Adding Erbitux to First Line Chemotherapy with Avastin Hurts More than Helps

Adding Erbitux to standard first line treatment for colorectal cancer of CAPOX with Avastin doesn’t help.  In fact, patients who receive the additional agent have a shorter time until their cancer gets worse and have worse side effects.

Results of a randomized phase III clinical trial that added the monoclonal antibody Erbitux® (cetuximab) to Xeloda® (capecitabine), oxaliplatin, and Avastin® (bevacizumab) showed shorter time to cancer progression for patients who got Erbitux in addition to the standard treatment. There was no difference in whether the tumor shrank or overall survival time. Patients who got Erbitux were about 20 percent more likely to have tumors get worse or to die than patients who didn’t.

This was the first chemotherapy treatment for metastatic cancer that these patients were given.  All of them had metastatic tumors that had spread beyond their colons.

While patients with wild-type (normal) KRAS genes in their tumors had longer progression-free time on Erbitux than those with KRAS mutations, that time did not reach the median progression-free interval for patients in the standard treatment group.

Doctors in the Netherlands randomly assigned 732 patients to a chemotherapy regimen of Xeloda and oxaliplatin with Avastin or the same regimen with the addition of an infusion of Erbitux every week.

  • Arm One (CAPOX plus Avastin):  Standard treatment of IV infusion of oxaliplatin and Avastin on the first day of each treatment cycle followed by 14 days of oral Xeloda and 7 days of rest.
  • Arm Two (CAPOX plus Avastin with added Erbitux): Experimental treatment with weekly IV Erbitux added to CAPOX/Avastin.

Comparing the  experimental and standard treatments, researchers found:

  • Significantly lower median time to progression of 9.4 months in the experimental group with Erbitux compared to 10.7 months with standard treatment.
  • No different in response rates: about half in each group had tumors shrink.
  • Median overall survival time was almost the same: 19.4 months in the Erbitux group, 20.3 months in the standard arm.

Looking at KRAS status in tumor tissue, the study learned,

  • There was a KRAS mutation in almost 40 percent (39.4%) of tumors.
  • Erbitux-treated patients with KRAS mutations had significantly shorter progression-free survival than Erbitux-treated patients with wild-type (normal) KRAS: 8.1 months versus 10.5 months.
  • Erbitux-treated patients with KRAS mutations also had shorter progression-free time than patients with KRAS mutations who didn’t receive Erbitux: 8.1 months versus 12.5 months.  They also had worse survival time: 17.2 vs 24.9 months.
  • Among Erbitux-treated patients, response rates were lower for those with KRAS mutations than for wild-type KRAS: 45.9 percent versus 61.9 percent.
  • For patients who didn’t get Erbitux, KRAS status made no difference in progression free survival or response rate.

Side effects and quality of life

  • There were worse side effects in the group treated with Erbitux, but most of the difference was due to severe skin rash.  When skin toxicity was excluded, about 3 out of 4 patients in both arms of the study experienced at least one serious adverse event.
  • Most common serious side effects were skin rash in the Erbitux group and hand-foot syndrome, diarrhea, neuropathy, hypertension, and fatigue for both.
  • Blood clots in veins were experienced by 6.8 percent of patients in the standard group and 8.2 percent of those receiving Erbitux.  Arterial blood clots occurred in 3.3 percent of standard and 2.2 percent of the experimental groups.
  • Measures of quality of life and overall health were similar in both groups at the beginning of the trial.  However, both improved significantly more with the standard treatment.  Global health measures didn’t change at all for the group that got Erbitux.

The results of the trial were similar to the lack of benefit in the PACCE trial which added similar EGFR-inhibitor Vectibix™ (panitumumab) to chemotherapy with 5-FU and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI).  Again, progression-free survival time was shorter with the addition of Vectibix and there was no difference in response rate.

Writing in the New England Journal of Medicine, Julien Tol, M.D. and colleagues concluded,

The addition of cetuximab to capecitabine, oxaliplatin,and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of theKRAS gene was a predictor of outcome in the cetuximab group.

SOURCE: Tol et al., New England Journal of Medicine, Volume 360, Number 6, February 5, 2009.

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