Randomized Phase III Study of Capecitabine, Oxaliplatin, and Bevacizumab with or without Cetuximab in Advanced Colorectal Cancer (ACC), the CAIRO2 Study of the Dutch Colorectal Cancer Group (DCCG)

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 31, 2008

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Presenter: Punt C.J.
Presenter's Affiliation: UMC St Radboud, Nijmegen, Netherlands
Type of Session: Scientific

Background

  • Prior studies have found an overall survival benefit in patients with advanced colorectal cancers (ACC) treated with fluoropyrimidine-based chemotherapy combined with bevacizumab (bev), as compared to fluoropyrimidine-based chemotherapy alone.
  • Cetuximab is a chimeric monoclonal antibody which binds to the epidermal growth factor receptor (EGFR) and has been shown to have efficacy in ACC.
  • Vascular endothelial growth factor (VEGF) and EGFR share several downstream pathways, and by inhibiting both receptors, there may be greater anti-tumor effect. 
  • There are preclinical and clinical trials which suggest that the combined use of EGFR and VEGFR inhibitors may be of benefit in patients with ACC.

Materials and Methods

  • The present study is a phase III randomized trial comparing patients treated with capcitabine (cap), oxalliplatin (OX), and bev (arm A) versus those treated with cap, OX, bev and cetuximab (Arm B). 
  • Dosing:

                         o       Arm A

§         Cap 1,000 mg/m2 orally bid day 1-14
§         OX 130 mg/m2 day 1
§         Bev 7.5 mg/kg IV day 1
 
o       Arm B
§         Same as arm A with the addition of cetuximab 400 mg/m2 iv in week one and 250 mg/m2 iv weekly thereafter
o       All cycles were given every three weeks
  • The primary endpoint of the present study was progression-free survival (PFS)
  • The secondary end points were overall survival (OS), response rate, and toxicity
  • Response was assessed every three weeks using the response evaluation criteria for solid tumors (RECIST) criteria
  • Toxicity was assessed with each cycle of chemotherapy
  • There was central review of all deaths within 30 days
  • The present study was powered to detect a change in median survival of three months (11 to 14 months) with a beta of 80% and p-value of 0.05 (two-tailed).
  •  Inclusion and exclusion criteria included:
o       Histologically confirmed ACC
o       18 or older
o       ACC which was not surgically curable
o       No prior systemic therapy
o       WHO 0-1 performance status
o       No use of anticoagulation
o       No prior coronary artery disease
 

Results

  • A total of 79 hospitals enrolled 755 patients from June 2005 to December 2006.
  • 731 patients had at least one cycle of chemotherapy
  • The median follow-up was 18.7 months
  • Demographics were well-balanced between the two arms aside from female gender representation, which was significantly higher in arm A
    • Median age was 62 yo (range 27-83)
  • Results are as follows:

 
Arm A
Arm B
p-value
Median PFS
10.7 months
9.6 months
0.018
Median OS
20.4 months
20.3 months
0.21
Response Rate
44%
44%
0.88

 
  • Toxicity was as follows:

 
Arm A
Arm B
p-value
Grade 3-4 toxicity
72%
82%
0.0013
Grade 3-4 toxicity excluding skin
72%
75%
0.37
Diarrhea
19%
26%
 
All grade toxicity
40%
84%
 
Death within 30 days of treatment
5%
5%
 
Death within 60 days of treatment
2.4%
1.9%
 
Treatment-related deaths
0..5%
1%
 

  • PFS: in arm B patients with grade III skin toxicity had a better progression free survival compared with those who had grade 0-1 toxicity (p<0.01)
  • K-ras expression was assessed using real-time polymerase chain reaction (PCR). There was no significant difference in K-ras expression between the two arms. Patients with mutant K-ras had a worse PFS when treated with cetuximab than those without the mutation. There was no difference in OS in mutant versus wild type K-ras patients.

Author's Conclusions

  • The addition of cetuximab to cap, OX and bev significantly worsened PFS but had no effect on OS.
  • There were higher rates of diarrhea and skin toxicity in arm B, but these toxicities were considered acceptable.
  • The grade of skin toxicity correlated with response to cetuximab.
  • Patients with K-ras mutations had a decrease in PFS when given cetuximab. Patients with wild type K-ras had the same outcome with and without cetuximab.
 

Clinical/Scientific Implications

  • The present study illustrates a problem that may continue to develop as more biological agents are used and combined with more standard chemotherapy drugs. It appears that subsets of patients may benefit while others may have a detriment in outcome from certain biological agents. As we use more biological agents concurrently, this relationship may become even more complicated. We need better biomarkers which may then allow us to improve our ability to identify patients who will benefit from a given therapy. This study shows that the combination of biological agents can worsen prognosis overall, but there may be a subset within the patient cohort who do benefit, in this case, those with a grade 3 skin reaction. The authors suggest that these patients may do better when treated with cetuximab, cap, OX and bev than those treated with cap, OX and bev alone. If we could select out these patients prior to initiating therapy, we may be able to better custom-tailor therapy for individual patients. 

 

  • Clearly, better systemic therapies are needed for the treatment of ACC. However, the simultaneous development of better molecular markers which are predictors of therapeutic effect are also needed. At this point, without a better ability to predict who will respond to combination therapy with cetuximab, along with the greater toxicity seen in arm B, and the worse PFS seen in arm B, combined therapy with cap, OX, bev and cetuximab can not be recommended in ACC.  

Patient Summary


News
Four-Drug Regimen Not Beneficial in Colorectal Cancer

Jul 31, 2014 - In patients with metastatic colorectal cancer, the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab is associated with significantly reduced progression-free survival and a lower quality of life, according to a report published in the Feb. 5 issue of the New England Journal of Medicine.



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