Study Shows No Survival Benefit of Cetuximab Over Cisplatin-Based Chemoradiation in Head and Neck Cancers

Kie Kian Ang, MD, PhD

Patients with locally advanced head and neck cancer gained no survival benefit with the addition of cetuximab to chemoradiation, results of a cooperative-group trial showed.

Two-year progression-free survival (PFS) was 63.4% with cetuximab versus 64.3% with cisplatin-based chemoradiation alone. Overall survival improved slightly with cetuximab, but the difference did not achieve statistical significance, according to data presented at the American Society of Clinical Oncology meeting in Chicago, Illinois, in June.

The current standard of care is platinum-based chemoradiotherapy, which often results in severe mucositis, according to the National Cancer Institute (NCI). Cetuximab (Erbitux), a monoclonal antibody that blocks the epidermal growth factor receptor, is potentially less toxic.

Kie Kian Ang, MD, PhD, offered 2 possible explanations for the trial’s negative results.

“In terms of radiation sensitization, we observed no synergy because cetuximab and cisplatin have similar mechanisms of action, predominantly inhibition of DNA repair and proliferation,” said Ang, professor of radiation oncology at the University of Texas MD Anderson Cancer Center in Houston. “In terms of systemic activity, the intensity of treatment may be too low compared to [a previous positive study].”

The findings came from the Radiation Therapy Oncology Group (RTOG) 0522 trial, which demonstrated in preclinical studies that cetuximab enhanced tumor response to cisplatin or radiation. Subsequently, 2 clinical trials validated the evidence, showing improved overall survival with the addition of cetuximab to chemotherapy or radiation therapy in patients with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC).

RTOG 0522 continued the line of clinical investigation by examining the potential benefits of adding cetuximab to cisplatin chemoradiation as first-line treatment for stage III-IV HNSCC.

Patients with locally advanced squamous cell carcinoma of the oropharynx, larynx, or hypopharynx received 2 3-week cycles of cisplatin at a dose of 100 mg/m2 plus a total radiation dose of 72 Gy delivered in 42 fractions over 6 weeks. Patients were randomized to receive cetuximab at a starting dose of 400 mg/m2 followed by 250 mg/m2 weekly or to no further therapy.

Investigators treated 895 randomized patients, and the primary endpoint was PFS. The trial was statistically powered to detect a 25% reduction in the hazard ratio for progression. Planned interim analyses occurred after 108, 217, and 325 events. The trial ended early after the third interim analysis showed that the trial was unlikely to meet the primary endpoint.

After a median follow-up of 2.4 years, the data showed no difference in PFS and a nonsignificant difference in 2-year overall survival: 82.6% with cetuximab and 79.7% without the monoclonal antibody.

Figure. Outcome by p16 Status in RTOG 0522 Trial

^aHazard ratios shown with 95% confidence interval. A hazard ratio <1 indicates a benefit for the cetuximab arm.

OS indicates overall survival; PFS, progression-free survival.

Adapted from Ang et al.J Clin Oncol. 2011;29(suppl; abstr 5500).

Patients in the cetuximab arm had a significantly higher incidence of severe (grade 3/4) mucositis (43% vs 33%; P = .004), in-field skin reactions (25% vs 15%; P <.001), and out-of-field skin reactions (19% vs 1%; P <.001). Late toxicity (>90 days), including persistent dysphagia, occurred in a similar proportion of patients in each treatment group.

As stipulated in the trial design, investigators analyzed treatment effect by p16 status among patients with oropharyngeal carcinoma, which accounted for about two-thirds of the study population (Figure). Of 321 patients with known p16 status (73% positive), the addition of cetuximab produced no benefit in PFS or overall survival in patients with p16-positive or p16-negative tumors.

Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas. J Clin Oncol. 2011;29(suppl; abstr 5500).