Medical Tribune September 2009 P8
David Brill
A novel lung cancer therapy could be of particular benefit to Asian patients, results of a recent trial suggest.
The international FLEX* study reported that adding the monoclonal antibody cetuximab to chemotherapy prolonged survival of advanced lung cancer patients from 10.1 months to 11.3 months.
Further analysis revealed, however, that Asians treated with the drug survived for a median of 19.5 months, whereas non-Asians survived only 9.6 months.
The randomized trial involved 1,125 patients – 121 of whom were from Asian centers (predominantly in Hong Kong, Taiwan, Singapore and South Korea). [Lancet 2009;373(9674):1525-31]
There are several possible explanations for the ethnic discrepancy but also questions that remain unanswered, according to Professor Kenneth O’Byrne, one of the FLEX investigators, who spoke to Medical Tribune during the recent ‘Best of ASCO’ conference in Singapore.
Asian lung cancer patients are more likely to be women, non-smokers and have adenocarcinomas than non-Asian patients – all groups which tend to survive longer, he said. Moreover, epidermal growth factor receptor (EGFR) mutations are more common among Asians – a characteristic which not only improves prognosis in itself, but also makes patients eligible for first-line EGFR tyrosine kinase inhibitors which can further improve outcomes.
“So there is a combination of reasons as to why but it’s not just that – there may be some intrinsic sensitivity to treatment here that’s not present in the West,” said O’Byrne, adding that further study is needed to better understand these biological similarities and differences.
Cetuximab is presently licensed for use only in colorectal and head and neck cancers. An application for lung cancer licensing was recently rejected by the European Medicines Agency (EMEA), but is currently under appeal from the manufacturer, Merck Serono.
The verdict has also come as a surprise to many experts in the field and will face “a strong challenge,” said O’Byrne, a consultant medical oncologist at St. James’s Hospital and a clinical professor at Trinity College, Dublin, Ireland. The FLEX trial was published before the EMEA decision, with investigators concluding that cetuximab can be considered as standard first-line therapy for all patients with advanced non-small cell lung cancer (NSCLC).
“Cetuximab is the first drug to show a survival benefit in all histological types: adenocarcinoma, squamous carcinoma – across the board. Secondly, the toxicities are all very predictable – we know how to manage them and they’re straightforward. Thirdly, not only was the FLEX trial positive but when you take in all the other trials together … as a collective they show a positive result,” said O’Byrne. He added that US National Comprehensive Cancer Network guidelines already recommend that the drug be considered for lung cancer patients, and that many oncologists in Europe have begun off-label usage.
O’Byrne acknowledged that cetuximab therapy would be costly, but noted that around half of patients display a strong predictive marker in the form of a skin rash, which develops after one round of chemotherapy. These patients tend to survive for around an extra 5 months, which may justify the cost, he said. More work is needed to confirm whether cetuximab offers any benefit for those who do not develop a rash, but it appears likely that therapy could be discontinued after one cycle in these patients, he said.
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*FLEX: First-Line Erbitux in Lung Cancer
Showing posts with label lung cancer. Show all posts
Showing posts with label lung cancer. Show all posts
Tuesday, October 20, 2009
Friday, September 25, 2009
Urine test could allow for lung cancer risk prediction
Medical Tribune August 2009 P12
David Brill
David Brill
A simple urine test could one day reveal which smokers are at greatest risk of developing lung cancer, according to a team of Singaporean, Chinese and American scientists.
The group recently reported the first link between elevation of certain urinary metabolites – total NNAL* – and increased lung cancer risk in humans. Cigarette smokers with the highest total NNAL levels were over twice as likely to develop lung cancer.
A commercially available test remains at least 5 years off, but the identification of these urinary biomarkers raises “an exciting possibility,” say the researchers.
“Such a test would enable doctors to screen more frequently for lung cancer in smokers with high levels of biomarkers, and provide a strong incentive for these smokers to quit smoking,” said study authors Associate Professor Yuan Jian-Min of the University of Minnesota, US, and Associate Professor Koh Woon-Puay of the National University of Singapore, in a joint statement to Medical Tribune.
“With the identification of new biomarkers, we could ultimately develop an assay that simultaneously quantifies a panel of tobacco carcinogens or their metabolites to best predict the risk of lung cancer for an individual smoker,” they said.
The work goes some way towards explaining why some smokers develop lung cancer while others do not. With over 60 established carcinogens in cigarette smoke, it may be that individual differences in the uptake and metabolism of particular chemicals play an important role in the development of cancer, the authors say.
One such carcinogen, NNK**, has been strongly linked to lung cancer but an epidemiological link had only been shown in animal studies.
Yuan, Koh and colleagues instead investigated levels of NNAL – a metabolite of NNK – in a nested case-control study using data on 63,257 men and women from the Singapore Chinese Health Study, and 18,244 men from the Shanghai Cohort Study. They identified 246 cases of incident lung cancer, and 245 matched controls. [Cancer Res 2009;69:2990-5]
The odds ratio of developing lung cancer was 2.11 for smokers who were in the highest tertile of urinary total NNAL before cancer diagnosis, compared to those in the lowest tertile (95% CI 1.25 – 3.54; P for trend = 0.005).
Combination with cotinine, a nicotine metabolite, further increased the predictive value of NNAL: the odds ratio for developing cancer was 8.47 for smokers in the highest tertile for both markers, compared to those in the lowest tertile (95% CI 3.69 – 19.46; P for trend – 0.005).
“Biomarkers for prediction of cancer risk are useful as proxy measures of outcome in interventional studies. Nevertheless, for smokers, the best intervention for the reduction of lung cancer risk is still to quit smoking,” added Yuan and Koh.
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* NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Total NNAL is the sum of NNAL and its glucuronides.
**NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
The group recently reported the first link between elevation of certain urinary metabolites – total NNAL* – and increased lung cancer risk in humans. Cigarette smokers with the highest total NNAL levels were over twice as likely to develop lung cancer.
A commercially available test remains at least 5 years off, but the identification of these urinary biomarkers raises “an exciting possibility,” say the researchers.
“Such a test would enable doctors to screen more frequently for lung cancer in smokers with high levels of biomarkers, and provide a strong incentive for these smokers to quit smoking,” said study authors Associate Professor Yuan Jian-Min of the University of Minnesota, US, and Associate Professor Koh Woon-Puay of the National University of Singapore, in a joint statement to Medical Tribune.
“With the identification of new biomarkers, we could ultimately develop an assay that simultaneously quantifies a panel of tobacco carcinogens or their metabolites to best predict the risk of lung cancer for an individual smoker,” they said.
The work goes some way towards explaining why some smokers develop lung cancer while others do not. With over 60 established carcinogens in cigarette smoke, it may be that individual differences in the uptake and metabolism of particular chemicals play an important role in the development of cancer, the authors say.
One such carcinogen, NNK**, has been strongly linked to lung cancer but an epidemiological link had only been shown in animal studies.
Yuan, Koh and colleagues instead investigated levels of NNAL – a metabolite of NNK – in a nested case-control study using data on 63,257 men and women from the Singapore Chinese Health Study, and 18,244 men from the Shanghai Cohort Study. They identified 246 cases of incident lung cancer, and 245 matched controls. [Cancer Res 2009;69:2990-5]
The odds ratio of developing lung cancer was 2.11 for smokers who were in the highest tertile of urinary total NNAL before cancer diagnosis, compared to those in the lowest tertile (95% CI 1.25 – 3.54; P for trend = 0.005).
Combination with cotinine, a nicotine metabolite, further increased the predictive value of NNAL: the odds ratio for developing cancer was 8.47 for smokers in the highest tertile for both markers, compared to those in the lowest tertile (95% CI 3.69 – 19.46; P for trend – 0.005).
“Biomarkers for prediction of cancer risk are useful as proxy measures of outcome in interventional studies. Nevertheless, for smokers, the best intervention for the reduction of lung cancer risk is still to quit smoking,” added Yuan and Koh.
------------------------------------------------------------------------------------------------
* NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Total NNAL is the sum of NNAL and its glucuronides.
**NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Monday, March 16, 2009
Gefitinib reduces toxicity for advanced lung cancer patients
Medical Tribune January 2009 P11
David Brill
Gefitinib is a viable second-line alternative to chemotherapy for advanced non-small-cell lung cancer, offering similar survival rates with fewer side effects, a large-scale international study has shown.
The drug represents “an important shift in the treatment paradigm for this disease,” the authors of the INTEREST* trial reported in The Lancet. [2008 Nov 22;372(9652):1809-18]
Patients who took oral gefitinib also had improved quality of life compared to those who received intravenous infusions of docetaxel.
Asian patients, women, non-smokers and patients with adenocarcinoma all had longer survival with gefitinib – echoing the findings of previous trials which have shown the drug to be of particular benefit in these subgroups. Unexpectedly, however, INTEREST also found similar survival patterns with docetaxel, suggesting that these may be generally-applicable prognostic factors unrelated to the specific treatment.
Gefitinib is not currently approved for routine use by the US FDA. However in some Asian countires it is authorized for second-line use. For example in Singapore patients are typically given a choice between second-line treatment options in the event that initial chemotherapy is unsuccessful.
“Should the patient go on to further chemotherapy or should they go on to other drugs like gefitinib? This study confirmed that gefitinib is just as good as chemotherapy but may have fewer side effects,” said Dr. Toh Chee Keong, a consultant medical oncologist at the National Cancer Centre Singapore (NCCS).
Given the choice, most patients prefer an oral drug to chemotherapy but the higher cost of gefitinib can sometimes be a prohibitive factor, he said.
It remains unclear exactly who will benefit most from each treatment and why, he added, but noted that in his experience a non-smoking status is the most powerful predictor of a positive response to gefitinib.
In contrast to previous trials, neither epidermal growth factor receptor (EGFR) gene copy-number nor EGFR protein expression predicted survival with gefitinib in INTEREST.
The study is one of the few phase III clinical trials to directly compare the efficacy of docetaxel with an EGFR tyrosine kinase inhibitor. The analysis included 1,433 patients who had not responded to previous chemotherapy, recruited from 149 centers in 24 countries between March 1 2004 and February 17 2006.
The most frequent side effects of gefitinib were acne, rash and diarrhea. Just 4 percent of patients taking the drug experienced serious adverse events – a similar rate to that seen at NCCS, where Toh estimates that “less than 5 percent” of patients on gefitinib develop side effects to the point where they have to stop therapy.
For docetaxel the most common side effects in the trial were hematological toxic effects, hair loss and weakness. Serious adverse events occurred in 18 percent of patients in this group.
The non-inferiority of gefitinib was demonstrated by the median overall survival, which was 7.7 months in patients taking the drug compared to 8 months for those taking docetaxel. One-year survival rates were 32 and 34 percent in the respective groups.
Gefitinib patients were twice as likely to have a “sustained and clinically relevant improvement in quality of life,” as measured by the Functional Assessment of Cancer Therapy-Lung score (odds ratio 1.99; P<0.0001).>
The drug represents “an important shift in the treatment paradigm for this disease,” the authors of the INTEREST* trial reported in The Lancet. [2008 Nov 22;372(9652):1809-18]
Patients who took oral gefitinib also had improved quality of life compared to those who received intravenous infusions of docetaxel.
Asian patients, women, non-smokers and patients with adenocarcinoma all had longer survival with gefitinib – echoing the findings of previous trials which have shown the drug to be of particular benefit in these subgroups. Unexpectedly, however, INTEREST also found similar survival patterns with docetaxel, suggesting that these may be generally-applicable prognostic factors unrelated to the specific treatment.
Gefitinib is not currently approved for routine use by the US FDA. However in some Asian countires it is authorized for second-line use. For example in Singapore patients are typically given a choice between second-line treatment options in the event that initial chemotherapy is unsuccessful.
“Should the patient go on to further chemotherapy or should they go on to other drugs like gefitinib? This study confirmed that gefitinib is just as good as chemotherapy but may have fewer side effects,” said Dr. Toh Chee Keong, a consultant medical oncologist at the National Cancer Centre Singapore (NCCS).
Given the choice, most patients prefer an oral drug to chemotherapy but the higher cost of gefitinib can sometimes be a prohibitive factor, he said.
It remains unclear exactly who will benefit most from each treatment and why, he added, but noted that in his experience a non-smoking status is the most powerful predictor of a positive response to gefitinib.
In contrast to previous trials, neither epidermal growth factor receptor (EGFR) gene copy-number nor EGFR protein expression predicted survival with gefitinib in INTEREST.
The study is one of the few phase III clinical trials to directly compare the efficacy of docetaxel with an EGFR tyrosine kinase inhibitor. The analysis included 1,433 patients who had not responded to previous chemotherapy, recruited from 149 centers in 24 countries between March 1 2004 and February 17 2006.
The most frequent side effects of gefitinib were acne, rash and diarrhea. Just 4 percent of patients taking the drug experienced serious adverse events – a similar rate to that seen at NCCS, where Toh estimates that “less than 5 percent” of patients on gefitinib develop side effects to the point where they have to stop therapy.
For docetaxel the most common side effects in the trial were hematological toxic effects, hair loss and weakness. Serious adverse events occurred in 18 percent of patients in this group.
The non-inferiority of gefitinib was demonstrated by the median overall survival, which was 7.7 months in patients taking the drug compared to 8 months for those taking docetaxel. One-year survival rates were 32 and 34 percent in the respective groups.
Gefitinib patients were twice as likely to have a “sustained and clinically relevant improvement in quality of life,” as measured by the Functional Assessment of Cancer Therapy-Lung score (odds ratio 1.99; P<0.0001).>
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*Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere
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