Does adding Erbitux to chemotherapy help people whose colorectal cancer has spread beyond the colon or rectum to distant body sites?
The answer is yes, according to a pooled analysis of two large randomized clinical trials comparing chemotherapy alone to chemotherapy plus Erbitux® (cetuximab). However, benefits depend on whether or not patient tumors have mutations of two genes, KRAS and BRAF.
Previous studies have shown that only patients with normal or wild type KRAS get any benefit from EGFR inhibitors Erbitux or Vectibix™ (panitumumab) so a combined analysis of the CRYSTAL and OPUS studies looked only a outcomes in KRAS wild type tumors. In addition, the research team studied the effect of mutations to BRAF.
They found that adding Erbitux to initial chemotherapy improved overall survival time, time until cancers got worse (progression-free survival), the percent of tumors that shrank with treatment (overall response rate) for tumors with wild-type KRAS. The best outcomes were in patients who had both wild-type KRAS and wild-type BRAF.
Overall, benefits were smaller for both chemotherapy and chemotherapy plus Erbitux when BRAF was mutated. But even in patients with BRAF mutations, adding Erbitux appeared to help.
The pooled analysis of KRAS wild type patients showed:
- Adding Erbitux to chemotherapy added four months to median survival time for the entire group of KRAS wild-type patients. With chemo alone, median overall was 19.5 months while it improved to 23.5 months with chemo and Erbitux.
- Progression-free survival was 7.6 months with chemo alone and 9.6 months with the combination of chemo and Erbitux.
- 38.5 percent of chemo only patients had tumors shrink at some point during their treatment compared to 57.3 percent of patients who also got Erbitux.
When just patients with both wild type KRAS and wild type BRAF were reviewed:
- Overall survival time was 21.1 months with chemo alone and 24.8 months with chemo plus Erbitux.
- Progression–free survival was 7.7 months with chemo and 10.9 months with the combination of chemo and Erbitux.
- Overall response rate was 40.9 percent for chemo and 60.7 percent for chemo and Erbitux.
Prognosis appeared to be poorer when KRAS wild type patients had mutated BRAF, but the researchers noted that there were too few BRAF mutated tumors to make the results statistically significant. However, adding Erbitux did improve outcomes. In those patients.
- Median overall survival was 9.9 months with chemo and 14.1 months with the addition of Erbitux.
- Progression-free survival was 3.7 months versus 7.1 months.
- Overall response was 13.2 percent for chemo alone and 21.9 percent with Erbitux and chemo.
In presenting the study results at the 2010 ASCO Annual Meeting in Chicago, Carsten Bokemeyer said,
Based on these results, BRAF mutations cannot be used as a relevant predictive marker for the use of cetuximab in first line therapy for metastatic colorectal cancer.
Bokemeyer and his colleagues concluded,
This analysis confirms that the addition of cetuximab to chemotherapy first line in patients with KRAS wild type tumors achieves a statistically significant improvement in overall response rate, progression-free survival, and overall survival compared with chemotherapy alone. The best outcome was observed in patients with KRAS wild type/BRAF wild type tumors (90% of KRAS wild type patients). BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to chemotherapy but the sample size may be too small to be reliable.
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