Newer Combination Therapies and Targets Reported for Advanced NSCLC

NEW ORLEANS-"In metastatic non-small-cell lung cancer, two agents are better than one as long as one of the agents is a platinum compound; three drugs are no better than two drugs; and carboplatin(Drug information on carboplatin) and cisplatin(Drug information on cisplatin) are similar," according to Alan Sandler, MD, associate professor of medicine at Vanderbilt University and director of thoracic oncology at the Vanderbilt-Ingram Cancer Center. Dr. Sandler spoke at a satellite symposium held in conjunction with the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO). His presentation highlighted newer combination therapies as well as chemotherapeutic options for elderly patients and molecularly targeted agents used in the treatment of non-small-cell lung cancer (NSCLC). ECOG 1594 Dr. Sandler discussed the use of newer agents in combination with a platinum agent for the treatment of patients with NSCLC. The results of a large randomized trial conducted by the Eastern Cooperative Oncology Group, ECOG 1594, which compared gemcitabine(Drug information on gemcitabine) (Gemzar)/cisplatin (Platinol), docetaxel (Taxotere)/cisplatin, and paclitaxel(Drug information on paclitaxel)/carboplatin (Paraplatin) to the reference arm of paclitaxel/ cisplatin, demonstrated no significant differences in response rates. Patients who received the gemcitabine and cisplatin regimen, however, demonstrated a significant increase in time to disease progression (4.2 months vs 3.4 months for paclitaxel/ cisplatin; P = .001). Dr. Sandler noted that there was a measurable 2-year survival with these regimens that had not been observed previously with combinations of platinums and other agents. Gemcitabine/cisplatin demonstrated the highest 1- and 2- year survival rates (33% and 11%, respectively), but these results were not statistically significant. Single-Agent vs Two-Drug Combination Dr. Sandler also addressed whether a single newer third-generation agent would be just as effective as a twodrug combination regimen. Data from three randomized trials were presented at the 2002 Annual Meeting of the American Society of Clinical Oncology (ASCO). In these trials, gemcitabine/ carboplatin was compared with single-agent gemcitabine; paclitaxel/ carboplatin was compared with single- agent paclitaxel; and docetaxel(Drug information on docetaxel)/ cisplatin was compared with singleagent cisplatin. Gemcitabine/carboplatin was the only combination that demonstrated a statistically significant difference in overall survival, compared with single- agent therapy. In this study, gemcitabine/ carboplatin produced median, 1-year, and 2-year survival of 10 months, 41%, and 16%, respectively, compared with 9 months, 32%, and 5%, respectively (P = .001), for singleagent gemcitabine (Figure 1). "These three studies," Dr. Sandler concluded, "emphasize the fact that doublet therapy is in fact better than single-agent therapy, and that platinum- based therapy remains the standard of care." Three Drugs No Better Than Two Given the increased efficacy of some doublet combination regimens over single-agent therapy, investigators have examined whether the addition of a third agent would further improve outcomes. "When you actually put it to the test of a randomized study," said Dr. Sandler, "the answer is no, three drugs are not better than two-drug regimens." In the first of two randomized trials presented, gemcitabine/cisplatin was compared with a three-drug regimen of gemcitabine/cisplatin/vinorelbine (Navelbine). Overall response rate (43.4% vs 38.6%) and median survival (8.7 months vs 7.9 months) were both higher with the gemcitabine/cisplatin regimen vs the gemcitabine/cisplatin/ vinorelbine regimen. In the second trial, which compared gemcitabine/carboplatin with MIP (mitomycin [Mutamycin], ifosfamide(Drug information on ifosfamide) [Ifex], and cisplatin), the combination of gemcitabine and carboplatin resulted in a statistically significant increase in median survival, compared with MIP (10 months vs 6.5 months, respectively). Carboplatin vs Cisplatin Similar The relative effectiveness of carboplatin vs cisplatin in the treatment of patients with NSCLC has been controversial since carboplatin was first introduced. Two randomized phase III trials in patients with stage IIIB or IV NSCLC have recently been completed that address this issue. In the first trial (TAX 326), patients were randomly assigned to receive docetaxel/cisplatin, docetaxel/carboplatin, or vinorelbine/cisplatin. Median survival was 10.9 months in the docetaxel/cisplatin arm, compared with 10.0 months in the control arm of vinorelbine/cisplatin (P = .122). Median survival in the docetaxel/ carboplatin arm was 9.1 months, which was not significantly different from the control arm. One-year survival was 47% in the docetaxel/cisplatin arm, 38% in the docetaxel/carboplatin arm, and 42% in the vinorelbine/cisplatin arm. The study was not designed to directly compare the docetaxel/cisplatin regimen with docetaxel/carboplatin, but to compare each of these arms with vinorelbine/cisplatin. In a second phase III trial, gemcitabine/ cisplatin was compared with gemcitabine/carboplatin. Reported response rates and time to disease progression were 47% and 6.1 months, respectively, in the gemcitabine/carboplatin arm compared with 48% and 5.6 months in the gemcitabine/cisplatin arm. On the basis of identical median survival (8.1 months in each arm), Dr. Sandler concluded that this study suggests cisplatin and carboplatin are equivalent when combined with gemcitabine in the treatment of patients with NSCLC. Treatment Considerations Dr. Sandler concluded, "Two agents are better than one, certainly at least as long as one is a platinum-based agent, and three agents are no better than two. The carboplatin/cisplatin debate is on, but I think in metastatic disease it is reasonable to consider them similar, although carboplatin certainly has a better toxicity profile than cisplatin." In randomized trials, the introduction of these newer third-generation chemotherapeutic agents combined with a platinum agent has resulted in longer median, 1-year, and 2-year survival results and improved quality of life compared with older cisplatinbased regimens. No combination of a newer agent and a platinum agent has demonstrated superiority as first-line therapy in patients with advanced NSCLC; however, toxicity profiles vary with these regimens. Chemotherapy for Elderly Selecting the most appropriate chemotherapy for elderly patients with NSCLC is another issue medical oncologists must address-namely, whether to treat these patients with single-agent therapy or a doublet regimen. A retrospective analysis of a study conducted by the ECOG, in which 15% of the 574 patients enrolled were ≥ 70 years old, revealed no difference in response rate or survival among this group compared with patients < 70 years of age. Overall response rates were 21.5% in patients < 70 years old compared with 23.3% in patients ≥ 70. In patients < 70 years old, median survival was 9.05 months, and 1- and 2-year survival rates were 38% and 14%, respectively. In patients ≥ 70 years of age, median survival was 8.53 months, 1-year survival was 29%, and 2-year survival was 12%. These results, said Dr. Sandler, suggest that elderly patients with good performance status should be able to tolerate cisplatinbased doublet therapy. In a study by the Cancer and Leukemia Group B, paclitaxel/carbopla tin was compared with single-agent paclitaxel; 30% of enrolled patients were > 70 years old and all patients had a performance status of 0 to 2. Overall survival was 8 months among patients who received paclitaxel/carboplatin vs 5.8 months among those who received single-agent paclitaxel (Figure 2). Elderly patients with good performance status, said Dr. Sandler, should be treated like younger patients, with an appropriate two-drug regimen. Targeting Growth Factors, Signal Transduction Many novel therapies are directed against HER1/epidermal growth factor receptor (HER1/EGFR), which is overexpressed in 50% to 80% of NSCLC patients; against vascular endothelial growth factor (VEGF), overexpression of which is associated with disease progression and decreased survival; or against signal transduction in tumor cells. The HER1/EGFR tyrosine kinase inhibitor erlotinib (OSI-774, Tarceva, investigational) has been studied in several phase II trials, said Dr. Sandler, including one of 56 patients with stage IIIb/IV or recurrent metastatic NSCLC who had received at least one platinum-based therapy. Seven patients had a partial response to 150 mg/day of erlotinib. Median survival was 8.6 months and the 1-year survival rate was 48%. Acneiform rash was the most common adverse event. Phase II trials of ZD1839 (gefitinib, Iressa) IDEAL 1 and IDEAL 2 (Iressa Dose Evaluation in Advanced Lung Cancer) found comparable or improved response rates (of approximately 20% in IDEAL 1 and 10% in IDEAL 2 patients) and reduced adverse events with a 250-mg vs 500-mg oral daily dose. In IDEAL 2, diseaserelated symptom improvement was achieved by 43% and 34% of patients receiving ZD1839 250 mg/day vs 500 mg/day. However, two phase III follow- up trials in chemonaive patients found no survival benefit when ZD1839 was added to regimens of paclitaxel/ carboplatin or gemcitabine/ cisplatin, Dr. Sandler said. In a trial investigating the role of angiogenesis in NSCLC, the recombinant humanized monoclonal antibody (rhuMAb) to VEGF was evaluated in 99 chemonaive patients with stage IIIb/ IV NSCLC who were randomized to carboplatin/paclitaxel alone or in combination with low-dose (7.5 mg/kg) or high-dose (15 mg/kg) rhuMAb VEGF. Response rates increased and time to tumor progression was prolonged with the antibody. There were six lifethreatening hemorrhages, apparently related to squamous cell histology, and an ECOG study is evaluating rhuMAb VEGF in patients without squamous cell tumors. In a recent phase II/III signal transduction blocking study at Stanford University, paclitaxel and carboplatin were combined with ISIS 3521, an antisense agent directed against protein kinase C alpha, which appears to be associated with the malignant process. The overall response rate was 42%, median survival time was 19 months, and the 1-year survival rate was 75%, Dr. Sandler reported. A randomized phase III study of 600 patients, comparing carboplatin/paclitaxel with or without ISIS 3521, has recently been completed, he said.