Novel Agents in the
Treatment of Lung Cancer
New Approaches to First-Line Therapies
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Anti-EGFR Antibody (Cetuximab) in Combination with Chemotherapy in First-line Treatment of NSCLC
Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), binds to the extracellular domain of EGFR, blocking ligand-activated signal transduction and receptor dimerization and promoting receptor internalization and degradation. In addition, it is hypothesized that cetuximab also acts against cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC). Despite minimal activity as a single agent in NSCLC, cetuximab appears to consistently improve out comes when added to chemotherapy.22
Following the demonstration of improved survival with cetuximab added to first-line chemotherapy in the FLEX trial,3 a meta-analysis was conducted of the 4 randomized phase II and III trials of first-line platinum-based chemotherapy with or without cetuximab (Table 1).3,22-25
(click table to view larger version)
All trials examined first-line therapy in advanced stage IIIB or IV NSCLC of any histologic subtype. The addition of cetuximab to chemotherapy yielded better response rates, with an odds ratio of 1.463 (95% CI, 1.201-1.783; P<0.001).22 Cetuximab also improved PFS, with a HR for progression of 0.899 (95% CI, 0.814-0.993; P=0.036), although there was no improvement in PFS. Patients treated with cetuximab had consistently improved survival in all 4 trials, with a HR of 0.878 (95%CI, 0.795-0.969; P=0.010). Median survival in patients treated with chemotherapy was 9.4 months (1-year survival 40.0%), and 10.3 months in those treated with cetuximab plus chemotherapy (1-year survival 44.8%; P=0.031). The meta-analysis also examined the subgroup of Caucasian patients in the 4 trials, similar to the preplanned analysis of Caucasian versus Asian patients in the FLEX trial.26 The HR for survival in Caucasian patients (n=1737) was 0.84 (95%CI, 0.75-0.93; P<0.001). The investigators reported no heterogeneity among trial outcomes. Thus, the meta-analysis further confirmed the modest yet statistically significant benefit in survival, PFS, and RR with the addition of cetuximab to first-line chemotherapy in all histologic subgroups of NSCLC patients.
Tailoring Therapy to Subgroups
As discussed below by Dr. Goss, it has been difficult to determine clinical predictors of efficacy for anti-EGFR antibody therapy. While early onset of rash appears to be a clinical predictor of benefit when cetuximab is added to chemotherapy compared to chemotherapy alone, to-date no molecular markers have been able to predict for benefit from cetuximab.
Cetuximab with Radiotherapy
Moving forward, there are multiple ongoing studies exploring the addition of cetuximab to radiotherapy and other systemic treatment combinations. SWOG 0536, a phase II study adding cetuximab to paclitaxel/carboplatin/bevacizumab in patients eligible for bevacizumab therapy, has recently been completed.27 Cetuximab 400 mg/m2 followed by 250 mg/m2 weekly was administered concurrent with paclitaxel/carboplatin and bevacizumab 15 mg/kg IV every 3 weeks for up to 6 cycles. Patients then continued on IV weekly cetuximab 250 mg/m2 plus bevacizumab 15 mg/kg every 3 weeks until progression. Of 104 evaluable patients, 3 developed grade 3-5 pulmonary hemorrhage, and there were 4 treatment-related deaths (2 from pulmonary hemorrhage). Partial response (PR) was seen in 54% of patients, and the median PFS and OS in the study cohort was 7 and 14 months respectively, with a 1-year survival rate of 57%. Correlative studies on a small subgroup of patients did not find that K-ras or EGFR mutation status predicted outcome,28 although a trend was seen for better RR and PFS in those with EGFR FISH-positive tumors treated with cetuximab.
Conclusion
Cetuximab added to first-line platinum-based chemotherapy is an option for advanced NSCLC patients of all histologic subtypes, with a modest yet clear survival benefit. However, tailoring therapy to a subgroup that may derive the most benefit remains a challenge. In the absence of molecular or clinical predictors of a group that derives greater benefit, many clinicians and patients may feel that cetuximab is not worth the additional cost and toxicity for such a modest improvement in survival. In particular, patients with nonsquamous histology now have additional options that may improve survival, including bevacizumab and pemetrexed-based chemotherapy. Further studies are exploring the impact of adding cetuximab to standard first-line options in the United States, such as the randomized SWOG 0819 trial of first-line paclitaxel/carboplatin plus bevacizumab in eligible patients, with or without cetuximab, followed by bevacizumab (in eligible patients) combined with cetuximab or placebo as maintenance therapy. The primary end point of this study is OS, with a co-primary end point of PFS in patients with EGFR FISH-positive tumors. Ongoing studies are investigating the value of cetuximab in stage III NSCLC, and with other systemic therapies. Further studies are needed to establish the role of cetuximab in the emerging options for maintenance therapy, including pemetrexed and erlotinib.