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KRAS Mutations Make a Difference In Response to Erbitux

Update from 2008 ASCO Meeting in Chicago

Three studies reported during the 2008 American Society of Clinical Oncology found that colorectal cancer patients whose tumors have mutated KRAS genes do not benefit from treatment with the EGFR-inhibitor Erbitux® (cetuximab).

At the same time, patients with tumors that aren’t aren’t mutated (wild-type) have significantly better results when Erbitux is added to either FOLFIRI or FOLFOX chemotherapy.

Two randomized trials of initial treatment of chemotherapy with or without Erbitux found responses and improved progression-free survival only in patients with wild-type KRAS. The CRYSTAL Phase III study compared FOLFIRI to FOLFIRI with the addition of cetuximab. The Phase II OPUS trial used FOLFOX as chemotherapy and compared FOLFOX to FOLFOX plus cetuximab. Neither found benefit for patients whose tumor had mutated KRAS.

However, both trials found that adding cetuximab to chemotherapy improved both tumor shrinkage (response rates) and the time until the cancer got worse (progression free survival) for people with wild-type KRAS.

Tumors can be tested for mutated KRAS before beginning treatment providing information that can help patients and doctors make better decisions about the right therapy for each individual.

KRAS curvesDuring the Plenary session at ASCO on Sunday, Dr. Eric Van Cutsem presented an analysis of tumors of patients enrolled in the CRYSTAL trial according to KRAS mutation status.

Thirty-five percent of patients in CRYSTAL had mutated KRAS in their tumors. When the two groups, FOLFIRI alone and FOLFIRI with cetuximab were compared, there was no difference in either response to treatment or progression-free survival.

However, wild-type KRAS made a significant difference. When cetuximab was added to FOLFIRI, response rate went up from 43 percent to 59 percent. Median progression-free survival improved from 8.7 months to 9.9 months.

At one year, 43 percent of patients with wild-type KRAS on FOLFIRI plus cetuximab still hadn’t had their cancer progress, compared to 25 percent of those on FOLFIRI alone.

Dr. Van Cutsem concluded,

KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy in first-line treatment of metastatic colorectal cancer. Cetuximab in combination with a standard first-line treatment for metastastic colorectal cancer is an important new option in patients with KRAS wild-type tumors.

The OPUS trial tells a similar story. OPUS compared FOLFOX alone to FOLFOX plus cetuximab for the initial or first-line treatment of colorectal cancer.

Dr. Carsten Bokemeyer reported the results of an analysis of both response rate and progression-free survival for wild-type KRAS and mutated KRAS in the OPUS study.

The OPUS trial had previously shown an increased response rate when cetuximab was added to FOLFOX, but this did not translate into better progression-free survival.

However, when the KRAS mutation groups were considered separately there there was an even better improvement in response rate for the wild-type group with cetuximab — an increase from 37 percent to 61 percent. Progression-free survival was almost 50 percent better, as well.

When there was a mutation in tumor k-ras, response rate appeared to fall somewhat, although this was not statistically significant. Progression-free survival was actually worse in the FOLFOX plus cetuximab group.

Dr. Bokemeyer and his team concluded,

These data suggest that the benefit from addition of cetuximab to standard treatment is higher for the population with wild-type KRAS. For patients with KRAS mutations, no benefit could be shown of adding cetuximab to FOLFOX in this study.

In a third ASCO presentation, Dr. Sabine Tejpar analyzed the impact of KRAS mutation when doses of cetuximab were increased.

The EVEREST trial selected patients who showed little or no skin rash when treated with FOLFIRI and cetuximab and randomly assigned them to continue the standard dose of cetuximab or have their dose increased until skin rash appeared.

Again, patients with wild-type KRAS did better. Response rate improved as dose increased. But, once more, those with mutant KRAS showed no benefit. Even with dose escalation, there were no responses to treatment.

There was no difference in skin rash between wild-type and mutated KRAS groups.

Dr. Tejpar and her team concluded,

These data suggest that patients with KRAS wild-type achieve considerable benefit from irinotecan plus cetuximab treatment. Patients with KRAS mutation did not profit from irinotecan plus cetuximab treatment and cetuximab dose escalation did not increase responses in these patients.

Previously, similar results were reported for clinical trials of Vectibix™ (panitumumab) that compared Vectibix to best supportive care for patients who had already had standard chemotherapy for colorectal cancer. In that trial patients with mutated KRAS had no benefit, either in response or progression-free survival.

Vectibix targets the same EGFR receptor on the surface of the cancer cell that Erbitux does. Signals to the cancer cell nucleus to divide are sent from the EGFR receptors through a pathway controlled by the KRAS gene. In normal, wild-type tumor cells, blocking that receptor reduces cancer growth. But if the gene is mutated, blocking EGFR doesn’t seem to have any positive effect.

What this means for patients

If you are currently taking either Erbitux® or Vectibix™, you should discuss continuing the drug with your doctor and having your tumor tested for KRAS mutations.

If your doctor recommends Erbitux or Vectibix, ask about testing your tumor for KRAS mutation before deciding on treatment.

Some points to remember during that talk:

  • Evidence in several clinical trials have shown no benefit when Erbitux was added to chemotherapy or used alone for patients whose tumors were KRAS mutated.
  • There can still be a benefit from chemotherapy or other biologic agents such as Avastin™ in patients with KRAS mutations.
  • Patients with wild-type KRAS had a significant increase in responses and time to cancer progression when Erbitux was added to either FOLFIRI or FOLFOX chemotherapy as an initial treatment.
  • Testing for KRAS is available and may be reimbursed by your insurance.
  • The presence or severity of skin rash doesn’t have anything to do with KRAS status and can’t be used to determine if you have a mutation or are wild-type.
  • Testing can be done with the sections of your tumor that were preserved in paraffin blocks at the time of your surgery. These blocks are available.
  • Since the mutation is in the tumor, a blood test will not tell you if you have a KRAS mutation. Your family members cannot inherit this mutation.
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