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Evaluation of the EGFR-Inhibitor Zalutumumab Given With Primary Curative (Chemo)radiation Therapy to Patients With Squamous Cell Carcinoma of the Head and Neck: Results of the DAHANCA 19 Randomized Phase 3 Trial

2014; Elsevier BV; Volume: 88; Issue: 2 Linguagem: Inglês

10.1016/j.ijrobp.2013.11.021

1879-355X

Jesper Grau Eriksen, Christian Maare, Jørgen Johansen, Hanne Primdahl, J. Evensen, Claus A. Kristensen, L.J. Andersen, Jens Overgaard,

Lung Cancer Treatments and Mutations

Purpose/Objective(s)Antibodies against the Epidermal Growth Factor receptor (EGFR-I) are suggested to increase tumor control and survival of patients (pts) with Head and Neck Squamous Cell Carcinomas (HNSCC) when combined with radiation therapy (RT). The study (NCT00496652) was conducted by the Danish Head and Neck Cancer group (DAHANCA) and aimed to evaluate if concurrent treatment with the EGFR-I zalutumumab during RT improved outcome in pts with HNSCC.Materials/Methods619 pts were accrued from November 2007 to June 2012. Eligible pts had biopsy-verified HNSCC of the oral cavity (4%), oropharynx (69%), hypopharynx (12%) and larynx (14%). Pts were stratified by tumor-site, stage (554 [89%] pts was stage III-IV), p16-status (75% of oropharyngeal carcinomas were positive) and concurrent cisplatin (70% of the pts). Pts were randomized to control-arm or zalutumumab-arm. The control-arm was primary accelerated RT predominantly 66-68 Gy, 2 Gy/fx, 6 fx/wk and concomitant daily hypoxic radiosensitization with nimorazole. Stage III-IV carcinomas received weekly cisplatin 40 mg/m2 during RT. Elective neck-dissection was not performed. The zalutumumab-arm was identical with the control-arm plus zalutumumab 8 mg/kg. First dose was given the week before start of RT and continued weekly during irradiation. Analyses were performed as intention-to-treat. Primary endpoint was Loco-regional control (LRC). Secondary endpoints were Disease-Specific Survival (DSS) and Overall Survival (OS).Results309 pts was in the control-arm and 310 in the zalutumumab-arm. Median observation time was 36 month (12-67 months). Patient and tumor parameters were well balanced. Treatment was generally well tolerated. 94% of the pts in the zalutumumab-arm experienced a skin-rash (29% had grade 3-4 rash). In total 13% were reported to stop zalutumumab due to rash. At time of analysis 126 LRC were verified, 71 pts were dead of disease and 45 were dead of other causes. The 3-year LRC rate was 78% in the zalutumumab-arm vs 79% in the control-arm, HR: 0.8 (95% CI: 0.6-1.2). This outcome was reflected in DSS: HR 1.0 (0.7-1.7) and OS: HR 0.9 (0.6-1.3). Effect of zalutumumab was not influenced by p-16 positivity (HR 1.0 [0.6-1.8]) nor p-16 negativity (HR 0.8 [0.5-1.4]).ConclusionsTreatment with zalutumumab was generally well tolerated. Addition of concomitant zalutumumab to primary (chemo-)radiation therapy and nimorazole for HNSCC did not increase locoregional control nor disease-specific or overall survival at 3 years. Purpose/Objective(s)Antibodies against the Epidermal Growth Factor receptor (EGFR-I) are suggested to increase tumor control and survival of patients (pts) with Head and Neck Squamous Cell Carcinomas (HNSCC) when combined with radiation therapy (RT). The study (NCT00496652) was conducted by the Danish Head and Neck Cancer group (DAHANCA) and aimed to evaluate if concurrent treatment with the EGFR-I zalutumumab during RT improved outcome in pts with HNSCC. Antibodies against the Epidermal Growth Factor receptor (EGFR-I) are suggested to increase tumor control and survival of patients (pts) with Head and Neck Squamous Cell Carcinomas (HNSCC) when combined with radiation therapy (RT). The study (NCT00496652) was conducted by the Danish Head and Neck Cancer group (DAHANCA) and aimed to evaluate if concurrent treatment with the EGFR-I zalutumumab during RT improved outcome in pts with HNSCC. Materials/Methods619 pts were accrued from November 2007 to June 2012. Eligible pts had biopsy-verified HNSCC of the oral cavity (4%), oropharynx (69%), hypopharynx (12%) and larynx (14%). Pts were stratified by tumor-site, stage (554 [89%] pts was stage III-IV), p16-status (75% of oropharyngeal carcinomas were positive) and concurrent cisplatin (70% of the pts). Pts were randomized to control-arm or zalutumumab-arm. The control-arm was primary accelerated RT predominantly 66-68 Gy, 2 Gy/fx, 6 fx/wk and concomitant daily hypoxic radiosensitization with nimorazole. Stage III-IV carcinomas received weekly cisplatin 40 mg/m2 during RT. Elective neck-dissection was not performed. The zalutumumab-arm was identical with the control-arm plus zalutumumab 8 mg/kg. First dose was given the week before start of RT and continued weekly during irradiation. Analyses were performed as intention-to-treat. Primary endpoint was Loco-regional control (LRC). Secondary endpoints were Disease-Specific Survival (DSS) and Overall Survival (OS). 619 pts were accrued from November 2007 to June 2012. Eligible pts had biopsy-verified HNSCC of the oral cavity (4%), oropharynx (69%), hypopharynx (12%) and larynx (14%). Pts were stratified by tumor-site, stage (554 [89%] pts was stage III-IV), p16-status (75% of oropharyngeal carcinomas were positive) and concurrent cisplatin (70% of the pts). Pts were randomized to control-arm or zalutumumab-arm. The control-arm was primary accelerated RT predominantly 66-68 Gy, 2 Gy/fx, 6 fx/wk and concomitant daily hypoxic radiosensitization with nimorazole. Stage III-IV carcinomas received weekly cisplatin 40 mg/m2 during RT. Elective neck-dissection was not performed. The zalutumumab-arm was identical with the control-arm plus zalutumumab 8 mg/kg. First dose was given the week before start of RT and continued weekly during irradiation. Analyses were performed as intention-to-treat. Primary endpoint was Loco-regional control (LRC). Secondary endpoints were Disease-Specific Survival (DSS) and Overall Survival (OS). Results309 pts was in the control-arm and 310 in the zalutumumab-arm. Median observation time was 36 month (12-67 months). Patient and tumor parameters were well balanced. Treatment was generally well tolerated. 94% of the pts in the zalutumumab-arm experienced a skin-rash (29% had grade 3-4 rash). In total 13% were reported to stop zalutumumab due to rash. At time of analysis 126 LRC were verified, 71 pts were dead of disease and 45 were dead of other causes. The 3-year LRC rate was 78% in the zalutumumab-arm vs 79% in the control-arm, HR: 0.8 (95% CI: 0.6-1.2). This outcome was reflected in DSS: HR 1.0 (0.7-1.7) and OS: HR 0.9 (0.6-1.3). Effect of zalutumumab was not influenced by p-16 positivity (HR 1.0 [0.6-1.8]) nor p-16 negativity (HR 0.8 [0.5-1.4]). 309 pts was in the control-arm and 310 in the zalutumumab-arm. Median observation time was 36 month (12-67 months). Patient and tumor parameters were well balanced. Treatment was generally well tolerated. 94% of the pts in the zalutumumab-arm experienced a skin-rash (29% had grade 3-4 rash). In total 13% were reported to stop zalutumumab due to rash. At time of analysis 126 LRC were verified, 71 pts were dead of disease and 45 were dead of other causes. The 3-year LRC rate was 78% in the zalutumumab-arm vs 79% in the control-arm, HR: 0.8 (95% CI: 0.6-1.2). This outcome was reflected in DSS: HR 1.0 (0.7-1.7) and OS: HR 0.9 (0.6-1.3). Effect of zalutumumab was not influenced by p-16 positivity (HR 1.0 [0.6-1.8]) nor p-16 negativity (HR 0.8 [0.5-1.4]). ConclusionsTreatment with zalutumumab was generally well tolerated. Addition of concomitant zalutumumab to primary (chemo-)radiation therapy and nimorazole for HNSCC did not increase locoregional control nor disease-specific or overall survival at 3 years. Treatment with zalutumumab was generally well tolerated. Addition of concomitant zalutumumab to primary (chemo-)radiation therapy and nimorazole for HNSCC did not increase locoregional control nor disease-specific or overall survival at 3 years.