Untreated Advanced Non-small Cell Lung Research Articles

Phase II study of irinotecan plus S-1 combination for previously untreated advanced non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group 0601

e19012 Background: Platinum-containing therapy is a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Platinum-free regimens can be alternative if they can provide similar efficacy with better tolerability. This study evaluated the efficacy and safety for combination of irinotecan and S-1, a newly developed oral 5-fluorouracil derivative, for chemotherapy-naïve advanced NSCLC. Methods: In this multicenter phase II trial, we initially planned to enroll 40 patients. Chemotherapy consisted of 4-week cycles of irinotecan (100 mg/m2 IV, day 1 and 15) and S-1 (80 mg/m2 orally, day 1–14). Primary end point was response rate; secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Association of UGT1A1 genotypes (*6 and *28) with frequency of severe toxicity was also examined. Results: A total of 112 cycles was administered into 40 patients (median, 3 cycles: range, 1–6). Median age was 64 years (range, 42–75); 29 patients (73%) had adenocarcinoma, and 8 patients (20%) had squamous cell carcinoma. Majority of the patients (32 cases, 80%) had stage IV disease. Twelve patients exhibited partial response (PR), and 17 patients exhibited stable disease (SD), resulting in response rate of 30% [95% confidence interval (95% CI), 16.6–46.5] and disease control rate of 72.5% (95% CI, 56.1–85.4). Median OS and PFS were 13.8 months (95% CI, 10.7–16.9) and 4.7 months (95% CI, 3.4–6.0), respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common non-hematologic toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). There were no treatment-related deaths. Among the 40 patients, there were 1 homozygous and 8 heterozygous for UGT1A1*6, whereas 7 heterozygous for UGT1A1*28; none of the patients had both genotypes. Patients with homozygous or heterozygous for UGT1A1*6 showed a trend for high incidence of grade 3 diarrhea (p = 0.055). No association of UGT1A1*28 with severe toxicity was observed in this study. Conclusions: Irinotecan and S-1 combination is an alternative treatment with tolerable toxicity for previously untreated advanced NSCLC. No significant financial relationships to disclose.

Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800 mg/m 2 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800 mg/m 2 plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6 mg/ml min plus paclitaxel 175 mg/m 2 plus ASA404 1800 mg/m 2 every 21 days for up to six cycles. The addition of ASA404 1800 mg/m 2 to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clinically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months. The data from this trial corroborate findings from a recent randomized phase II trial, which suggested improvements in efficacy variables, including survival, when ASA404 1200 mg/m 2 was added to standard therapy for advanced NSCLC. The manageable safety profile, lack of adverse pharmacokinetic interactions and efficacy outcomes seen in this single-arm study suggest that ASA404 1800 mg/m 2 is a viable dose for future combination studies.

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml−1 min and paclitaxel 175 mg m−2 (CP, n=36) or standard therapy plus ASA404 1200 mg m−2 (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.

Phase II study of combination chemotherapy with S-1 and weekly cisplatin in patients with previously untreated advanced non-small cell lung cancer

We aimed to evaluate the efficacy and safety of combination chemotherapy with S-1 and low-dose weekly cisplatin in patients with advanced non-small cell lung cancer (NSCLC). In this phase II trial, previously untreated patients with stage IIIB/IV NSCLC were treated with oral administration of S-1 at 80 mg/m(2) for 21 days and three consecutive weekly low doses of cisplatin (25 mg/m(2)) followed by a 2-week rest period. Twenty-six patients were eligible for the assessment of efficacy and safety. Six partial responses were observed with an overall response rate of 23.1% (95% confidence interval: 12.3-31.6%). The median survival time and median progression-free survival were 13.4 months and 5.4 months, respectively. Grade 3/4 hematologic toxicities were observed in 9 patients (34.6%), including one grade 4 neutropenia and thrombocytopenia. As for non-hematologic adverse reactions, although grade 3 events were observed in 4 patients (15.3%), no severe renal toxicity or vomiting was found. S-1 and weekly low-dose cisplatin combination chemotherapy in patients with advanced NSCLC showed an acceptable response rate, overall survival time, and toxicity. Because this regimen can be performed in an outpatient setting, it might be an alternative useful and convenient option. Further investigations with a large population are required to confirm our results.

A randomized study of docetaxel plus cisplatin versus paclitaxel plus cisplatin in previously untreated advanced non-small cell lung cancer.

Docetaxel is an active agent in the second-line treatment for non-small cell lung cancer (NSCLC), many clinical trials have demonstrated that it has similar efficacy to common first-line regimens for NSCLC. A randomized study was conducted to compare docetaxel plus cisplatin (DC) versus paclitaxel plus cisplatin (PC) for patients with advanced non-small cell lung cancer as the first-line regimen. Ninety patients with previously untreated advanced non-small cell lung cancer were randomly assigned to receive either DC or PC. Patients received docetaxel 75mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in DC group and paclitaxel 150mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in PC group. The cycle of two regimens was repeated every 3 weeks. Response and toxicity were evaluated in patients who completed two cycles of chemotherapy at least. Overall survival rate was 31.1% in DC group and 33.3 % in PC group. The median survival time was 10.2 months in DC group and 10.4 months in PC group. Median time to tumor progression was 4.4 months in DC group and 4.9 months in PC group. 1- and 2-year survival rate were 35.6% and 8.9% in DC group and 37.8% and 11.1% in PC group respectively. There were no significant differences in response rate, median survival time, median time to tumor progression and survival rate between two groups (P >0.05). Leucopenia, anemia, nausea and vomiting, and alopecia were the most common grade III and IV toxicities in DC and PC groups, there were no significant differences in grade III and IV toxicities between two groups(P >0.05). There were no treatment-related deaths in both groups. DC has similar response rate and survivals with PC, and its toxicity is well-tolerated. Docetaxel plus cisplatin is an effective first-line treatment of non-small cell lung cancer.

Phase II study of uracil‐tegafur plus cisplatin in patients with previously untreated advanced non‐small cell lung cancer

A multi-institutional phase II trial combining uracil-tegafur (UFT) and cisplatin (CDDP) was conducted in patients with previously untreated advanced non-small cell lung cancer (NSCLC) to evaluate the safety and efficacy of this combined treatment regimen. The entry criteria for this study were previously untreated NSCLC, measurable disease, age <80 years, performance status <2, and adequate haematological, hepatic and renal function. Patients were treated with 400 mg/m(2) oral UFT from day 1 to day 14 and 80 mg/m(2) cisplatin on day 15. The treatment course was repeated every 3 weeks. Of the 68 patients enrolled, 64 (27 with stage IIIB and 37 with stage IV disease) were eligible for treatment. Twenty of the 64 patients responded to the chemotherapy (response rate 31.3%; 95% CI 21.2-43.4%). The median survival time was 8.6 months, and the 1-year survival was 41.5%. Haematological toxicity >or=WHO grade 3 was seen in 3 (4.7%) patients. For non-haematological toxicities, anorexia with WHO grade 3 was seen in 8 (12.5%) patients, nausea and vomiting with WHO grade 3 in 4 (6.3%), diarrhoea with WHO grade 4 in 1 (1.6%), and liver dysfunction with WHO grade 4 in 1 (1.6%) patient. The combination of oral UFT plus cisplatin was found to be a safe and active treatment against advanced NSCLC. The observed low toxicity of this combined regimen may warrant its application to the treatment of elderly patients.

6579 POSTER Randomized phase II trial of irinotecan combined with paclitaxel or gemcitabine in untreated advanced non-small cell lung cancer

6579 POSTER Randomized phase II trial of irinotecan combined with paclitaxel or gemcitabine in untreated advanced non-small cell lung cancer

Phase II trial of bevacizumab plus pemetrexed and carboplatin in previously untreated advanced nonsquamous non-small cell lung cancer

18163 Background: A randomized phase III trial has demonstrated the efficacy and safety of high dose bevacizumab (15 mg/kg) with carboplatin and paclitaxel in previously untreated advanced nonsquamous NSCLC (Sandler et al, NEJM 2006). Pemetrexed has also shown significant activity in advanced NSCLC. Clinical investigation of combination bevacizumab (BEV), pemetrexed (PEM) and carboplatin (CARBO) is therefore of interest in this population. Methods: Phase II, open label study in stage IIIB/IV NSCLC: eligible patients have non- squamous histology and no prior chemotherapy, brain metastasis, gross hemoptysis, tumor proximity to major vessels, uncontrolled hypertension or anticoagulation. All patients receive PEM (500 mg/m2), CARBO (AUC 6) and BEV (15 mg/kg) every 21 days. Patients are pretreated with vitamin B12 1,000 mcg every 9 weeks and folic acid 1 mg daily. Responses are assessed every 2 cycles. Patients with CR, PR or SD receive maximum of 6 cycles followed by BEV (15 mg/kg) maintenance. Our primary objective is to determine time to progression and secondary objectives include response rate, overall survival, and safety of the combination. Results: 14 patients (9 female/ 5 male; median age 62 years; range 34–77; 2 stage IIIB/12 stage IV, all ECOG PS 0 or 1) have been entered. Median number of cycles received is 5.5 (range 2 - 15). 12 patients are evaluable for response. 9 patients continued to have disease control at a median duration of 20.2 weeks (range 5–52) with 6 PRs and 3 SDs (response rate 60%; disease control rate 75%). 5 patients proceeded to BEV maintenance with 2 still ongoing. Overall survival data is immature to date. Toxicity data is available for all patients. Grade 3/4 toxicities have included neutropenia (4), nausea/vomiting (2), BEV related allergic reaction (1) and epistaxis (1). Conclusions: Combination BEV, PEM and CARBO is safe, well tolerated and shows promising activity to date. The regimen is not associated with alopecia, neuropathy or arthralgias/myalgias, and is conveniently administered. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.

Prospective randomised phase II study of gemcitabine and vinorelbine versus gemcitabine and docetaxel combination in patients with previously untreated advanced non-small cell lung cancer

17052 Background: Previous comparative studies have shown similar efficacy and less toxicity with either the Gemcitabine(G)/Vinorelbine(V) or Gemcitabine/Docetaxel(D) combination with respect to platinum-based chemotherapies in patients with advanced NSCLC. This trial was designed to test the efficacy and safety of both GV and GD combination in non-selected patients with advanced NSCLC. Methods: Patients (n = 39) with ≤75 years of age, KPS ≥ 60% and adequate haematological, renal and hepatic function were randomly assigned to: G 1250 mg/m2 i.v. d1 and d8 plus either V 25 mg/m2 i.v. d1 and d8 or D 35 mg/m2 i.v. d1 and d8 every 3 weeks. Prophylactic i.v. ranitidine (50 mg), diphenhydramine (25 mg) and dexamethasone (8 mg) were prescribed just prior to the administration of taxane that was given over 30 minutes immediately before gemcitabine. Results: Baseline characteristics were comparable in GV (n = 20) and GD (n = 19) arms: median age (67 years) and KPS (70%), most patients were male (79%), had metastatic disease (85%) and adenocarcinoma histology (55%). Treatment indicated objective response of 7 (35%) versus 6 (31%) patients, median time-to-treatment failure of 120 versus 90 days, and overall survival of 209 versus 177 days in GV and GD arms respectively. The most common non-haematological toxicities were (GV versus GD; No. of patients): grade 2–4 pulmonary toxicity in 1 versus 7 (37%); grade 2–3 diarrhoea in 0 versus 4 (21%) and oedemas 1 versus 3. Grade 2–4 haematological toxicities in 5 versus 2 patients. All side effects were reversible phenomena since resolution was achieved by suspending the treatment and in the case of the pulmonary toxicity, by the prescription of additional corticoids. Conclusion: The combination of Gemcitabine/Docetaxel does not have a favourable safety profile with this schedule of administration, particularly in terms of pulmonary toxicity. Further patients’ enrolment was stopped and the study has been terminated. This kind of toxicity and alternative schedules of GD combination warrant further investigation. No significant financial relationships to disclose.

Phase II trial of erlotinib in elderly patients (age &gt; 70) with previously untreated advanced non-small cell lung cancer (NSCLC): An analysis of quality of life and symptom response

7168 Background: Elderly patients derive survival benefit but significant toxicity from chemotherapy for NSCLC. Erlotinib is associated with reasonable toxicity and has a survival benefit for relapsed patients previously treated with 1–2 chemotherapy regimens. This targeted agent may prove an effective and well-tolerated first-line therapy in elderly patients with advanced disease. Methods: 80 patients (chemo-naïve, age ≥ 70, PS 0–2, stage IIIB/IV NSCLC) were treated with erlotinib 150 mg/d as part of a phase II study. Primary endpoint was survival. QoL was a secondary endpoint, as assessed by LCSS at baseline and q4 weeks until progression. The primary endpoint of QoL analysis was to determine changes from baseline in LCSS score. Patients were eligible for QoL analysis if they completed an LCSS questionnaire at baseline and ≥ 1 other monthly follow-up visit. Each of 9 items was assessed on a 100mm visual analog scale from 0 (best) to 100 (worst); symptom improvement or worsening was based on a change of ≥ 10mm, with decreased scores implying improvement. Score differences between the baseline and best follow-up response of each subscale and total LCSS are assessed by the signed rank test. Results: 64 patients (80%) were eligible for QoL analysis. There was a trend towards improvement in QoL, based on the total LCSS score. Statistically significant improvements in dyspnea, cough, fatigue, and pain were seen, both in terms of median changes from baseline and the proportion of patients improved (Table). No patients were symptomatic for hemoptysis at baseline, so improvement could not be calculated. Conclusions: Erlotinib in elderly patients with advanced NSCLC was associated with encouraging survival (10.9 mo), a trend towards improved QoL, and statistically significant improvements in key symptoms of dyspnea, cough, fatigue, and pain. Mixed effects longitudinal modeling showing changes in LCSS over time will be presented at the conference. [Table: see text] [Table: see text]

Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma

Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2). Nonsmall cell lung carcinoma (NSCLC) overexpresses HER-2 protein in approximately 20% of cases. In the current study, the authors combined trastuzumab with weekly taxanes in an attempt to improve outcomes over standard chemotherapy in patients with advanced NSCLC. The primary objective was to determine whether docetaxel plus trastuzumab or paclitaxel plus trastuzumab was the superior regimen based on response and toxicity, and to determine whether either regimen was appropriate for further testing in a randomized Phase III trial. After stratification based on the results of HER-2 immunohistochemistry, chemotherapy-naive patients were randomized to receive trastuzumab plus docetaxel or trastuzumab plus paclitaxel. The study was designed so patients with or without HER-2 overexpression would be distributed equally between the study arms. Immunohistochemistry for HER-2 protein expression was attempted for 182 pathologic samples from 169 patients. Twenty-eight of the 179 evaluable samples (16%) revealed 2+ or 3+ staining. The objective response rate was 23% (7 of 30 patients) in the patients treated with docetaxel plus trastuzumab and 32% (11 of 34 patients) in the patients treated with paclitaxel plus trastuzumab (P=0.76, Wilcoxon test). No difference was noted in the median survival (16 mos vs. 14 mos) or 1-year survival (57% vs. 55%) (P=0.998). Toxicities were mild in both treatment arms. No difference with regard to response rates or survival was noted between HER-2-positive (2+ or 3+) and HER-2-negative (0-1+) patients. The expression of HER-2 protein in patients with advanced NSCLC in this study was found to be similar to that reported in previous series. The response rates and toxicities for patients treated with docetaxel and trasuzumab or paclitaxel and trasuzumab were not significantly different, though survival in both arms was better than expected. HER-2 expression status did not appear to affect outcomes for this uniform group of patients who were treated in a comparable fashion. Because of the infrequency of HER-2 overexpression, and the absence of improved outcomes in patients with NSCLC who were treated with trastuzumab plus chemotherapy in other studies, neither regimen tested will be advanced to a Phase III trial.

1127 POSTER Phase II study of the EGFR tyrosine kinase inhibitor erlotinib in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma

1127 POSTER Phase II study of the EGFR tyrosine kinase inhibitor erlotinib in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma

O-188 Phase II study of the EGFR tyrosine kinase inhibitor erlotinib (Tarceva) in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma

O-188 Phase II study of the EGFR tyrosine kinase inhibitor erlotinib (Tarceva) in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma

Phase II study of the EGFR tyrosine kinase erlotinib in patients ≥ 70 years of age with previously untreated advanced non-small cell lung carcinoma

7148 Background: Chemotherapy for patients ≥ 70 with advanced NSCLC is associated with survival benefits but with increased toxicity compared with younger patients. Erlotinib has shown promising activity and a tolerable side effect profile, and it has been approved in the treatment of patients who have failed prior chemotherapy. We have conducted a single center, phase II trial of erlotinib in patients ≥ 70 years with previously untreated advanced NSCLC. Methods: Patients who were chemotherapy-naïve, IIIB/IV, PS 0–2, were enrolled and treated with erlotinib, 150 mg p.o.q.d, until evidence of disease progression or toxicity. Median survival is the primary endpoint. Secondary endpoints include response rate, toxicity, quality of life (measured by LCSS), and gene sequencing for EGFR and K-ras mutations, and EGFR copy number (CN). Results: From 3/03 to 8/04, 58 patients were treated; all were evaluable for survival and toxicity; 55 were evaluable for response. Demographics: median age 76 (range 70–91); 55% male; 91% PS 0/1; 73% adenocarcinoma or BAC; smoking status: current/former/never: 3/49/6. Toxicity: Rash (81%) and diarrhea (69%) were the most common toxicities. Toxicity ≥ grade 3: 5 rash, 3 interstitial pneumonitis, 2 anorexia, 2 hand-foot syndrome, 2 elevations in PT/PTT, 1 GI bleed, 1 hemoptysis, 1 diarrhea, and 1 glossitis. Eight patients were discontinued from study due to toxicity. There was one treatment-related death (pneumonitis). Response: CR 0, PR 6 (10.9%), SD 30 (54.5%), and PD 19 (34.5%). Median survival for all patients was 10.5 months. Median duration of PR and SD was 13.75 and 3.5 months, respectively. In 21 pts with available tissue, EGFR mutations were found only in 3/5 responders. K-ras mutations were found in 1/7 with stable disease and 2/9 with disease progression. EGFR CN did not correlate with treatment outcome. Conclusions: Erlotinib appears to be relatively well tolerated and demonstrates encouraging activity and median survival in patients ≥ 70 years of age with previously untreated advanced NSCLC. Accrual is continuing to 80 patients, and updated response, survival, quality of life, and EGFR/K-ras sequencing will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech

Single agent gefitinib in poor performance status patients with previously untreated advanced non-small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial

7086 Background: Gefitinib has single agent activity and excellent tolerability in patients (pts) with refractory non-small cell lung cancer (NSCLC) and may be of benefit to previously untreated poor performance status (PS) pts. Methods: The objectives were to evaluate the feasibility/toxicity, response rate, and symptom response (SR) of gefitinib in a total of 60 poor PS untreated pts. Eligible pts had no prior systemic therapy; ECOG PS 2, 3; stage IV or IIIB NSCLC; adequate organ function. Gefitinib 250 mg/day was given orally until disease progression, with initial evaluation at 8 weeks. Symptoms were evaluated at baseline and SR weekly using the Lung Cancer Subscale (LCS) of the FACT-L. Results: Twenty-five pts of the required 60 pts have enrolled to date (male/female 17/8); median age 64 (range 58–84); ECOG PS 2/3 20/5; stage IIIB/IV 7/18; bronchioalveolar/adenocarcinoma/squamous/large cell/or other 2/8/8/6/1. The median treatment duration was 3 months (range 1–7) and duration of follow-up 1.2 months...

Preliminary results from a phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in patients &gt; 70 years of age with previously untreated advanced non-small cell lung carcinoma

7080 Background: Chemotherapy for patients ≥ 70 years of age with advanced NSCLC can be associated with greater toxicities than in younger patients. The identification of an efficacious therapy with minimal systemic toxicity would be particularly beneficial to elderly subjects. Erlotinib (Tarceva™) has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We thus chose to conduct a single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC. Methods: Patients: chemotherapy naïve, IIIB (w/malignant effusion)/IV, PS 0–2; treated with erlotinib, 150 mg p.o. q.d., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate, quality of life (using LCSS), changes in FDG-PET, and analysis of EGFR signaling pathway from pre-treatment tumor specimens. Results: From 3/03 to 12/03, 36 pts were treated; 30 evaluable for toxicity and response; 1 for toxicity only; 5 too early. M/F: 19/17; median age 76 (70–86); PS 0/1/2:6/28/2; Path: adeno, 56%; squamous 14%; adeno w/BAC features, 11%; BAC, 11%; NSCLC unclassified 11%, large cell, 2%. Smoking: current/former/never: 2/30/4. Toxicity: rash 77%(grade 1/2: 92%, grade 3: 8%, grade 4:0%), diarrhea 61% (grade 1/2: 100%, grade3/4:0%). Other ≥ grade 3 toxicities: pneumonitis 2/31 (6.5%) and lacrimation 1/31 (3.2%). One patient died from drug toxicity (pneumonitis); 3/31 (9.6%) were dose reduced; 2/31 (6.5%) discontinued. Response: CR:0; PR: 4 (13.3%; 95% CI 5 - 29%); SD: 14 (46.6%; 95% CI 31–64%); PD:12 (40%). Median duration of response and stable disease: 6.8 (range 3.5–7.5+) and 3.5 months (range 1.5–8.0+), respectively. Survival and FDG-PET imaging are too early to evaluate. Conclusions: Erlotinib appears to be well tolerated and demonstrates encouraging activity in patients ≥ 70 years of age with previously untreated advanced NSCLC. Accrual is continuing to 60 patients and updated response, survival and FDG-PET data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Preliminary results from a phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in patients &gt; 70 years of age with previously untreated advanced non-small cell lung carcinoma

7080 Background: Chemotherapy for patients ≥ 70 years of age with advanced NSCLC can be associated with greater toxicities than in younger patients. The identification of an efficacious therapy with minimal systemic toxicity would be particularly beneficial to elderly subjects. Erlotinib (Tarceva™) has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We thus chose to conduct a single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC. Methods: Patients: chemotherapy naïve, IIIB (w/malignant effusion)/IV, PS 0–2; treated with erlotinib, 150 mg p.o. q.d., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate, quality of life (using LCSS), changes in FDG-PET, and analysis of EGFR signaling pathway from pre-treatment tumor specimens. Results: From 3/03 to 12/03, 36 pts were treated; 30 evaluable for toxicity and response; 1 for toxicity only; 5 too early. M/F: 19/17; median age 76 (70–86); PS 0/1/2:6/28/2; Path: adeno, 56%; squamous 14%; adeno w/BAC features, 11%; BAC, 11%; NSCLC unclassified 11%, large cell, 2%. Smoking: current/former/never: 2/30/4. Toxicity: rash 77%(grade 1/2: 92%, grade 3: 8%, grade 4:0%), diarrhea 61% (grade 1/2: 100%, grade3/4:0%). Other ≥ grade 3 toxicities: pneumonitis 2/31 (6.5%) and lacrimation 1/31 (3.2%). One patient died from drug toxicity (pneumonitis); 3/31 (9.6%) were dose reduced; 2/31 (6.5%) discontinued. Response: CR:0; PR: 4 (13.3%; 95% CI 5 - 29%); SD: 14 (46.6%; 95% CI 31–64%); PD:12 (40%). Median duration of response and stable disease: 6.8 (range 3.5–7.5+) and 3.5 months (range 1.5–8.0+), respectively. Survival and FDG-PET imaging are too early to evaluate. Conclusions: Erlotinib appears to be well tolerated and demonstrates encouraging activity in patients ≥ 70 years of age with previously untreated advanced NSCLC. Accrual is continuing to 60 patients and updated response, survival and FDG-PET data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Single agent gefitinib in poor performance status patients with previously untreated advanced non-small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial

7086 Background: Gefitinib has single agent activity and excellent tolerability in patients (pts) with refractory non-small cell lung cancer (NSCLC) and may be of benefit to previously untreated poor performance status (PS) pts. Methods: The objectives were to evaluate the feasibility/toxicity, response rate, and symptom response (SR) of gefitinib in a total of 60 poor PS untreated pts. Eligible pts had no prior systemic therapy; ECOG PS 2, 3; stage IV or IIIB NSCLC; adequate organ function. Gefitinib 250 mg/day was given orally until disease progression, with initial evaluation at 8 weeks. Symptoms were evaluated at baseline and SR weekly using the Lung Cancer Subscale (LCS) of the FACT-L. Results: Twenty-five pts of the required 60 pts have enrolled to date (male/female 17/8); median age 64 (range 58–84); ECOG PS 2/3 20/5; stage IIIB/IV 7/18; bronchioalveolar/adenocarcinoma/squamous/large cell/or other 2/8/8/6/1. The median treatment duration was 3 months (range 1–7) and duration of follow-up 1.2 months (range 0.5–6 months). Grade 3/4 toxicities included: rash (1/10), diarrhea (0/0), elevated liver function test (0/0), dry skin/pruritis (0/0), and stomatitis (0/0). Eighteen pts are now evaluable for response. No partial responses have been seen. Eleven pts (61%) had stable disease and 8 of these 11 pts remain on study. Seven pts (39%) had progressive disease. Six of the 11 pts with stable disease had improved SR. Of the 25 pts enrolled, 8 have expired. Conclusions: Gefitinib is safe, well-tolerated and useful for symptom improvement as first-line therapy for some pts with poor PS. Further follow-up and additional evaluable pts will be provided. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca

New targets and new treatments in non-small cell lung cancer

New agents directed against molecular targets have now been tested in large prospectively randomized clinical trials for patients with untreated advanced non-small cell lung cancer (NSCLC). The trials have included small molecule inhibitors of receptor tyrosine kinases (gefitinib and erlontinib), monoclonal antibodies directed against either the ligands (bevicizumab against vascular endothelial growth factor) or their receptors (trastuzumab against ErbB2) and antisense nucleotides directed against mRNA coding for molecular targets (ISIS 3521 against protein kinase C alpha). The largest mature trials have included agents directed against ErbB1 (epidermal growth factor receptor). Two different small molecule inhibitors of erbB1 (gefitinib and erlontinib) and have been tested in 4 large international randomized trials. Two trials treated patients with advanced NSCLC with either gemcitabine and cisplatin or the same chemotherapy drugs combined with two different doses of gefitinib or one dose of erlontinib (INTACT 1 and TALENT). The other two trials treated patients with advanced NSCLC with either paclitaxel and carboplatin or the same chemotherapy drugs combined with either one of two doses of gefitinib or a single dose of erlontinib (INTACT 2 or TRIBUTE respectively). The results of INTACT 1 and INTACT2 showed no significant difference in survival between those treated with conventional combination chemotherapy and those treated with the same chemotherapy plus gefitinib. The results of the TRIBUTE and TALENT studies showed their primary endpoints of improving overall survival were not met. The monoclonal antibody, bevacizumab, is being tested in an ongoing clinical trial. The trial will compare the outcome of patients with untreated advanced adenocarcinoma of the lung treated with paclitaxel plus carboplatin to those treated with the same chemotherapy drugs plus bevacizumab. The results are scheduled to be available in 2005–2006. Although the initial trials adding newly developed molecular targeted agents have not shown initial success when added to conventional combination chemotherapy, further clinical trials are needed to ultimately define their role in the treatment of non-small cell lung cancer.

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m 2), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47–75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4–59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m 2 of gemcitabine and 100 mg/m 2 of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.