As reported in The Lancet Oncology by Jeffrey D. Bradley, MD, of Washington University, and colleagues, the phase III Radiation Therapy Oncology Group 0617 trial showed no survival benefit of high- vs standard-dose radiotherapy or addition of cetuximab (Erbitux) to concurrent pacli­taxel/carboplatin chemoradiation in patients with inoperable stage IIIA or IIIB non–small cell lung cancer (NSCLC).¹ Higher-dose radiation therapy was associated with poorer survival.

Study Details

In the open-label 2×2 factorial trial, patients from the United States and Canada were randomly assigned 1:1:1:1 between November 2007 and November 2011 to receive 60-Gy radiotherapy (n = 166), 74-Gy radiotherapy (n = 121), 60-Gy radiotherapy and cetuximab (n = 147), or 74-Gy radiotherapy and cetuximab (n = 110), with all patients receiving concurrent once-weekly chemotherapy with paclitaxel at 45 mg/m² and carboplatin at area under the curve (AUC) 2.

Two weeks after chemoradiation, patients received two cycles of consolidation paclitaxel at 200 mg/m² and carboplatin at AUC 6 separated by 3 weeks. Radiation was given in 2-Gy daily fractions with either intensity-modulated or three-dimensional conformal radiation therapy. Cetuximab was given at 400 mg/m² on day 1 followed by 250 mg/m² weekly continued through consolidation therapy. The primary endpoint was overall survival.

Patients had a median age of 64 years, and most were male (55%–64%), white (82%–89%), had Zubrod performance status of 0 (55%–59%), and were current smokers (43%–51%); 47% to 54% received three-dimensional conformal radiotherapy, 89% to 91% underwent positron-emission tomography (PET) staging, 42% to 47% had squamous histology and 34% to 42% had adenocarcinoma, and 63% to 66% had stage IIIA disease. Overall, 41% to 47% had epidermal growth factor receptor (EGFR) H-score available (see sidebar, “Calculating H-Score”); of them, 46% to 52% had high EGFR expression (H-score ≥ 200).

No Improvement in Survival

Median follow-up for the radiotherapy comparison was 22.9 months. Median overall survival was 20.3 months (95% confidence interval [CI] = 17.7–25.0 months) in the high-dose group vs 28.7 months (95% CI = 24.1–36.9 months) in the standard-dose group (hazard ratio [HR] = 1.38, P = .004).

Median follow-up for the cetuximab comparison was 21.3 months. Median overall survival was 25.0 months (95% CI = 20.2–30.5 months) in the cetuximab group vs 24.0 months (95% CI = 19.8–28.6 months) in the no cetuximab group (HR = 1.07, P = .29).

Both the radiation and cetuximab comparisons crossed prespecified futility boundaries.

In a planned retrospective analysis, median overall survival was 19.5 months with cetuximab vs 29.6 months without cetuximab in patients with EGFR H-score < 200 (P = .056) and 42.0 months vs 21.2 months among those with high EGFR expression (P = .032).

Median progression-free survival was 9.8 months in the 74-Gy group vs 11.8 months in the 60-Gy group (P = .12) and 10.8 months in the cetuximab group vs 10.7 months in the no-cetuximab group (P = .89). Two-year local failure rates were 38.6% with 74 Gy vs 30.7% with 60 Gy (P = .13) and 38.2% with cetuximab vs 30.7% without cetuximab (P = .20). Two-year distant metastasis rates were 51.0% with 74 Gy vs 46.6% with 60 Gy (P = .48) and 52.6% with cetuximab vs 42.0% without cetuximab (P = .09).

Toxicity

There was no significant difference in the frequency of grade ≥ 3 adverse events between the 74-Gy group and the 60-Gy group (79% vs 76%), but severe esophagitis was more common with high-dose radiotherapy (21% vs 7%, P < .0001). Cetuximab was associated with an increased frequency of grade ≥ 3 adverse events vs no cetuximab (86% vs 70%, P < .0001). Grade ≥ 3 pulmonary events occurred in 19% of the 74-Gy group vs 20% of the 60-Gy group, and grade ≥ 3 radiation pneumonitis occurred in 4% vs 7%. There were more treatment-related deaths with high-dose vs standard-dose radiotherapy (8 vs 3 patients) and with vs without cetuximab (10 vs 5 patients).

The investigators noted that the median overall survival achieved with standard-dose radiotherapy and weekly concurrent followed by consolidation paclitaxel/carboplatin was higher than expected and appeared to constitute a new benchmark with chemoradiation in this setting. However, they also noted that the use of staging PET in the majority of patients may have resulted in stage migration that contributed to the better-than-expected outcomes.

They concluded: “74-Gy radiation given in 2-Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for [the entire group, but there was a suggestion of benefit in those with high EGFR expression].” ■

Disclosure: The study was funded by the National Cancer Institute and Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187-199, 2015.

See commentary by Laurie E. Gaspar, MD, FASTRO, FACR, MBA.