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Avastin Benefits Not Affected by KRAS Mutations

Colorectal cancer patients with a KRAS mutation in their tumors benefit when Avastin® (bevacizumab) is added to chemotherapy, as do patients with no mutation or wild-type KRAS.

Both the time until cancer got worse (progression-free survival) and time patients lived after beginning treatment (survival) were better when Avastin was added to chemotherapy regardless of tumor KRAS mutation.  Avastin did not improve overall response rates in the patients with KRAS mutations.

However, overall prognosis is worse for patients with KRAS mutations than those with wild-type KRAS with either chemotherapy alone or chemotherapy with Avastin.  As a group, they tend to live for a shorter time and have their tumors progress more quickly.

Results of an analysis of 280 tumor samples from an earlier Phase III trial comparing chemotherapy with Camptosar® (irinotecan), 5FU, and leucovorin to the same chemotherapy plus Avastin were presented at the World Congress on Gastrointestinal Cancer in Barcelona in June, 2008.

The original study (AVF-2107) randomly assigned a bolus chemotherapy regimen of irinotecan, 5FU, and leucovorin (IFL) or IFL plus Avastin for the initial treatment of metastatic colorectal cancer.  Results showed that adding Avastin improved response, progression-free survival, and survival.

To discover whether a mutation in the tumor KRAS gene made a difference in how Avastin helped patients, researchers performed a DNA sequence analysis on 280 available tumors.  Originally, 812 patients were enrolled in the trial, but the smaller group was very similar.  Test results were correlated with overall survival, progression-free survival, and response rates.

Progression-free survival

  • Original study group:  6.2 months for IFL alone, 10.0 months with Avastin
  • Wild-type KRAS: 7.4 months for IFL, 13.5 months with Avastin
  • Mutant KRAS: 5.5 months for IFL, 9.3 months with Avastin

Overall survival

  • Original study group: 15.6 months for IFL, 20.3 months with Avastin
  • Wild-type KRAS: 17.6 months for IFL, 27.7 months with Avastin
  • Mutant KRAS: 13.5 months for IFL, 19.9 months with Avastin

Response to treatment (combination of complete and partial responses)

  • Overall study group:  38.6 percent for IFL alone, 54.3 percent with added Avastin
  • Wild-type KRAS:  37.3 percent versus 60.0 percent
  • Mutant KRAS: 41.2 percent versus 43.2 percent

Although both patients with wild-type KRAS and mutated KRAS benefited from adding Avastin to chemotherapy, both progression-free survival and survival was better for wild-type KRAS patients, with chemotherapy alone and with chemotherapy plus Avastin.  Avastin didn’t appear to add to the percentage of patients with mutated KRAS who responded to treatment.

In a news release from Barcelona, Dr. Herbert Hurwitz, Duke University in Durham, North Carolina, and principal investigator of AVF2107 said,

These data demonstrate that the addition of Avastin to standard chemotherapy is active for patients with metastatic colorectal cancer with both K-ras wild type and mutant tumors. The high response rate, PFS, and OS in the K-Ras wild type group are impressive and confirm that Avastin should be part of the first line management of patients irrespective of K-Ras status. On a practical level, K-ras testing is not needed to initiate treatment with Avastin.

SOURCE: Hurwitz et al., Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer is Independent of K-ras Mutation Status, Poster 35, World Congress on GI Cancer, June 2008.

Disclosure: C3 has accepted funding for projects and educational programs from Genentech, the manufacturers of Avastin, in the form of unrestricted educational grants. C3 has ultimate authority over website content.

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2 Comments

  1. Steve T said:

    What the article does NOT mention is that Avastin has not proven effective in patients that have previously been treated with an Avastin containing regimen in the front line setting. Both Erbitux and Vectibix are approved for either second or third line use after front line failure. After front line therapy, it becomes increasingly harder to show any benefit to therapy. Avastin’s own PI states that Avastin should not be continued after front line failure. KRAS testing is particularly important in second line, (and later) therapy and only with EGFR inhibitors, as they seem to predict an individual’s prospects for success. The fact that Genentech is suggesting that KRAS testing is not necessary is true. However, if the patient has already had Avastin in the front line and has progressed, Avastin is not effective and those patients should be tested for KRAS to see if they might be benefit from therapy with an EGFR inhibitor,..not merely a c hange in chemo and recycling Avastin.

  2. Anonymous said:

    The article was very specific and discussed the benefits of Avastin regardless of Kras status.

    Here are several points that I would like to highlight:

    1. The Hurwitz trial is a first line treatment for Colorectal Cancer in combination of Avastin and IFL. REGARDLESS OF Kras STATUS, all patients who received the Avastin treatment benefited. Therefore, there is NO NEED FOR KRAS TESTING with Avastin treatment.

    2. Indeed, cetuximab is approved for 2nd line or 3rd line treatment. But, according to the result of the cetuximab study, patients who received the CHEMOTHERAPY ALONE with mutated Kras benefited more than with the addition of cetuximab. This study is in the first line setting, and the more it is important to test the Kras status of the patient who are to receive a second or third line treatment.

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