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ASCO 2008 Report: Lung Cancer

New findings signal an era of targeted medicine.

Cetuximab for Non–Small-Cell Lung Cancer

Investigators presented results from the First-Line in Lung Cancer with Erbitux (FLEX) trial, a phase III study in which the efficacy and safety of the epidermal growth factor receptor (EGFr)-targeted monoclonal antibody cetuximab (Erbitux) plus chemotherapy was compared with that of chemotherapy alone in a cohort of 1125 patients with advanced non–small-cell lung cancer (NSCLC; J Clin Oncol 2008; 26:suppl:abstract 3). Patients with stage IIIB or IV EGFr-detectable NSCLC were randomized either to receive cetuximab (400 mg/m² initial dose, then 250 mg/m² weekly) plus cisplatin (80 mg/m² on day 1) plus vinorelbine (25 mg/m² on day 1 and day 8) every 3 weeks or to receive cisplatin plus vinorelbine alone (control group). Overall survival (OS), calculated after 868 events had occurred, was superior in the cetuximab group compared with the control group (11.3 vs. 10.1 months; hazard ratio, 0.871; P=0.0441). One-year survival also was higher in the cetuximab group than in the control group (47% vs. 42%). The predominant adverse event in both groups was acneiform rash; however, febrile neutropenia was more common in the cetuximab group. The only other phase III randomized trial to show a survival benefit in NSCLC is a 2005 study of bevacizumab (Avastin) plus chemotherapy (E4599).

Comment: Because the current study included a relatively broad population — patients with squamous-cell tumors, performance status 2, and ongoing anticoagulation were not excluded from participation — cetuximab now is considered another acceptable agent for first-line treatment of NSCLC. However, because the benefit of this drug is modest, we must identify additional markers that characterize patients who would benefit most from cetuximab therapy. — JP

Comment: The superior survival results seen in this study for patients who received cetuximab and chemotherapy indicate that the regimen could offer a new therapeutic option for patients with EGFr-expressing tumors. Perhaps more important, this strategy could lengthen survival in NSCLC patients who are not eligible to receive bevacizumab. However, at present, the FDA has approved cetuximab to treat only patients with colon cancer or head and neck cancer. Survival results that could confirm these benefits are being investigated in another phase III study of a different chemotherapy doublet, with or without cetuximab, in unselected stage IV NSCLC patients. If a cetuximab-plus-chemotherapy regimen does receive FDA approval for treatment of NSCLC patients, this therapeutic strategy could provide modest survival benefit for a relatively large group of stage IV NSCLC patients and should generate further study as a treatment for patients with locally advanced disease or as a postoperative treatment for early-stage patients. — PB

PostOperative Cisplatin for NSCLC

Individual phase III trials and a meta-analysis in which cisplatin-containing doublets were compared with no additional therapy for early-stage NSCLC have demonstrated a treatment-associated survival advantage for patients with metastasis to lobar, hilar, and ipsilateral mediastinal lymph nodes. To update 5-year data from the International Adjuvant Lung Cancer Trial (IALT; N Engl J Med 2004; 350:351), the first and largest trial to show a survival advantage for postoperative adjuvant therapy in NSCLC patients, investigators presented results based on a median follow-up of 7.5 years (J Clin Oncol 2008; 26:suppl:abstract 7507). In IALT, 1867 patients with completely resected stage IB–3A NSCLC were randomized to receive either a cisplatin-containing regimen or no additional therapy.

The additional 3 years of follow-up confirmed the OS and disease-free survival (DFS) benefits of cisplatin-based chemotherapy during the first 5 years after surgery. However, OS results changed significantly between the period before 5-year follow-up and the period after 5-year follow-up (hazard ratio, 0.86; P=0.01 vs. HR, 1.45; P=0.04; for interaction, P=0.006), as did DFS results (HR, 0.85; P=0.006 vs. HR, 1.33; P=0.16; for interaction, P=0.04). Evaluation of cause of death showed no difference between the incidence of lung cancer deaths before and after 5 years. Although more non–lung cancer deaths occurred in chemotherapy-treated patients during the entire 8-year follow-up period (HR, 1.35; P=0.06), the explanation for the excess late mortality isn’t clear.

Confirming results of a previous subset analysis, the investigators observed that chemotherapy was associated with significantly longer survival in patients whose tumors expressed low levels of ERCC1 (a DNA repair enzyme) and that chemotherapy was not associated with longer survival in patients whose tumors expressed high levels of ERCC1.The authors concluded that cisplatin-containing chemotherapy was associated with better OS at 5 years, but an excess of deaths in chemotherapy patients occurred after that point. In addition, they suggested that eligibility for trials designed to test postoperative chemotherapy should be limited to patients whose tumors express low levels of ERCC1.

Comment: Because individual trials and a meta-analysis showed that patients with completely resected early-stage NSCLC experienced longer OS after treatment with postoperative cisplatin-containing doublets, these regimens have become conventional therapy. In the current trial, higher risk for deaths after 5 years was unexpected and unexplained, but this observation raises the possibility that chemotherapy produces some long-term detrimental effects. An alternative explanation for the excess deaths at 5 years after treatment is that patients who would have succumbed early to recurrent lung cancer experienced a higher rate of death related to cardiovascular and respiratory effects from cigarette smoking. This late mortality indicates that this group of patients warrants long-term follow-up. The investigators’ confirmation of ERCC1 as a predictor of benefit from cisplatin-containing adjuvant therapy highlights the need for continued study of ERCC1 expression and other molecular markers in the quest to develop individualized cancer therapy. — PB

Pemetrexed-Based Maintenance Therapy

In another important trial, results showed that maintenance therapy with pemetrexed (Alimta, an antifolate), administered after induction of platinum-based chemotherapy, doubled the time to progression in patients with advanced NSCLC (J Clin Oncol 2008; 26:suppl:abstract 8011. In this phase III study, 663 patients with stage IIIB or IV disease that had not progressed during 4 cycles of platinum-based induction chemotherapy were randomized in a 2:1 ratio to receive pemetrexed (500 mg/m²) or placebo in 21-day cycles until disease progression. All patients received best supportive care and supplemental vitamin B₁₂, folic acid, and dexamethasone. Patients who received pemetrexed achieved significantly longer progression-free survival than did those who received placebo (4.04 vs. 1.97 months; HR, 0.599; P<0.0001). Thus far, OS has been longer, but not significantly so, in the pemetrexed group than in the placebo group (13.0 vs. 10.2 months; HR, 0.798; P=0.06). The incidence and severity of adverse effects were similar in both groups, although the most significant effect, moderate-to-severe anemia, occurred in more patients in the pemetrexed group than in the placebo group (4.5% vs. 1.4%). Patients with nonsquamous histology received the greatest benefit from pemetrexed. — JP

Small-Cell Lung Cancer

Several studies of small-cell lung cancer (SCLC) also were presented. In the SWOG 0124 trial, researchers randomized 671 patients with previously untreated extensive-stage SCLC to receive cisplatin plus irinotecan (Camptosar) or cisplatin plus etoposide (J Clin Oncol 2008; 26:suppl:abstract 7512. Overall efficacy was similar in both groups, with more myelosuppression in the etoposide arm and more diarrhea in the irinotecan arm. Another phase III trial of carboplatin plus pemetrexed versus carboplatin plus etoposide showed that carboplatin plus pemetrexed was inferior; this trial was terminated early (J Clin Oncol 2008; 26:suppl:abstract NSA). — JP

Prognostic Gene-Expression Signature

In the JBR.10 trial, investigators noted that patients with stage II NSCLC experienced less benefit from adjuvant chemotherapy than did patients with stage IB disease (N Engl J Med 2005; 352:2589). In a new study, investigators sought to identify a prognostic gene-expression signature that could be used to categorize patients with limited treatment options into those at high risk or low risk for short-term mortality (J Clin Oncol 2008; 26:suppl:abstract 7510). The objective was to test the performance of this signature in patients with stage I disease against other available public data sets and to evaluate the predictive value of the signature for benefit from adjuvant chemotherapy. Using banked tissue from 133 patients in the JBR.10 trial (62 were observed only; 71 were treated with chemotherapy), investigators identified a 15-gene expression signature that separated the 62 patients in the observation arm into those at high or low risk for death (33 and 29 patients, respectively; P<0.0001). The signature was validated in five independent gene-expression data sets that included tissue samples from 372 patients with stage I or II NSCLC. Chemotherapy significantly lowered risk for death in high-risk patients (P<0.0001). This benefit was observed for patients with high-risk stage IB disease (P=0.007) or stage II disease (P=0.0059) but not for patients with low-risk disease (P=0.008). Further prospective trials are required to confirm that we can accurately select patients who will benefit most from adjuvant chemotherapy. — JP

— Jyoti D. Patel, MD, and Philip Bonomi, MD

Dr. Patel is an Assistant Professor of Medicine in the Division of Hematology/Oncology of Northwestern University Feinberg School of Medicine. Dr. Bonomi is Director of Oncology at Rush University Medical Center in Chicago, Illinois.

Published in Journal Watch Oncology and Hematology July 22, 2008