No Survival Benefit from Adding Cetuximab to Chemoradiotherapy in Patients with Stage III Non-Small Cell Lung Cancer

Results from an intergroup randomised phase III comparison of standard- vs. high-dose chemoradiotherapy plus/minus cetuximab

The results of the RTOG 0617 phase III trial presented at the Presidential Symposium of the 15th World Conference on Lung Cancer (27-30 October 2013, Sydney, Australia) show that the high-dose radiotherapy with concurrent chemotherapy was not superior and may be worse than standard chemoradiotherapy in term of overall survival. The RTOG researchers also found that cetuximab provided no survival benefit in addition to standard chemoradiotherapy for patients with stage III non-small cell lung cancer (NSCLC).

Two Primary Objectives

The RTOG 0617 study had two primary objectives. The first was to compare the overall survival differences of standard-dose (60Gy) vs. high-dose (74Gy) radiotherapy with concurrent chemotherapy. The second was to compare chemoradiotherapy with the addition of cetuximab. Cetuximab is a monoclonal antibody targeting EGFR with activity when combined with chemotherapy in metastatic NSCLC, and head and neck cancer, and with radiotherapy in locally advanced head and neck cancer, according to background of the study.

This phase III trial randomised patients in a 2x2 factorial design. Concurrent chemoradiotherapy included weekly paclitaxel and carboplatin. Patients randomised to cetuximab received a 400 mg/m2 loading dose on day 1 followed by weekly doses of 250 mg/m2. It was planned that all patients receive 2 cycles of consolidation chemotherapy.

This is the initial report of survival outcome based on cetuximab. The trial was designed for 450 evaluable patients with 80% power and a 1-sided alpha of 0.0125 to detect a 29% reduction in overall survival failure for each comparison (radiotherapy and cetuximab).

In total, 544 patients were accrued in the study, and 419 and 465 were eligible for radiotherapy and cetuximab analyses. Median follow up is 18.7 months. Cetuximab delivery was acceptable in both the concurrent and consolidation phases. Therapy related ≥ grade 3 non-hematologic toxicity was higher in the cetuximab group; 70.5% vs. 50.7% (p < 0.0001). Grade 4 and 5 events were 35.8% and 28.2%, respectively.

Median survival was 23.1 vs. 23.5 months, and 18-month overall survival rates were 60.8% vs. 60.2% in the cetuximab vs. non-cetuximab arms, respectively (p = 0.484, HR = 0.99), which crossed a protocol-specified futility boundary for early reporting. As previously reported, median survival times and 18-month overall survival rates for standard- and high-dose arms were 28.7 vs. 19.5 months, and 66.9% vs. 53.9% respectively (p = 0.0007, HR = 1.56). There was no significant interaction between radiotherapy dose and the use of cetuximab.

The 18-month overall survival  rates in the 4 arms of this trial (60 Gy, 74 Gy, 60 Gy plus cetuximab, and 74 Gr plus cetuximab) are 67.9%, 52.3%, 67.1% and 58.0%, respectively.

Conclusions

The authors concluded that in patients receiving chemoradiotherapy for stage III NSCLC, 74 Gy is not superior to and may be worse than standard radiotherapy dose in terms of overall survival. Cetuximab provides no survival benefit in the setting of chemoradiotherapy for stage III NSCLC. According to the second author of the study and presenter, Dr Gregory Masters, medical oncologist at the Helen F. Graham Cancer Center in Delaware, USA, this study helps clarify radiation dosing in locally-advanced, stage III NSCLC. Cetuximab should not be considered a standard component in the treatment of stage III NSCLC patients. Newly designed Cooperative Group trials are underway to help individualise therapy in this patient setting.

The World Conference on Lung Cancer is the world’s largest meeting dedicated to lung cancer and other thoracic malignancies. The 2013 theme is 'Next-Generation Lung Cancer Care.'