Nasser Hanna

Multicenter Phase I/II Study of Cetuximab With Paclitaxel and Carboplatin in Untreated Patients With Stage IV Non–Small-Cell Lung Cancer

PURPOSE Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non-small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment. PATIENTS AND METHODS Patients with tumor evidence of EGFR by immunohistochemistry, performance status of 0 to 2, and measurable disease received paclitaxel 225 mg/m2 with carboplatin area under the curve = 6 on day 1 every 3 weeks. Cetuximab was administered at 400 mg/m2, 1 week before paclitaxel and carboplatin, then weekly at 250 mg/m2. The regimen continued until disease progression or intolerable toxicity. RESULTS Thirty-one of 32 enrolled patients were treated. The most common cetuximab toxicity was rash in 84% of patients (grade 3 in 13%). Pharmacokinetic sampling did not reveal an interaction between carboplatin, paclitaxel, and cetuximab. An objective response was observed in eight patients (26%). With a median follow-up of 19 months, the median time to progression was 5 months, median survival was 11 months, and the 1- and 2-year survival rates were 40% and 16%, respectively. CONCLUSION The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated in this population of stage IV patients. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone. A randomized phase II trial has completed accrual.

Second-Line Treatment of Advanced Non-small Cell Lung Cancer

After failure of first-line chemotherapy for advanced non-small cell lung cancer, many patients remain candidates to receive further antitumor treatment. To guide clinical management of these patients and to suggest priorities for clinical research, an International Panel of Experts met in Naples (Italy) in April 2007. Results and evidence-based conclusions are presented in this article. Single-agent chemotherapy with docetaxel or pemetrexed is the recommended option for unselected patients with performance status 0 to 2 who are candidates for second-line chemotherapy for advanced non-small cell lung cancer. Docetaxel has demonstrated superiority compared with best supportive care. Pemetrexed has been shown to be noninferior to docetaxel, with a more favorable toxicity profile. Erlotinib is effective in pretreated patients, and can be given second-line in patients not suitable or intolerant to chemotherapy, and in all patients as third-line treatment after failure of second-line chemotherapy. Gefitinib failed to show superiority to placebo as second- or third-line treatment, but it has been shown to be noninferior to docetaxel. In selected patients such as lifetime nonsmokers or those of East-Asian ethnicity, erlotinib, or gefitinib (where licensed) may be considered as second-line treatment even if they are fit for chemotherapy. Best supportive care in addition to active treatment remains important for all patients, but may be the exclusive option for patients unsuitable for more aggressive therapy. Further research is mandatory, to find better treatments, and to identify clinical and molecular predictive markers of efficacy, both for chemotherapy and for novel biologic agents.

Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130

Objectives: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC. Materials and Methods: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m2 on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m2 with increments of 5 mg/m2 per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response. Results: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m2, AMR 30 mg/m2) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response. Conclusions: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.