Even in colorectal cancer patients with wild-type KRAS mutations, there was no increase in overall survival time or in the time it took before cancer progressed when Erbitux® (cetuximab) was added to FOLFOX or CAPOX chemotherapy.

More tumors got smaller with Erbitux treatment, but there was an increase in both serious gastrointestinal toxicity and severe skin rash when the drug was added.

Patients with tumor mutations in any of three genes — KRAS, BRAF, or NRAS — had poorer survival.

Study Design

The COIN trial enrolled 2,445  patients who had not received previous treatment for advanced colorectal cancer in one of three arms:

• ARM A: Standard chemotherapy with either 5-FU, leucovorin, and oxaliplatin (FOLFOX) or oral Xeloda and oxaliplatin (CAPOX).
• ARM B: FOLFOX or CAPOX plus Erbitux (cetuximab)
• ARM C: Intermittent treatment (results reported in another paper.)

Only the results of Arms A and B and patients with wild-type KRAS are discussed in  The Lancet current article. This included 729 patients — 367 on the standard treatment Arm A and 362 who also received Erbitux on Arm B.

Patients were treated until their cancer progressed.

Results for Arms A and B

At the time results were analyzed 71 percent of patients had died in both groups, more than 90 percent of colorectal cancer.

• Overall survival in the chemo only group was 17.0 months and 17.9 months in the group that got chemo plus cetuximab.
• Progression-free survival was 8.6 months in both groups.
• 57 percent of the chemo only group responded with tumor shrinkage compared to 64 percent of the cetuximab group.

Side effects

• 14 patients in the chemo group had severe skin rash (grades 3 or higher) compared to 114 in the cetuximab arm.
• 67 patients in chemo group had severe gastrointestinal toxicity compared to 97 in the cetuximab arm.

Influence of tumor gene mutations

For the 1,630 patients in Arms A and B

• 43% had KRAS mutations
• 8% had BRAF mutations
• 4% had NRAS mutations

Effects of tumor mutations on survival

• No mutations of BRAF, KRAS, or NRAS:  median survival 20.1 months
• Any mutation of BRAF, KRAS, or NRAS:  median survival 13.6 months
• BRAF mutation: 8.8 months
• KRAS mutation: 14.4 months
• NRAS mutation: 13.8 months

Median progression-Free Survival ranged for 5.6 months for patients with BRAF mutations to 9.0 months for patients whose tumors had none of the mutations.

Professor Timothy S. Maugham and investigators in the Medical Research Council COIN trial concluded,

This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

SOURCE

Maughan et al., The Lancet, Volume 337, Number 9783, Pages 2103 – 2114, 18 June 2011 doi:10.1016/S0140-6736(11)60613-2

On Monday, April 25th, Fight Colorectal Cancer held a free patient webinar that tackled the somewhat complex but fascinating topic of personalized medicine.

Personalized medicine is what the cancer community calls treatments that are tailored to each patient’s genetic makeup. It is the future of cancer care and in some cases, it is already making a big difference in the ways patients are treated.

You can learn about these cutting edge treatments and about emerging findings in an archive of the webinar below.

Our thanks to Carolyn Grande, CRNP, AOCNP for leading the discussion. She a phenomenal educator on this topic and a member of our Medical Advisory Board. She graciously donated her time to bring this information to patients.

Medicine that is tailored to each patient’s genetic makeup is the future of cancer care. In some cases, it is already making a big difference in the ways patients are treated. Learn about these cutting edge treatments and about emerging findings that will be important for future diagnoses and treatments of colorectal cancer. Discussion led by Carolyn Grande, CRNP, AOCNP.

Dr. Lenz

We are making significant progress in understanding what genetic alterations in tumors really mean.

Over the last two years, we have learned or the first time that there is an alteration in a gene called KRAS in colon cancer, and tumors which have this mutation do not respond to treatment with Erbitux® (cetuximab) or Vectibix® (panitumumab).

This is the first time we have a marker to test for sensitivity of an antibody we have to treat colon cancer.

It is very important to know that patients with tumors who carry a KRAS mutation (alteration) are not doing worse overall. They just don’t have any benefit from an antibody which targets the Epithelial Growth Factor Receptor (EGFR).

Only a few weeks ago, an international group showed for the first time that the different mutations we see in KRAS are not all the same. A mutation is usually a change in one spot (exon) on the gene, but it may happen at many different locations in the gene. The effect may be different depending on the location where it occurs.

Most of the KRAS mutations are in two areas, exon 12 and exon 13. Depending on their location these changes will have different impact on the protein function, and, therefore, maybe all will not  predict resistance to Erbitux.

The investigators have preliminary data that patients with tumor mutations in exon 13 may benefit from Erbitux. These are important findings and in the future may mean that patients with KRAS mutations in exon 13 may receive Erbitux therapy.

In my practice I am making sure that I identify all these patients, who are up to 20% of all patients with KRAS mutations. In the next couple of months, we will have more information which will give us a more conclusive answer.

Dr. Edith Mitchell

Last night, Dr. Edith Mitchell of Thomas Jefferson University Kimmel Cancer Center in Philadelphia, PA, updated colorectal cancer patients on the latest research and treatment news in an online webinar.

Dr. Mitchell highlighted the most important news for colon and rectal cancer patients to come from the 2011 Gastrointestinal Cancers Symposium held in San Francisco last month. She answer such questions as…

“Can doctors determine the chances that my cancer may return?”

“Can my doctors determine if I need chemotherapy?”

“Does Avastin or Erbitux benefit my stage III cancer treatment?”

“Are there any promising new treatments on the horizon?”

You can view the webinar online here.

The patient webinars are a program of the Colorectal Cancer Coalition and are offered to patients at no cost. If you would like to support this program through a financial donation, visit our Donate page.

Although we know that KRAS tumor mutations limit benefit from Erbitux, about six out of ten colorectal cancer patients have normal or wild type KRAS. Yet Erbitux doesn’t work for many of them either.

There may be a simple way to predict early in treatment whether Erbitux is going to help to not.

Significantly more patients whose blood levels of magnesium dropped more than 50 percent after their first treatment with irinotecan and Erbitux had their tumors shrink. It also took longer before their cancer got worse, and they lived longer.

Doctors in Italy measured magnesium levels in the blood of patients getting Erbitux and irinotecan for advanced colorectal cancer. All had previously gotten worse after standard therapy with oxaliplatin and irinotecan. Tests were done before treatment and 7, 14, 21, and 28 days later.

Comparing patients whose magnesium levels fell more than fifty percent (hypomagnesemia) to those whose didn’t:

• Median response rates were 55.8 percent in the hypomagnesemia group versus 16.7 percent in patients without it.
• Time to cancer progression was 6.3 months versus 3.6 months.
• Overall survival time was 11.0 months versus 8.1 months.

B. Vincenzi and the team in Rome concluded,

We have shown that early hypomagnesemia could be a predictor of efficacy and outcome in those patients. Magnesium circulating level is an easy and inexpensive biomarker to routinely be detected in patients treated with

Patients need to be aware that this was a small trial in less than 150 patients. Before depending on it to continue or stop treatment, studies with more patients are critical.

SOURCE: Vincenzi et al., Annals of Oncology,Advqnce Access,November 29, 2010.

Dr. Lenz

Recent data suggest that some KRAS mutations act like normal or wild-type KRAS. Maybe for those mutations, Erbitux could be used for treatment.

A recent publication in the Journal of the American Medical Association by Dr. Sabine Tejpar using an international collaboration showed that some mutations act like wild-type KRAS and that these patients actually may benefit from Erbitux therapy.

Maybe we were wrong thinking that all KRAS mutations are the same. Haven’t we learned from our mistakes before?

A G13D mutation, which means it is found in exon 13, is a relatively uncommon one. Testing cell lines with this mutation shows that these cells act like they have a wild (normal) type of KRAS, considering cell growth and sensitivity to Erbitux therapy. This held up in the animal models.

When they tested the G13D mutation in patients treated with Erbitux or Erbitux combinations, patients with this mutation did as well as those with wild-type KRAS. The interaction of sensitivity to cetuximab (Erbitux) remained significant after multivariate analyses.

Maybe we jumped too quickly to the assumption that a mutation is a mutation. We just learned a similar story about PI3K mutations, where only exon 20 mutations are associated with Erbitux sensitivity not the ones in exon 9. We need to learn to distinct the quality of mutation to make the RIGHT decision.

Please discuss your specific mutation analysis with your treating oncologist.

Previously: All KRAS Mutations May Not Be Alike

Disclosure:  The Colorectal Cancer Coalition has received funding from Eli Lilly & Company, Bristol-Myers Squibb and ImClone Systems, the companies that manufacture and market Erbitux, in the form of unrestricted educational grants.  The Coalition has ultimate authority over website content.

There is some evidence that patients having a specific type of KRAS gene mutation may respond better to Erbitux® (cetuximab) chemotherapy than others who have KRAS-gene mutations.

Previous studies have shown that people with KRAS-mutated tumors did not respond to Erbitux®, and practice guidelines now recommend testing all tumor cells for the mutation before starting Erbitux therapy in patients with recurrent, advanced colorectal cancer.

The study, reported in the Oct. 27 Journal of the American Medical Association (JAMA), examined both the data and tissue samples of 579 patients in several studies who received Erbitux® between 2001 and 2008 for chemotherapy-refractory cancer. Those patients with “codon-13” mutations had longer overall and progression-free survival by several months than those with other KRAS mutated tumor cells. Laboratory tests of tumor cell responses also showed that codon-13-mutated cells responded to cetuximab when other KRAS-mutated cells did not.

The study authors concluded that “Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.”

What it means for patients:

Current evidence has shown the codon-13 type of KRAS mutation to be relatively rare, and more research on therapy response is necessary. It is probably too soon to change recommendations for therapy for those having the codon-13 mutation.

Source: Journal of the American Medical Association, Oct. 27, 2010

Disclosure:  The Colorectal Cancer Coalition has received funding from Eli Lilly & Company, Bristol-Myers Squibb and ImClone Systems, the companies that manufacture and market Erbitux, in the form of unrestricted educational grants.  The Coalition has ultimate authority over website content.

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.

SOURCE:  Bokemeyer et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3506.

Disclosure:  C3 has received funding from Bristol Myer Squibb and ImClone Systems in the form of unrestricted educational grants.  C3 has ultimate authority over website content.

Adding Erbitux® (cetuximab) to standard chemotherapy for stage III colon cancer didn’t improve patient outcomes and added more side effects.

All of the patients in the NO147 trial had cancer that had spread to their lymph nodes and had surgery before beginning chemotherapy. They had normal or wild-type KRAS genes in their tumors.They were randomly assigned to FOLFOX chemotherapy for 6 months or FOLFOX plus Erbitux. 

The trial was closed before the planned number of patients were enrolled because an analysis showed that there was no benefit to the additional Erbitux and continuing the trial would not help patients.

NO147 randomized 1,760 patients with wild-type KRAS to either FOLFOX — oxaliplatin, leucovorin, and continuous infusion 5-FU — or FOLFOX plus cetuximab for 12 treatments.   The primary goal of the trial was to discover which therapy resulted in the best disease-free survival three years later.  Researchers also wanted to measure three-year overall survival and compare serious side effects.

They found:

• For all patients there was no difference in disease-free survival with 74.1 percent of patients getting FOLFOX alone disease-free at 3 years compared to 73.3 percent on the FOLFOX plus cetuximab regimen.
• FOLFOX only patients had a trend toward better overall survival with 87.3 percent alive at 3 years compared to 82.1 percent when cetuximab was added.
• Disease-free survival for patients over the age of 70 was worse in the cetuximab arm with 63.8 percent alive without colon cancer at three years compared to 78.0 who only got FOLFOX.

Serious side effects were worse with cetuximab.  65 out of every 100 patients had a grade 3 or worse side effect when they got both FOLFOX and cetuximab compared to 45 of every 100 on the FOLFOX only treatment. In addition to a skin rash that is typical for Erbitux, patients on the drug also had more risk for severe diarrhea.

Fewer patients were able to complete all 12 treatment cycles when cetuximab was added.

Both serious side effects and differences in disease-free and overall survival were increased in patients who were 70 and over.

Erbitux has shown benefits both as a single drug and when it is combined with chemotherapy for patients with metastatic colorectal cancer that has already spread to sites beyond the colon so it was unclear why this benefit didn’t extend to patients without metastases.

Dr. Stephen Alberts, the Mayo Clinic oncologist who led the trial said,

The sum of data to date from trials for metastatic colorectal cancer suggested that cetuximab would provide benefit in these stage III patients with KRAS wild-type tumors, and so our findings are unexpected. It is difficult to understand how an agent that helps patients with metastatic cancer is not beneficial to those with less advanced disease. At this point we are focusing our efforts on identifying a biological explanation for these findings.

He went on,

Based on what we found, any use of cetuximab in stage III colon cancer is not supported by the results of our trial.

Dr. Alberts and the trial team concluded,

In this randomized phase III trial the addition of cetuximab to modifiedFOLFOX6 was of no benefit for patients with resected stage III wild-type KRAS colon cancer.

SOURCE:  Alberts et al., 2010 ASCO Annual Meeting Abstracts, #CRA3507

Dr. Alberts discusses the trial and its results below.

Disclosure:  C3 has received educational grants from Bristol-Myers Squibb, ImClone, sanofi-aventis, and Pfizer who were sponsors of the NO147 trial in addition to the National Cancer Institute. C3 has ultimate control over content of our website.