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.

Sgt. Joshua T. Rose and Iron (Photo by Tina Susman)

Briefly: Pancreatic cancer occurs in about on in five Lynch syndrome families, increasing risk for the cancer substantially.

Colorectal cancer patients whose tumors don’t have EGFR on immunohistochemical testing can still benefit from Erbitux treatment.

Patients learn more and like medical consultations better when doctors sit side-by-side with them to view tests.

Gastroenterologists deployed in Iraq are using their skills to help military working dogs.

Research Reports

• Among families with Lynch syndrome, one in five had at least one person with pancreatic cancer.  Data from 6,342 individuals in 147 families in familial cancer registries at Dana-Farber Cancer Institute in Boston and University of Michigan Comprehensive Cancer Center in Ann Arbor included 47 cases of pancreatic cancer in Lynch families, evenly spread between men and women.  There was a 3.68 percent risk of having pancreatic cancer before age 70, almost nine times the risk in the general population. Fay Kastrinos, MD, MPH and her team reported their study results in the October 28, 2009 issue of the Journal of the American Medical Association.
• Some colorectal cancer patients whose tumors did not express the epidermal growth factor receptor (EGFR) when tested with immunohistochemical staining still responded to treatment with Erbitux© (cetuximab), when given as a single drug (monotherapy). Seven of 85 patients (8.2 percent) had tumors shrink.  For the group, median time to cancer progression was 2.1 months with median overall survival of 10 months.  About 40 percent of patients were alive one year after treatment began.  Study results were similar to other clinical trials of cetuximab monotherapy restricted to patients with EGFR positive tumors.Rafal Wierzbicki and colleagues published their phase II clinical trial results in Investigational New Drugs, online October 15, 2009.

Other Headlines

• When doctors and patients sat side by side at a semicircular table facing a computer screen during a consultation, they shared more information and patients said they were more satisfied with the visit than in a conventional office.  The computer displayed the patient’s electronic medical record, test results, and Internet pages with other health information.  Watch Dr. Victor Montori of the Mayo Clinic who led the randomized Space and Interaction Trial (SIT) discuss the results.
• Gastroenterologists in Iraq are using their skills — and their colonoscopes — to help military working dogs return to duty.  Deployed in Iraq, the doctors removed buttons, tacks, and rocks swallowed by the dogs.  They also stemmed bleeding, found fungal infections, and discovered a large cancer in one dog, who died.  Leon Kundrotas, MD, FACG and Timothy Cassidy, DO presented their work with military dogs in a poster at the American College of Gastroenterology Annual Meeting in San Diego last week.

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.

I attended the European Meeting for Medical Oncology in Berlin two weeks ago, and some new data were presented. Let’s start with the good news which is consistent with all the data we have. In a large randomized phase III trial called CRYSTAL comparing FOLFIRI with or without Erbitux® (cetuximab), the data showed that in patients with wild-type KRAS response rate went up to 60% and time to tumor progression increased about 30% but, so far no overall survival benefit was shown.  The trial was criticized for that.

At the meeting in Berlin after more wild-type KRAS testing was completed there was significant survival benefit for patients treated with Erbitux supporting the impact of this drug in patients with wild-type KRAS for tumor shrinkage, prolongation of time to tumor growth and overall survival. Every patients should be tested for wild-type KRAS prior any treatment decisions.

There is however discussion whether overall survival is a valid endpoint because of many possibilities to receive the drug tested later on in another trial or if approved on the market since overall survival depends on what therapies are available beyond the first regimen. Many trials now look at response rates and time to tumor progression since this is not changed by other therapies following progression of disease with possible crossover of patients to the drug tested.

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.

Dr. Lenz also receives consultant fees, honoraria, and research funding from corporations, including ImClone, Bristol Myers Squibb, and Eli Lilly.  See his full disclosures.

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.

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.

The FDA has updated the indication and usage for Vectibix™  (panitumumab) and Erbitux® (cetuximab) to include a statement that:

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX or VECTIBIX in patients whose tumors had K-ras mutations in codon 12 or 13 and that the use of ERBITUX or VECTIBIX is not recommended for the treatment of colorectal cancer with these mutations.

The American Society of Clinical Oncology (ASCO) recommends that patients whose treatment might include monoclonal antibodies against EGFR have their tumors tested for KRAS and that those with tumor KRAS mutations not be treated with those antibodies.

Provisional Clinical Opinion: Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.

The National Comprehensive Cancer Network updated their guidelines for colorectal cancer treatment last November to include testing for KRAS mutations and not treating only those patients without mutations (wild-type) with Erbitux or Vectibix.

New to the NCCN Guidelines is the recommendation that a determination of the KRAS gene status of either the primary tumor or a site of metastasis should be part of the pre-treatment work-up for all patients diagnosed with metastatic colorectal cancer.

Another important update to the NCCN Guidelines is that the epidermal growth factor receptor (EGFR) inhibitors, cetuximab (Erbitux®, Bristol-Myers Squibb Company/ImClone Systems Incorporated) and panitumumab (Vectibix®, Amgen), either as single agents, or, in the case of cetuximab, in combination with other agents, are now recommended only for patients with tumors characterized by the wild-type KRAS gene.

Amgen, the manufacturers of Vectibix and ImClone Systems, who make Erbitux, announced the changes in press releases.

C3 has more information about KRAS mutations and the studies that showed no benefit for treatment with cetuximab or panitumumab for patients whose tumors had those mutations.

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

Results of a randomized phase III clinical trial that added the monoclonal antibody Erbitux® (cetuximab) to Xeloda® (capecitabine), oxaliplatin, and Avastin® (bevacizumab) showed shorter time to cancer progression for patients who got Erbitux in addition to the standard treatment. There was no difference in whether the tumor shrank or overall survival time. Patients who got Erbitux were about 20 percent more likely to have tumors get worse or to die than patients who didn’t.

This was the first chemotherapy treatment for metastatic cancer that these patients were given.  All of them had metastatic tumors that had spread beyond their colons.

While patients with wild-type (normal) KRAS genes in their tumors had longer progression-free time on Erbitux than those with KRAS mutations, that time did not reach the median progression-free interval for patients in the standard treatment group.

Doctors in the Netherlands randomly assigned 732 patients to a chemotherapy regimen of Xeloda and oxaliplatin with Avastin or the same regimen with the addition of an infusion of Erbitux every week.

• Arm One (CAPOX plus Avastin):  Standard treatment of IV infusion of oxaliplatin and Avastin on the first day of each treatment cycle followed by 14 days of oral Xeloda and 7 days of rest.
• Arm Two (CAPOX plus Avastin with added Erbitux): Experimental treatment with weekly IV Erbitux added to CAPOX/Avastin.

Comparing the  experimental and standard treatments, researchers found:

• Significantly lower median time to progression of 9.4 months in the experimental group with Erbitux compared to 10.7 months with standard treatment.
• No different in response rates: about half in each group had tumors shrink.
• Median overall survival time was almost the same: 19.4 months in the Erbitux group, 20.3 months in the standard arm.

Looking at KRAS status in tumor tissue, the study learned,

• There was a KRAS mutation in almost 40 percent (39.4%) of tumors.
• Erbitux-treated patients with KRAS mutations had significantly shorter progression-free survival than Erbitux-treated patients with wild-type (normal) KRAS: 8.1 months versus 10.5 months.
• Erbitux-treated patients with KRAS mutations also had shorter progression-free time than patients with KRAS mutations who didn’t receive Erbitux: 8.1 months versus 12.5 months.  They also had worse survival time: 17.2 vs 24.9 months.
• Among Erbitux-treated patients, response rates were lower for those with KRAS mutations than for wild-type KRAS: 45.9 percent versus 61.9 percent.
• For patients who didn’t get Erbitux, KRAS status made no difference in progression free survival or response rate.

Side effects and quality of life

• There were worse side effects in the group treated with Erbitux, but most of the difference was due to severe skin rash.  When skin toxicity was excluded, about 3 out of 4 patients in both arms of the study experienced at least one serious adverse event.
• Most common serious side effects were skin rash in the Erbitux group and hand-foot syndrome, diarrhea, neuropathy, hypertension, and fatigue for both.
• Blood clots in veins were experienced by 6.8 percent of patients in the standard group and 8.2 percent of those receiving Erbitux.  Arterial blood clots occurred in 3.3 percent of standard and 2.2 percent of the experimental groups.
• Measures of quality of life and overall health were similar in both groups at the beginning of the trial.  However, both improved significantly more with the standard treatment.  Global health measures didn’t change at all for the group that got Erbitux.

The results of the trial were similar to the lack of benefit in the PACCE trial which added similar EGFR-inhibitor Vectibix™ (panitumumab) to chemotherapy with 5-FU and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI).  Again, progression-free survival time was shorter with the addition of Vectibix and there was no difference in response rate.

Writing in the New England Journal of Medicine, Julien Tol, M.D. and colleagues concluded,

The addition of cetuximab to capecitabine, oxaliplatin,and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of theKRAS gene was a predictor of outcome in the cetuximab group.

SOURCE: Tol et al., New England Journal of Medicine, Volume 360, Number 6, February 5, 2009.