminase (6 patients). After a median follow-up of 38 months, there were no deaths due to prostate cancer. The estimated PSA relapse-free survival rate at 4 years (Kaplan-Meier) was 97%, the salvage therapy-free survival rate was 91%, and the overall survival rate was 87%. These figures compared favorably with those of matched patients treated with radiation only at higher doses. The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer.

Gefitinib

Gefitinib (Iressa) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that offers treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in particular in those who are harbouring EGFR mutations. In a large phase III trial (IPASS) in chemotherapy-naive Asian patients with adenocarcinoma who were never smokers or former light smokers, oral gefitinib was more effective than carboplatin plus paclitaxel in prolonging progression-free survival (PFS). In a prespecified subgroup analysis, EGFR-mutation-positive status was associated with a positive response to gefitinib treatment. Furthermore, a trial in chemotherapy-naive patients with NSCLC that was restricted to those with EGFR mutations found that gefitinib recipients had significantly longer PFS than carboplatin plus paclitaxel recipients. In large phase III trials (INTEREST, V-15-32) in unselected, previously treated patients, the overall survival (OS) in gefitinib recipients was noninferior to, or not significantly different from, that of docetaxel recipients. In a placebo-controlled trial in previously treated patients (ISEL), pre-planned subgroup analyses in Asian patients and non-smokers showed that in these subgroups gefitinib prolonged OS, and that EGFR biomarkers predicted a positive response to gefitinib. Gefitinib was also associated with greater improvements in quality of life (QOL) in both chemotherapy-naive and previously treated patients. A head-to-head trial of gefitinib versus erlotinib in EGFR-mutation-positive patients would help position gefitinib relative to erlotinib in this population. Further research is also required to identify factors associated with non-response to EGFR-tyrosine-kinase inhibitors in EGFR-mutation-positive patients. Gefitinib was a generally well tolerated treatment, with rash and diarrhoea being the most common treatment-emergent adverse events. Interstitial lung disease (ILD) is a serious co-morbidity of NSCLC associated with gefitinib and other cancer treatments; ILD-type events occurred with an overall incidence of approximately 1% in gefitinib recipients participating in clinical trials, and were more common in Asian patients. Notably, gefitinib was associated with significantly fewer haematological and neurological adverse effects than comparator chemotherapy regimens. Gefitinib as monotherapy is an effective treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations.

9003 Response and progression-free survival in 1006 patients with known EGFR mutation status in phase III randomized trials of gefitinib in individuals with non-small cell lung cancer

9003 Response and progression-free survival in 1006 patients with known EGFR mutation status in phase III randomized trials of gefitinib in individuals with non-small cell lung cancer

9002 A phase III, first-line trial of gefitinib versus cisplatin plusdocetaxel for patients with advanced or recurrent non-small cell lungcancer (NSCLC) harboring activating mutation of the epidermal growthfactor receptor (EGFR) gene: a preliminary results of WJTOG 3405

9002 A phase III, first-line trial of gefitinib versus cisplatin plusdocetaxel for patients with advanced or recurrent non-small cell lungcancer (NSCLC) harboring activating mutation of the epidermal growthfactor receptor (EGFR) gene: a preliminary results of WJTOG 3405

Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non–Small Cell Lung Cancer with EGFR Mutations

Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non-small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation-positive non-small cell lung cancer. We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non-small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. Seven eligible trials were identified for a total of 148 non-small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naïve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non-small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.

A phase I/II trial of gefitinib given concurrently with radiotherapy in patients with nonmetastatic prostate cancer

e16079 Background: We estimated the safety and tolerability of 250 mg gefitinib q.d. given concurrently with three- dimensional conformal radiotherapy (3D-CRT) in patients with non-metastatic prostate cancer (PC). Methods: 42 patients with T2/T3N0M0 PC were treated in a single centre, non-randomized study (study code ZD1839/IL0118). PSA&lt;20 and good performance status (WHO 0–1) were required. Adjuvant or neo-adjuvant hormonal treatments were not allowed. 250 mg gefitinib q.d. was started one week before and lasted for the duration of radiation therapy. 50.4 Gy (1.8 Gy/day) of 3D-CRT was administered to the tumor, prostate and seminal vesicles, followed by a 22 Gy booster (2 Gy/day) for a 72.4 Gy total dose. EGFR expression, presence of EGFRvIII and activated pEGFR were studied. Levels of serum TNF, IL-1 α and IL-6 were also evaluated. Results: Maximum tolerated dose was not reached in phase I (12 patients) and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication and 12 (28.6%) prematurely discontinued because of adverse events. Dose-limiting toxicities were recorded in 16 (38.1%) patients, the most common of which was grade 3–4 transaminase increase (6 patients). After median follow-up of 38 months nobody had died of PC. The estimated PSA-free survival rate at 4 years (Kaplan-Meier) was 97%, hormone-free survival 91% and overall survival 87%. These figures compared favourably with matched, non-randomized patients treated with radiation only. Data on biochemical analyses will be presented. Conclusions: The combination of gefitinib and radiation is reasonably well tolerated and has promising activity in non-metastatic PC. A randomized study is being discussed for evaluating the efficacy of the approach. [Table: see text]

A phase II trial of gefitinib and pegylated interferon alfa 2b (PEG-IFN) in previously-treated renal cell carcinoma (RCC)

e16115 Background: Modulation of the epidermal growth factor receptor (EGFR) pathway is relevant to IFN activity in RCC. Cell lines sensitive to IFN's antiproliferative effects downregulate EGFR, while IFN treatment of resistant cells precludes such an effect. (Eisenkraft et al, Cancer Res. 1991) Lack of EGFR down-regulation may thus be responsible in part for IFN resistance. To explore this hypothesis, we conducted a trial of the EGFR tyrosine kinase inhibitor gefitinib plus PEG-IFN in RCC patients (pts). Methods: Unresectable or metastatic RCC pts (no limit on prior therapies; performance status 0–2, and adequate end-organ function) were eligible. Prior IFN was allowed. Dose schedule: PEG-IFN SQ weekly (6μg/kg/week or 4 μg/kg/week) × 12 weeks and gefitinib 250 mg po daily until progression. A 6-month progression free survival (PFS) rate of 50% was considered promising (vs. 30%) in a two-stage design incorporating the Green-Dahlberg rule. We accrued 21 patients in the first-stage of accrual. Results: Pt characteristics: Males -16; median age - 56 years; Prior nephrectomy - 12. All had &gt; 1 prior systemic therapy . Accrual slowed with increased use of small molecule kinase inhibitors, bevacizumab, and temsirolimus for RCC. At 6 months, PFS was 26% (95% CI: 9%, 49%); 20% (4 pts) had died. Best responses by RECIST: complete (1), partial (4), stable (8); progression (4). Response duration: CR (35+ months) and PR (3, 5, 5, 38+ months). Median time to treatment failure was 18.4 weeks (95%CI: 7.4, 24.9). Median PFS and overall survival were 23 and 53 weeks, respectively. Most common treatment-related toxicities were leucopenia, thrombocytopenia, rash, nausea, diarrhea, and hyperglycemia. Conclusions: Although gefitinib plus PEG-IFN did not meet the pre-specified 6-month PFS of 50%, it appears to have activity similar to other first-line therapies even in this previously-treated setting. (Supported by Astra Zeneca) [Table: see text]

Randomized phase II trial of gefitinib plus anastrozole or fulvestrant in postmenopausal, metastatic breast cancer

1013 Background: Preclinical data documents interactions between the signal transduction pathways for ER and for EGFR, and these interactions may relate to endocrine resistance in ER+ breast cancer. Limited clinical data is available. Methods: This multi-institutional, single-stage, non-comparative, randomized phase II study tested the EGFR tyrosine kinase inhibitor gefitinib 250 mg daily PO plus endocrine therapy with either anastrozole 1 mg/day PO (AG Arm) versus fulvestrant 250 mg IM every 4-weeks (FG Arm). Eligible pts were postmenopausal women with ER+ and/or PgR+ measurable metastatic breast cancer with no prior endocrine therapy for metastatic disease, no prior adjuvant AI or fulvestrant, no more than two chemotherapy regimens for metastatic disease, ECOG status 0–2, no CNS metastasis, and adequate bone marrow, liver, and renal function. Primary endpoint was RECIST determined clinical benefit (CR+PR+SD for ≥6 mos) and secondary endpoints were toxicity and interaction of biomarkers with clinical benefit. Results: 148 pts were registered, and 142 pts are eligible and analyzable, 73 to AG and 69 to FG. Treatment groups were balanced for race, age, ECOG status, and sites of disease. Median follow-up is 35 mos. Median N of 4-week cycles of treatment is 6 (range 1–42) in both groups. Treatment was terminated for disease progression in 74% v 75%, toxicity 7% v 10%, death 1% v 3%, withdrawal 8% v 1%, and other 3% v 7% in the AG v FG arms, respectively. Clinical benefit rate (95% CI) is 42% (30%-53%) v 38% (28%-52%) for AG v FG, respectively. Response rates are CR 3% v 4%, PR 21% v 17%, SD for ≥6 mos 18% v 17% for AG v FG. Median PFS is 5.7 mos v 5.2 mos and median OS is 30.2 mos v 23.8 mos for AG v FG, respectively. Overall worst toxicity grade experienced for AG is G1 and 2 = 62%; G3 = 28%; G4 = 4%, G5 = 3%; for FG was G1 and 2 = 58%; G3 = 27%; G4 = 7%; G5 = 4%. G3 + G4 + G5 toxicities occurring in ≥5% of either treatment are diarrhea (5% v 13%), SGOT elevation (7% v 8%), and infection without neutropenia (1% v 6%) for AG v FG. Conclusions: Both anastrozle and fulvestrant are active endocrine agents in combination with gefitinib and both are generally well tolerated. Anastrozole plus gefitinib appears to be the better combination to take forward for phase III comparisons. [Table: see text]

Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer

Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment. The IC(50) of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial. In vitro, gefitinib inhibited cell proliferation with differing IC(50), and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappaB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients. Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.

High Incidence of Oral Dysesthesias on a Trial of Gefitinib, Paclitaxel, and Concurrent External Beam Radiation for Locally Advanced Head and Neck Cancers

To report a high incidence of oral mucosal dysesthesia occurring in patients on a pilot study of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa) in combination with paclitaxel (Taxol) and external beam radiation therapy for the treatment of locally advanced squamous cell carcinoma of the head and neck. Nine patients were enrolled on a pilot phase I trial of oral gefitinib 250 mg/d with 6 weekly doses of paclitaxel (36 or 45 mg/m) and concurrent radiation therapy [66-76 Gray (Gy)]. All had stage III/IVA-B squamous cell carcinoma of the head and neck. Patients were evaluated twice weekly by physicians and daily by nursing for adverse events. Six of 9 patients (67%) developed a grade 3 "burning" quality oral dysesthesia. These patients received at least 50 Gy (range 50-70 Gy) to the oral tongue. The patients without grade 3 oral dysesthesia received less than 50 Gy radiation to the oral tongue. The oral dysesthesia was exacerbated by the ingestion of neutral pH liquids such as water. Of the 6 patients, all eventually developed common toxicity criteria grade 3/4 mucositis; however, symptoms continued after resolution of the mucositis. Gabapentin (Neurontin) was administered to 2 patients as a treatment for painful mucosal neuropathy. Both patients had near resolution of symptoms despite the evolution of oral mucositis. Development of "burning"-type oral dysesthesia occurred in patients treated with the combination of gefitinib, paclitaxel, and external beam radiation of the oral tongue. This dysesthesia was improved by the use of gabapentin.

A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer

BackgroundGefitinib inhibits the epidermal growth factor receptor tyrosine kinase and preclinical studies indicate that it may enhance CPT-11 cytotoxicity. This randomized phase II trial investigates the feasibility and efficacy of gefitinib and 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) in patients with metastatic colorectal cancer. Patients and methodsPatients were randomized to FOLFIRI ± gefitinib 250 mg daily p.o. Patients randomized to FOLFIRI + gefitinib without disease progression after 6 months continued to receive gefitinib alone until disease progression. ResultsFrom October 2002 to September 2004, 100 patients were enrolled. Twenty-three patients (47.9%) in the FOLFIRI arm and 23 (45.1%) in the FOLFIRI + gefitinib arm experienced an objective response. The median progression-free survival and overall survival were 8.3 and 18.6 months in the FOLFIRI arm, and 8.3 and 17.1 months in the FOLFIRI + gefitinib arm, respectively. In the combination arm, grades 3–4 adverse events were experienced by 35 (67.3%) patients versus 25 patients (52.1%) in the FOLFIRI arm; 12 patients (23.1%) withdrew for an adverse event in the FOLFIRI + gefitinib arm and 5 (10.4%) in the FOLFIRI arm. ConclusionsThese data show that adding gefitinib to FOLFIRI does not improve the efficacy of FOLFIRI regimen. These disappointing results could be related to the high toxicity observed that led to significant dose reductions and delays.

Gefitinib in Advanced Non-Small Cell Lung Cancer: Does It Deserve a Second Chance?

There has been intense investigation into the epidermal growth factor receptor (EGFR) as a therapeutic target in the treatment of non-small cell lung cancer (NSCLC). Currently there are two EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, approved for the treatment of advanced NSCLC. In a phase III trial (BR.21), treatment with erlotinib resulted in a statistically significant improvement in overall survival in patients who had experienced progression after one or two previous chemotherapy treatments in comparison with best supportive care (BSC). In contrast, in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, treatment with gefitinib did not result in a statistically significant improvement in overall survival time in comparison with BSC in patients who had received one or two previous chemotherapy treatments and were refractory to or intolerant of the previous chemotherapy. After the results of the ISEL trial, the U.S. Food and Drug Administration restricted the use of gefitinib, and gefitinib was effectively removed from routine clinical practice within the U.S. However, gefitinib was approved in other countries and clinical trials investigating gefitinib continued. Recently the Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) trial met the primary endpoint of demonstrating noninferiority in terms of overall survival for gefitinib (250 mg daily) in comparison with docetaxel (75 mg/m(2) every 3 weeks). Patients treated with gefitinib experienced a lower rate of treatment-related toxicity and higher rate of improvement in quality of life. Results of recent gefitinib trials have been provocative, and suggest a role for gefitinib in the treatment of advanced NSCLC.

A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck

Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3+3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

A phase I trial of gefitinib and sirolimus in adults with recurrent glioblastoma multiforme (GBM)

2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of rapamycin (mTOR) also promotes GBM growth and rapamycin blocks the interaction of mTOR with its target proteins. Therefore, the novel therapeutic approach by combination of gefitinib (iressa), and sirolimus (rapamycin) should have a synergistic effect in treating GBM. A possible mechanism of EGFR TKI resistance may be targeted by mTOR antagonists. The primary objective is to evaluate the safety, toxicity of gefitinib and sirolimus with a secondary end point of determining time to tumor progression, overall survival and quality of life in recurrent GBM. Methods: Eligible patients aged 18 years or older with recurrent GBM, who were treated previously with surgery, radiation, chemotherapy with or without immunotherapy (vaccine) and KPS > 40% are eligible. Gefitinib is dosed at 500 mg/day with those receiving dexamethasone or enzyme inducing anti-epileptic drugs (EIAED) escalated to 1,000 mg/day. Sirolimus is dosed at 2 mg/day and adjusted to levels of 4–12 nanograms/ml. They were co-administered on a continuous oral daily dosing. Neurological exam, KPS, laboratory parameters and NCI CTC are initially obtained every 2 weeks and then monthly. MRI scans of the brain and FACT-Br are performed every two months. Results: To date 21 patients have enrolled and 18 are evaluable. There are 13 male and 5 female with a median age of 51.6 years (range 23–72 years), a median KPS of 60% (range 50–80%) and 12 patients were on EIAED. Diarrhea, rash and mucositis were the most common toxicities as expected. There were 3 patients with grade 3/4 non-hematological toxicities with rash, renal failure, hypotension, dyspnea, coagulopathy, and elevated LFT. One patient developed wound infection which was not related to these drugs. There were 2 (11%) minor response and 6 (33%) stable disease (range 1–18 months) with a clinical benefit of 44%. Conclusions: Oral daily co-administration of getifinib and sirolimus is safe, tolerable in this heavy treated group of patients with modest antitumor activity. The median progressive free survival time and time to tumor progression is to be determined. No significant financial relationships to disclose.