June 6, 2011 — The results of a new study do not confirm that adding the epidermal growth factor receptor–targeted monoclonal antibody cetuximab to standard oxaliplatin-based first-line combination chemotherapy in patients with advanced colorectal cancer is beneficial.
Although cetuximab increased the response rate, it did not boost progression-free or overall survival in KRAS wild-type patients, or even in patients selected by additional mutational analyses of their tumors, the study team reported online June 4 in The Lancet.
The findings from the Medical Research Council COIN study were simultaneously reported at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting.
"The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended," chief investigator Timothy S. Maughan, MD, FRCR, from Cardiff University, United Kingdom, and colleagues conclude in their report.
The findings from a second analysis of the COIN study, published online June 4 in Lancet Oncology, suggest that for most patients with a normal platelet count before starting treatment, planned treatment holidays are an option that may offer improved quality of life without compromising survival time.
Medical Research Council COIN Study
In the study, 1630 previously untreated patients with advanced colorectal cancer fit for chemotherapy were randomly assigned to a continuous combination of oxaliplatin and fluoropyrimidine chemotherapy (the control group), to the same continuous combination plus cetuximab, or to the same combination chemotherapy in an intermittent schedule. The choice of fluoropyrimidine therapy was capecitabine or infused fluouroracil plus leucovorin.
This study was "enriched for patients most likely to benefit from cetuximab — those with KRAS wild-type tumours," Madeleine Hewish, MRCP, and David Cunningham, MD, from the Royal Marsden Hospital, Surrey, United Kingdom, note in a linked comment in The Lancet.
However, apart from a modest increase in the rate of tumor regression, cetuximab had no significant effect on progression-free survival or overall survival, the comment authors point out.
Dr. Maughan and colleagues report that the overall response rate increased from 57% with chemotherapy alone to 64% with the addition of cetuximab (P = .049).
However, median overall survival was 17.9 months in the control group vs 17.0 months in the cetuximab group, yielding a hazard ratio (HR) with cetuximab of 1.04 (95% confidence interval [CI], 0.87 - 1.23; P = .67).
Likewise, there was no effect on progression-free survival, which was 8.6 months in the control group (interquartile range, 5.0 - 12.5) and the cetuximab group (interquartile range, 5.1 - 13.8; HR, 0.96; 95% CI, 0.82 - 1.12; P = .60).
Even patients with tumors wild-type for genes tested within the RAS-RAF-MAP kinase pathway, who would be most likely to benefit from cetuximab, did not appear to benefit from the drug, the study team reports.
However, BRAF, KRAS, and NRAS mutations did have a "potent prognostic effect" on the outcome of patients with advanced colorectal cancer, irrespective of treatment received, the researchers say. Overall survival was 8.8 months in those with BRAF-mutant tumors, 14.4 months in those with KRAS mutant tumors, and 20.1 months in all wild-type tumors.
This study highlights the "fundamental importance of these changes and emphasizes the need to stratify future trials for these factors and to seek specific therapeutic approaches within these molecular subgroups," Dr. Maughan and colleagues write.
What Went Wrong?
In their comment, Dr. Hewish and Dr. Cunningham offer several possible explanations for the COIN results, one being that oxaliplatin may not be the best chemotherapy drug for cetuximab.
"This notion fits with preclinical data," they say. "However, when cetuximab is combined with a fluorouracil-irinotecan doublet it can improve tumour control rates and overall survival in first-line treatment and does appear to facilitate a higher rate of resection of metastatic disease in the liver," the clinicians point out.
The results of the COIN study, they conclude, "should prompt a review of present guidance from the UK National Institute of Health and Clinical Excellence, which recommends that patients with liver-only metastatic disease should receive an oxaliplatin-based chemotherapy doublet with cetuximab, and that irinotecan should be reserved for patients for whom oxaliplatin is deemed to be contraindicated and not tolerated."
Treatment Holidays An Option for Some
A second part of the COIN trial, led by Richard A. Adams, MD, FRCP, from the School of Medicine, Cardiff University, United Kingdom, and colleagues, assessed the risks and benefits of shortening the duration of initial chemotherapy from 6 months to 12 weeks (restarting therapy on disease progression). This was accomplished by comparing standard continuous chemotherapy with the same chemotherapy given with planned treatment holidays.
The results showed that intermittent chemotherapy did not increase or significantly decrease survival. Median survival in the intention-to-treat population was 15.8 months with continuous treatment and 14.4 months with intermittent treatment. In the per protocol population, median survival was 19.6 months and 18.0 months, respectively. "The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary [of 1.162]," the investigators note.
"Subgroup analyses," they report, "suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break."
Specifically, they found that a raised platelet count, defined as 400,000/μL or higher, was associated with poor survival with intermittent chemotherapy. The HR for comparison of continuous vs intermittent treatment in patients with a normal platelet count was 0.96 (95% CI, 0.80 - 1.15; P = .66) vs 1.54 (95% CI, 1.17 - 2.03; P = .0018) in patients with a raised platelet count (P = .0027 for interaction).
"There seems to be a large subpopulation of patients for whom intermittent therapy provides similar survival benefit” the authors write, adding that the results of this trial provide a basis for discussion of options between patients and clinicians.
In their comment, Dr. Hewish and Dr. Cunningham write that, "unsurprisingly," intermittent chemotherapy was associated with fewer chemotherapy-related side effects such as fatigue, nausea or vomiting, "but disappointingly," no improvement in global quality of life, and a significant increase in reporting of pain.
"Thus, we would urge caution in stopping treatment after 3 months. If clinicians and their patients choose this approach, we would recommend careful selection of patients and close monitoring for progressive disease so that chemotherapy can be reintroduced before the therapeutic window is closed," they write.
The COIN trial was supported by Cancer Research UK, Cancer Research Wales, UK Medical Research Council, and Merck KGgA. Dr. Maughan, Dr. Adams, and other study authors have disclosed financial relationships with Roche and Merck Serono as well as Amgen, AstraZeneca, and Dako Limited. One author is an employee of the UK Medical Research Council. Dr. Cunningham has received research funding from Amgen, Roche, Merck Sharpe and Dohme, Sanofi-Aventis, and Merck Serono. Dr. Hewish has disclosed no relevant financial relationships.
Lancet. Published online June 4, 2011. Maughan article
Lancet Oncology. Published online June 4, 2011. Adams et al article
Lancet. Published online June 4, 2011. Hewish and Cunningham comment
Although cetuximab increased the response rate, it did not boost progression-free or overall survival in KRAS wild-type patients, or even in patients selected by additional mutational analyses of their tumors, the study team reported online June 4 in The Lancet.
The findings from the Medical Research Council COIN study were simultaneously reported at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting.
"The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended," chief investigator Timothy S. Maughan, MD, FRCR, from Cardiff University, United Kingdom, and colleagues conclude in their report.
The findings from a second analysis of the COIN study, published online June 4 in Lancet Oncology, suggest that for most patients with a normal platelet count before starting treatment, planned treatment holidays are an option that may offer improved quality of life without compromising survival time.
Medical Research Council COIN Study
In the study, 1630 previously untreated patients with advanced colorectal cancer fit for chemotherapy were randomly assigned to a continuous combination of oxaliplatin and fluoropyrimidine chemotherapy (the control group), to the same continuous combination plus cetuximab, or to the same combination chemotherapy in an intermittent schedule. The choice of fluoropyrimidine therapy was capecitabine or infused fluouroracil plus leucovorin.
This study was "enriched for patients most likely to benefit from cetuximab — those with KRAS wild-type tumours," Madeleine Hewish, MRCP, and David Cunningham, MD, from the Royal Marsden Hospital, Surrey, United Kingdom, note in a linked comment in The Lancet.
However, apart from a modest increase in the rate of tumor regression, cetuximab had no significant effect on progression-free survival or overall survival, the comment authors point out.
Dr. Maughan and colleagues report that the overall response rate increased from 57% with chemotherapy alone to 64% with the addition of cetuximab (P = .049).
However, median overall survival was 17.9 months in the control group vs 17.0 months in the cetuximab group, yielding a hazard ratio (HR) with cetuximab of 1.04 (95% confidence interval [CI], 0.87 - 1.23; P = .67).
Likewise, there was no effect on progression-free survival, which was 8.6 months in the control group (interquartile range, 5.0 - 12.5) and the cetuximab group (interquartile range, 5.1 - 13.8; HR, 0.96; 95% CI, 0.82 - 1.12; P = .60).
Even patients with tumors wild-type for genes tested within the RAS-RAF-MAP kinase pathway, who would be most likely to benefit from cetuximab, did not appear to benefit from the drug, the study team reports.
However, BRAF, KRAS, and NRAS mutations did have a "potent prognostic effect" on the outcome of patients with advanced colorectal cancer, irrespective of treatment received, the researchers say. Overall survival was 8.8 months in those with BRAF-mutant tumors, 14.4 months in those with KRAS mutant tumors, and 20.1 months in all wild-type tumors.
This study highlights the "fundamental importance of these changes and emphasizes the need to stratify future trials for these factors and to seek specific therapeutic approaches within these molecular subgroups," Dr. Maughan and colleagues write.
What Went Wrong?
In their comment, Dr. Hewish and Dr. Cunningham offer several possible explanations for the COIN results, one being that oxaliplatin may not be the best chemotherapy drug for cetuximab.
"This notion fits with preclinical data," they say. "However, when cetuximab is combined with a fluorouracil-irinotecan doublet it can improve tumour control rates and overall survival in first-line treatment and does appear to facilitate a higher rate of resection of metastatic disease in the liver," the clinicians point out.
The results of the COIN study, they conclude, "should prompt a review of present guidance from the UK National Institute of Health and Clinical Excellence, which recommends that patients with liver-only metastatic disease should receive an oxaliplatin-based chemotherapy doublet with cetuximab, and that irinotecan should be reserved for patients for whom oxaliplatin is deemed to be contraindicated and not tolerated."
Treatment Holidays An Option for Some
A second part of the COIN trial, led by Richard A. Adams, MD, FRCP, from the School of Medicine, Cardiff University, United Kingdom, and colleagues, assessed the risks and benefits of shortening the duration of initial chemotherapy from 6 months to 12 weeks (restarting therapy on disease progression). This was accomplished by comparing standard continuous chemotherapy with the same chemotherapy given with planned treatment holidays.
The results showed that intermittent chemotherapy did not increase or significantly decrease survival. Median survival in the intention-to-treat population was 15.8 months with continuous treatment and 14.4 months with intermittent treatment. In the per protocol population, median survival was 19.6 months and 18.0 months, respectively. "The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary [of 1.162]," the investigators note.
"Subgroup analyses," they report, "suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break."
Specifically, they found that a raised platelet count, defined as 400,000/μL or higher, was associated with poor survival with intermittent chemotherapy. The HR for comparison of continuous vs intermittent treatment in patients with a normal platelet count was 0.96 (95% CI, 0.80 - 1.15; P = .66) vs 1.54 (95% CI, 1.17 - 2.03; P = .0018) in patients with a raised platelet count (P = .0027 for interaction).
"There seems to be a large subpopulation of patients for whom intermittent therapy provides similar survival benefit” the authors write, adding that the results of this trial provide a basis for discussion of options between patients and clinicians.
In their comment, Dr. Hewish and Dr. Cunningham write that, "unsurprisingly," intermittent chemotherapy was associated with fewer chemotherapy-related side effects such as fatigue, nausea or vomiting, "but disappointingly," no improvement in global quality of life, and a significant increase in reporting of pain.
"Thus, we would urge caution in stopping treatment after 3 months. If clinicians and their patients choose this approach, we would recommend careful selection of patients and close monitoring for progressive disease so that chemotherapy can be reintroduced before the therapeutic window is closed," they write.
The COIN trial was supported by Cancer Research UK, Cancer Research Wales, UK Medical Research Council, and Merck KGgA. Dr. Maughan, Dr. Adams, and other study authors have disclosed financial relationships with Roche and Merck Serono as well as Amgen, AstraZeneca, and Dako Limited. One author is an employee of the UK Medical Research Council. Dr. Cunningham has received research funding from Amgen, Roche, Merck Sharpe and Dohme, Sanofi-Aventis, and Merck Serono. Dr. Hewish has disclosed no relevant financial relationships.
Lancet. Published online June 4, 2011. Maughan article
Lancet Oncology. Published online June 4, 2011. Adams et al article
Lancet. Published online June 4, 2011. Hewish and Cunningham comment
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