Results of the first interim analysis of PETACC8 intergroup trial do not support adding cetuximab to adjuvant chemotherapy in patients with resected stage III colon cancer
European multicentre phase III study tested oxaliplatin-based adjuvant chemotherapy with or without cetuximab in KRAS wild type patients
- Date : 04 Jul 2012
- Topic : Gastrointestinal cancers
The primary analysis of a randomised phase III, academic, European intergroup PETACC8 trial has not shown a benefit from adding cetuximab to standard adjuvant FOLFOX4 chemotherapy regimen in patients with resected stage III, KRAS wild type colon cancer. The results were presented by Dr Julien Taieb of the Hôpital Européen Georges Pompidou, Paris, France, the PETACC-8 Principal Investigator, at the ESMO 14th World Congress on Gastrointestinal Cancer in Barcelona, Spain (27 June – 1 July 2012).
FOLFOX is a standard adjuvant therapy for stage III colon cancer. The rationale for this adjuvant study was finding that adding cetuximab to FOLFOX is beneficial in patients with metastatic KRAS wild-type (wt) colon cancer. It is the second study to test cetuximab in the adjuvant setting. Previously, the addition of cetuximab to mFOLFOX6 in the US N0147 trial, failed to show a benefit in the adjuvant context.
PETACC8 assessed the potential benefit of cetuximab added to oxaliplatin-based adjuvant chemotherapy
Large clinical trials are needed to show significant benefits from new adjuvant chemotherapy in the treatment of digestive tract cancer. Considering the large number of patients to enroll, several co-operative groups decided to come together under the name of PETACC (Pan-European Trials in Alimentary Tract Cancer). This consortium is composed of over a dozen European national and international co-operative groups. Each group may propose projects which are then discussed and approved by the PETACC General Assembly. Although the operational part of the PETACC trials is centralised for consistency (procedures, quality assurance, etc.), each group maintains its individuality within the general framework.
This major pan-European collaboration has been launched to investigate whether cetuximab in combination with oxaliplatin-based chemotherapy (FOLFOX-4) will reduce disease recurrence and prolong survival in fully resected stage III colon cancer after surgery. Scientists from the Fédération Francophone de Cancérologie Digestive (FFCD) led this intergroup study in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC), and with the national groups involved in the PETACC structure. This study, sponsored and coordinated by the FFCD, and supported by Merck-Serono and Sanofi-Aventis, was conducted in 2559 European patients, including 1602 whose tumours were KRAS wild-type, all with stage III, fully resected colon cancer.
Primary endpoint of this multinational/multicenter adjuvant study was disease free survival, and secondary disease free survival rate at 3 years, overall survival, treatment compliance, 5-year overall survival rate, safety, and biological study for evaluation of markers predictive for relapse and/or treatment efficacy. Planned accrual of 1407 KRAS wt patients provided a 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided α=0.05; an interim analysis was planned after 65% of the events.
The study eligibility criteria were patients aged ≥18 and <75 years, with pathologically confirmed stage III colon adenocarcinoma, regardless of EGFR status, curative R0 resection performed not less than 28 and not more than 56 days prior to randomisation, no metastatic spread at baseline assessment, no prior chemotherapy, no prior abdominal or pelvic irradiation, WHO performance status 0, 1 or 2, signed written informed consent obtained prior to any study specific screening procedures. Additional criterion was that patients with childbearing potential should use effective contraception.
The study criteria were amended in mid 2008, and only patients with KRAS wt could be randomised. The KRAS assessment was centrally determined.
Patients were randomised and stratified according to presence or not of obstruction and perforation, and stage of the disease (T1-3 vs.T4, N1 vs.N2). Patients in the arm A received cetuximab (400 mg/m² first infusion then 250 mg/m² weekly) plus FOLFOX4. Patients in the arm B received FOLFOX4 alone. The cycle duration in both arms was 14 days (2 weeks) with a total of 12 planned cycles (24 weeks).
A total of 1602 KRAS wt patients were included in the interim analysis (811 in arm A and 791 in arm B) with a median follow-up of 39.6 months at the time of the interim analysis. No difference was seen between the arms for disease-free survival. The conditional power to have a positive result at the end of the study under a HR of 1.75 was lower than 1%.
Three-year disease-free survival was 78.0% in arm A and 75.1% in arm B. The frequency of any adverse event grade ≥ 3 was significantly increased in arm B (66.2% in arm A vs. 80.9% in arm B). Diarrhoea, vomiting, mucositis, skin disorders (grade ≥ 3) and failure to complete 12 cycles were also significantly higher in arm B.
The authors concluded that the primary analysis of this randomised phase III trial has not shown a benefit for adding cetuximab to FOLFOX4 in patients with resected stage III KRAS wt. colon cancer. They noticed some differences in subgroup of patients with higher tumour stage, presence of obstruction, elderly, and women. Subgroup and biomarker analyses are still ongoing.
The pre-specified interim analysis of efficacy data does not support the use of cetuximab in the adjuvant treatment of stage III colon cancer. The study investigators did not observe an improvement in disease-free survival after 3.3 years of median follow-up. Unfortunately, since the introduction of FOLFOX as standard treatment, all attempts to further improve prevention of disease recurrence have proved unsuccessful.
The study investigators planned follow-up duration per subject of 3 to 6 years, final analysis after 6 years and overall survival analysis upon 9 years. But their results from this early analysis show a very little probability to expect positive results at the end of the study.
This study opens questions on possible different mechanisms of the action of cetuximab in the adjuvant and metastatic setting. Despite the negative outcome of this study, gastrointestinal cancer experts note that the rationale for EGFR signature is still relevant in this setting.
All PETACC8 researchers should be congratulated for their pan-European effort in conduction and coordination of this complex academic study.
Commenting on the study, which he was not involved in, Dr. Alberto Sobrero, ESMO spokesperson, said: “Both the US NO147 trial reported at ASCO 2010 and the PETACC 8 study presented at the ESMO World GI Congress are negative. The studies had an almost identical design, were done on a molecularly selected population, with a very large patient accrual, allowing rather precise estimation of the potential benefit, even if small. Adding cetuximab to oxaliplatin-based adjuvant chemotherapy was detrimental in the American study, even in patients with KRAS wild type tumours; it will be extremely interesting to see ‘how negative’ the results of the PETACC8 study are: will this trial mark the end of the anti-EGFR strategy in the adjuvant setting, or are subgroups identified in the European study where a superstar effect was observed, thus re-vitalising the interest in this antibody?"
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