- 作者：Jan B Vermorken ; Jan St?hlmacher-Williams ; Irina Davidenko ; Lisa Licitra ; Eric Winquist ; Cristian Villanueva ; Paolo Foa ; Sylvie Rottey ; Krzysztof Skladowski ; Makoto Tahara ; Vasant R Pai ; S ; rine Faivre ; Cesar R Blajman ; Arlene A Forastiere ; Brian N Stein ; Kelly S Oliner ; Zhiying Pan ; Bruce A Bach ; on behalf of the SPECTRUM investigators
- 刊名：Lancet Oncology
- 出版年：2013
- 出版时间：July, 2013
- 年：2013
- 卷：14
- 期：8
- 页码：697-710
- 全文大小：614 K
Summary
Background
Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.Methods
This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with , number .
Findings
Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11¡¤1 months (95 % CI 9¡¤8-12¡¤2) in the panitumumab group and 9¡¤0 months (8¡¤1-11¡¤2) in the control group (hazard ratio [HR] 0¡¤873, 95 % CI 0¡¤729-1¡¤046; p=0¡¤1403). Median progression-free survival was 5¡¤8 months (95 % CI 5¡¤6-6¡¤6) in the panitumumab group and 4¡¤6 months (4¡¤1-5¡¤4) in the control group (HR 0¡¤780, 95 % CI 0¡¤659-0¡¤922; p=0¡¤0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19 % ] of 325 included in safety analyses vs six [2 % ] of 325), diarrhoea (15 [5 % ] vs four [1 % ]), hypomagnesaemia (40 [12 % ] vs 12 [4 % ]), hypokalaemia (33 [10 % ] vs 23 [7 % ]), and dehydration (16 [5 % ] vs seven [2 % ]). Treatment-related deaths occurred in 14 patients (4 % ) in the panitumumab group and eight (2 % ) in the control group. Five (2 % ) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67 % ) patients, of whom 99 (22 % ) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11¡¤7 months [95 % CI 9¡¤7-13¡¤7] vs 8¡¤6 months [6¡¤9-11¡¤1]; HR 0¡¤73 [95 % CI 0¡¤58-0¡¤93]; p=0¡¤0115), but this difference was not shown for p16-positive patients (11¡¤0 months [7¡¤3-12¡¤9] vs 12¡¤6 months [7¡¤7-17¡¤4]; 1¡¤00 [0¡¤62-1¡¤61]; p=0¡¤998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0¡¤70 [95 % CI 0¡¤47-1¡¤04]).
Interpretation
Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.
Funding
Amgen Inc.