Author: Neil Osterweil, Oncology Report Digital Network
The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.
The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.
Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.
The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.
“Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge,” Dr. Harari said.
“We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition,” he said.
Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.
A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.
At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.
Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).
However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.
In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.
Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.