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.

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.

Although their cancer was initially too extensive to be surgically removed (resected) chemotherapy combined with Erbitux allowed about a third of patients to have surgery that completely removed all visible signs of liver tumors.  Tumor shrinkage occured in about two out of three patients, despite which chemotherapy was used.

During a phase II clinical trial in Germany and Austria, 111 patients with colorectal cancer that had spread to their liver were treated with Erbitux and either FOLFOX6 (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin).  All were considered to have liver tumors that could not be removed surgically.

Every eight weeks, CT scans or MRIs were used to measure any tumor shrinkage (response). After 16 weeks and then every 8 weeks for two years, a local, multidisciplinary team decided whether the situation had changed and patients were able to have surgery.

The study found:

• 38 of 53  patients (68 percent) on FOLFOX6 had a partial or complete response to treatment with measurable tumor shrinkage compared to 30 of 53 (57 percent) of those on FOLFIRI.  This difference between chemotherapies was not significant.
• 20 of 53 patients (38 percent) on FOLFOX were able to have surgery that removed all signs of cancer in the liver, including tumor margins (R0 resection) while 16 of 53 (30 percent) of FOLFIRI patients had an R0 resection.  Again, this was not a significant difference.

The study included patients with both KRAS and BRAF mutations.  Normal or wild-type KRAS made a difference in response to treatment with 70 percent of KRAS wild-type tumors shrinking compared to 41 percent of tumors with KRAS mutations.

Serious side effects included skin rash in 34 percent of patients and lowered white cell counts (neutropenia) in 23 percent.

Dr. Gunner Folbrecht and the CELIM team concluded,

Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability.

After the trial was over, a team of radiologists reviewed patient scans at the beginning and end of treatment to access how many could have had surgery initially and how many after chemotherapy (resectability rate). The radiologists didn’t know which patients had been able to have surgery or what chemotherapy they received.  The team found that the percentage whose tumors could have been operated on almost doubled during treatment from 32 percent initially to 60 percent after chemotherapy with Erbitux.

In a comment in HemOnc Today, Alan Vernook, MD, points out that although all patients had to have unresectable tumors to be included in the trial, the blinded retrospective review found that almost a third could have had surgery initially.  He urges multidisciplinary team involvement in treatment of patients with liver mets.

One interesting finding is that these patients were deemed unresectable at the outset as part of eligibility criteria. Yet, in a blinded independent retrospective review, about 30% of the patients were felt to be resectable. So, on one hand, the treatment effect of this study brings us the hope that in KRAS wild-type patients, cetuximab plus chemotherapy may make more patients resectable. But, it also raises the question that deeming who is resectable at the outset is in the eye of the beholder. So, this study emphasizes the need for more and more multidisciplinary therapy and the idea that one surgeon’s unresectable is another surgeon’s resectable.

SOURCE:  Folprecht et al, The Lancet, early online November 25, 2009.

Disclosure: C3 has accepted funding for projects and educational programs from ImClone Systems and Eli Lilly in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Because the analysis showed that patients were not benefiting from adding Erbitux to FOLFOX chemotherapy, the trial has been closed according to a news release from the National Cancer Institute.

The study — N0147 — randomized patients with stage III colon cancer after surgery to receive either FOLFOX chemotherapy alone or FOLFOX and Erbitux.  Once information about the importance of the KRAS gene for Erbitux benefit was discovered, all patients in the trial had their tumors tested for KRAS mutations and only those with normal or wild-type KRAS were included in the DMC analysis.

According to the NCI news report , there was some initial evidence that addition of Erbitux may have been harmful, especially in patients older than 70.

The study was led by the North Center Cancer Treatment Group (NCCTG) and sponsored by the NCI.

NCCTG N)-147 was officially titled: A Randomized Phase III Trial of Oxaliplatin Plus 5-Fluorouracil/Leucovorin With or Without Cetuximab After Curative Resection for Patients with Stage III Colon Cancer

Currently the use of Erbitux for colorectal cancer is limited to patients with metastatic disease who do not have mutations in the KRAS gene.

Disclosure: C3 has accepted funding for projects and educational programs from ImClone Systems and Eli Lilly in the form of unrestricted educational grants. C3 has ultimate authority over website content.

It is important to know that in the UK Avastin is not approved, and Erbitux was only recently approved in patients with organ limited disease based on the chance of curative resections in patients initially deemed not to be resectable. However it is difficult to judge what the COIN results mean. The response rates in the patients with wild-type KRAS was significantly increased to 64%, so far so good. The problem is that the time to tumor progression and overall survival was not improved in patients with wild-type KRAS and Erbitux therapies.

I would caution not to jump quickly to conclusions since these data require a closer look. It is certainly surprising that about 40 percent of patients died in the first year which is much higher than any other study, which is usually about 20 percent, suggesting that these patients were sicker than in other trials.

In the UK, which reflects a pretty frugal health system, CT scans to monitor success of therapy are done every three months, not every six weeks as  in  United States or other parts of Europe. This makes it much more difficult to see a difference in results, particularly when we expect a time to tumor progression between 7 and 9 months. We also have to recognize that the CT findings are not centrally reviewed which means they can change when scans are reviewed by an expert panel (numbers always change from the investigator reading to an independent panel).

However the most interesting data are that the patients who received Erbitux and Xeloda had significant side effects leading to two dose reductions meaning that these patients received much less chemotherapy. This group seemed to have no benefit from Erbitux, but the patients who received FOLFOX did. We don’t know for sure why there are why are there more side effects with Xeloda and Erbitux, but both have overlapping GI and skin toxicities.Whether there is also some biological interaction we don’t know yet.

These data certainly need more evaluation and detailed review to be able to fully understand them.

Disclosure: C3 has accepted funding for projects and educational programs from Bristol-Myers Squibb and ImClone Systems in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Where you live in the United States makes a big difference in your risk of being uninsured from more than 40 percent of people living in Houston to a little more than 3 percent of those in Worchester, MA.

A new method of testing cancer drugs directly on fresh tumor tissue may speed drug development by reducing the need for the earliest human testing.

Research Reports

• Although patients with a variety of cancers will develop skin rash from Erbitux®  (cetuximab) treatment, colorectal cancer patients are almost twice as likely to get a high-grade rash. Reviewing over 2,000 participants in 16 different trials, analysts found that 88 percent of patients develop some skin rash, with 11 percent having high-grade rashes.  Almost 13 percent (12.6 percent) of colorectal cancer patients had the more severe high-grade rash compared to 6.6 percent of patients with other cancers. The study, led by Xiao Su, was published in the August 2009 issue of Oncology.
• Men and younger patients are more likely to develop a high-grade rash from Erbitux® (cetuximab).  In a review of a clinical trial of Erbitux in over 900 patients with colorectal cancer, 7 percent of men and 3 percent of women developed severe (grade 3) rash.  Six percent of patients under age 70 and 2 percent of older patients had severe rash. Amina Jatoi and a team from the Mayo Clinic report their study results in the August 2008 issue of Oncology.

Other Headlines

• Where you live makes a big difference in whether or not you have health insurance in the United States according to an census analysis of Congressional districts reported by the Associated Press. The percentage of uninsured ranged from 40.1 percent in Houston to 3.4 percent in Worchester, MA.   State policies, types of jobs, and demographics influence lack of insurance.  Large numbers of Hispanics, young people from 20 to 24, older adults from 60 to 64, and people working in farming, fishing, construction, and support jobs increased percentages of uninsured.
• A new method has been developed to test the response of new cancer drugs in human tissue.  The test may speed the development of cancer drugs by reducing early testing in humans.  Using fresh slices of tumor tissue, the assay was able to predict the cancer-killing response to drugs and also which drugs blocked critical cancer-related cell pathways. Ilona Schonn and her team from Hamburg presented a research poster at ECCO/ESMO in Berlin.

Patients in the BOND study had already gotten worse on standard chemotherapy and were receiving either Erbitux® (cetuximab) alone or in combination with irinotecan.  CT scans  for about a third of them showed at least a 10 percent decrease in the size of their tumors six weeks into treatment.

Of 289 patients in the study, 99 or 34 percent had tumor size decrease at the six-week scan, 190 or 66 percent showed no change.

Comparing those who responded to treatment at six weeks with those who didn’t:

• Median time to progression was 6.1 months compared to 1.5 months.
• Overall survival was 13.7 months compared to 6.9 months.

In predicting long-term outcome, early tumor shrinkage was more important than skin rash, another way of estimating how well Erbitux is working.

H. Piessevaux and the study team in Belgium concluded,

Tumor shrinkage at 6 weeks is a strong predictor of time to progression and overall survival in metastatic colorectal cancer patients treated with cetuximab with or without irinotecan. This suggests early tumor shrinkage is the hallmark of efficacy of cetuximab and reliably identifies the subpopulation that is sensitive to the drug. Early tumor shrinkage can be used as a marker of efficacy in clinical practice, as such or in combination.

SOURCE: Piessevaux et al., Annals of Oncology, Volume 20, Number 8, August 2009.