November 3, 2011 — Adding the targeted agent cetuximab (Erbitux) to chemotherapy significantly improves overall survival in some patients with nonsmall-cell lung cancer (NSCLC), and an approach to identifying the patients who will benefit has now been found.
The finding comes from an analysis of the FLEX study, published online November 4 in the Lancet Oncology. It was presented earlier this year at the World Conference on Lung Cancer, and reported at the time by Medscape Medical News.
The analysis shows that NSCLC patients who have a high expression of epidermal growth-factor receptor (EGFR) in their tumors have the best response when cetuximab (a monoclonal antibody directed against EGFR) is added to chemotherapy. This high EGFR expression was found in 31% of patients who were tested.
"This is the first predictive biomarker for overall survival in advanced NSCLC," lead author Robert Pinker, MD, from the Vienna Medical University in Austria, reported at the meeting.
Patients with this high EGFR expression who were treated with the combination had a median overall survival of 12 months, compared with 9.6 months for those treated with chemotherapy alone (hazard ratio [HR], 0.73; P = .011), "with no meaningful increase in side effects," the researchers report.
One-year survival with the combination was 50%, compared with 37% with chemotherapy alone; 2-year survival was 24% and 15%, respectively.
"I believe that this is such an improvement in survival — one that we have never seen before — that this [treatment] should be available to our patients," Dr. Pinker said at the meeting.
However, other lung cancer experts at the meeting were cautious in their reactions to the finding, emphasizing that it needs to be validated prospectively before being incorporated into clinical practice.
These sentiments are echoed in a comment accompanying the publication of the findings.
This seems to be "an encouraging step toward personalized medicine for patient subgroups with advanced lung cancer who will potentially receive cetuximab," write editorialists Fred Hirsch, MD, from the University of Colorado Cancer Center, Aurora, and Roy Herbst, MD, from the Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut.
However, they emphasize that "further prospective validation is essential."
This is already planned in a large ongoing prospective phase 3 study (SWOG 0819), which is comparing cetuximab plus chemotherapy with chemotherapy alone.
Reanalysis of Results
The results of the FLEX study were first presented at the 2008 annual meeting of the American Society of Clinical Oncology, and subsequently published in the Lancet (2009;373:1525-1531). The trial involved 1125 chemotherapy-naive adult patients with advanced EGFR-expressing stage 3B or stage 4 NSCLC, who were randomly assigned to chemotherapy plus cetuximab or chemotherapy alone. The results showed a small but significant improvement in median overall survival with the combination (11.3 vs 10.1 months; HR, 0.87; P = .04).
However, progression-free survival was similar in both groups (median, 4.8 months).
When these results were first presented, discussant Thomas J. Lynch, MD, professor of medicine at Harvard University in Boston, Massachusetts, wondered about the "marginal" improvement in overall survival. He pointed out that it would cost about $62,000 to add cetuximab to the chemotherapy regimen. He questioned whether a "median of 1.4 months is worth it, especially if we don't know if the quality of life has been improved."
"If we can bring survival up to 2.5 months, then it would be in line with other therapies," Dr. Lynch said at the time.
Since the original presentation of the data, the FLEX investigators have been looking for a biomarker to predict which patients will respond best to the combination of cetuximab plus chemotherapy, Dr. Pinker explained.
Now they report having found one — high EGFR expression. In the subgroup of patients with high EGFR expression, the difference in overall survival between those treated with cetuximab plus chemotherapy and those treated with chemotherapy alone is nearly exactly what Dr. Lynch asked for at that meeting (12.0 vs 9.6 months; a difference of 2.4 months).
Maybe Other Biomarkers?
The biomarker was found during the immunochemistry assessment of tumor EGFR expression in 1121 of the 1125 patients participating in the FLEX study. The researchers assigned an immunohistochemistry score (H score) and determined a cutoff point (200 or more on a scale of 0 to 300) for high EGFR rates. The immunohistochemistry assessment was carried out prospectively, but the determination of the cutoff point was retrospective, based on response rates.
It is this retrospective part of the analysis that is causing concern for the experts who say that prospective validation of the findings is needed. "Even if the H score system was prespecified in the FLEX study, the cutoff value of 200 for high expression versus low expression was not," the editorialists note.
"The H score assessment seems to help select a group of patients that may particularly benefit," the editorialists note. However, they also wonder whether other approaches — such as automated assessment of EGFR protein expression (i.e., AQUA assessment) or other digital scoring systems (i.e., ACIS < APERIO or LECIA) — can improve the selection of patients for treatment with cetuximab and similar drugs.
The FLEX study was supported by Merck KGaA, the manufacturers of cetuximab. Dr. Pinker reports receiving consulting fees, honoraria, and travel to meetings from Merck Serono and Merck KGaA. Three of his coauthors are employees of Merck KGaA. Dr. Hirsch reports serving as a consultant to Merck Serono, Bristol-Myers Squibb, Lilly-ImClone, Pfizer, OSI/Roche/Genentech, Celgene, and Boehringer Ingelheim; and is coinventor on a patent for predicting clinical outcome in response to EGFR inhibitors in cancer licensed to Abbott. Dr. Herbst reports serving as a consultant to Bristol-Myers Squibb and OSI/Roche/Genentech.
Lancet Oncol. Published online November 4, 2011. Abstract, Comment
The finding comes from an analysis of the FLEX study, published online November 4 in the Lancet Oncology. It was presented earlier this year at the World Conference on Lung Cancer, and reported at the time by Medscape Medical News.
The analysis shows that NSCLC patients who have a high expression of epidermal growth-factor receptor (EGFR) in their tumors have the best response when cetuximab (a monoclonal antibody directed against EGFR) is added to chemotherapy. This high EGFR expression was found in 31% of patients who were tested.
"This is the first predictive biomarker for overall survival in advanced NSCLC," lead author Robert Pinker, MD, from the Vienna Medical University in Austria, reported at the meeting.
Patients with this high EGFR expression who were treated with the combination had a median overall survival of 12 months, compared with 9.6 months for those treated with chemotherapy alone (hazard ratio [HR], 0.73; P = .011), "with no meaningful increase in side effects," the researchers report.
One-year survival with the combination was 50%, compared with 37% with chemotherapy alone; 2-year survival was 24% and 15%, respectively.
"I believe that this is such an improvement in survival — one that we have never seen before — that this [treatment] should be available to our patients," Dr. Pinker said at the meeting.
However, other lung cancer experts at the meeting were cautious in their reactions to the finding, emphasizing that it needs to be validated prospectively before being incorporated into clinical practice.
These sentiments are echoed in a comment accompanying the publication of the findings.
This seems to be "an encouraging step toward personalized medicine for patient subgroups with advanced lung cancer who will potentially receive cetuximab," write editorialists Fred Hirsch, MD, from the University of Colorado Cancer Center, Aurora, and Roy Herbst, MD, from the Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut.
However, they emphasize that "further prospective validation is essential."
This is already planned in a large ongoing prospective phase 3 study (SWOG 0819), which is comparing cetuximab plus chemotherapy with chemotherapy alone.
Reanalysis of Results
The results of the FLEX study were first presented at the 2008 annual meeting of the American Society of Clinical Oncology, and subsequently published in the Lancet (2009;373:1525-1531). The trial involved 1125 chemotherapy-naive adult patients with advanced EGFR-expressing stage 3B or stage 4 NSCLC, who were randomly assigned to chemotherapy plus cetuximab or chemotherapy alone. The results showed a small but significant improvement in median overall survival with the combination (11.3 vs 10.1 months; HR, 0.87; P = .04).
However, progression-free survival was similar in both groups (median, 4.8 months).
When these results were first presented, discussant Thomas J. Lynch, MD, professor of medicine at Harvard University in Boston, Massachusetts, wondered about the "marginal" improvement in overall survival. He pointed out that it would cost about $62,000 to add cetuximab to the chemotherapy regimen. He questioned whether a "median of 1.4 months is worth it, especially if we don't know if the quality of life has been improved."
"If we can bring survival up to 2.5 months, then it would be in line with other therapies," Dr. Lynch said at the time.
Since the original presentation of the data, the FLEX investigators have been looking for a biomarker to predict which patients will respond best to the combination of cetuximab plus chemotherapy, Dr. Pinker explained.
Now they report having found one — high EGFR expression. In the subgroup of patients with high EGFR expression, the difference in overall survival between those treated with cetuximab plus chemotherapy and those treated with chemotherapy alone is nearly exactly what Dr. Lynch asked for at that meeting (12.0 vs 9.6 months; a difference of 2.4 months).
Maybe Other Biomarkers?
The biomarker was found during the immunochemistry assessment of tumor EGFR expression in 1121 of the 1125 patients participating in the FLEX study. The researchers assigned an immunohistochemistry score (H score) and determined a cutoff point (200 or more on a scale of 0 to 300) for high EGFR rates. The immunohistochemistry assessment was carried out prospectively, but the determination of the cutoff point was retrospective, based on response rates.
It is this retrospective part of the analysis that is causing concern for the experts who say that prospective validation of the findings is needed. "Even if the H score system was prespecified in the FLEX study, the cutoff value of 200 for high expression versus low expression was not," the editorialists note.
"The H score assessment seems to help select a group of patients that may particularly benefit," the editorialists note. However, they also wonder whether other approaches — such as automated assessment of EGFR protein expression (i.e., AQUA assessment) or other digital scoring systems (i.e., ACIS < APERIO or LECIA) — can improve the selection of patients for treatment with cetuximab and similar drugs.
The FLEX study was supported by Merck KGaA, the manufacturers of cetuximab. Dr. Pinker reports receiving consulting fees, honoraria, and travel to meetings from Merck Serono and Merck KGaA. Three of his coauthors are employees of Merck KGaA. Dr. Hirsch reports serving as a consultant to Merck Serono, Bristol-Myers Squibb, Lilly-ImClone, Pfizer, OSI/Roche/Genentech, Celgene, and Boehringer Ingelheim; and is coinventor on a patent for predicting clinical outcome in response to EGFR inhibitors in cancer licensed to Abbott. Dr. Herbst reports serving as a consultant to Bristol-Myers Squibb and OSI/Roche/Genentech.
Lancet Oncol. Published online November 4, 2011. Abstract, Comment
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