This was posted on the ASCO site:
Efficacy of Erlotinib [Tarceva] Explored in Three Studies
A late-breaking abstract on the role of the epidermal growth factor (EGF) receptor inhibitor erlotinib in non-small lung cancer treatment appeared to contradict the results of two studies of the same drug presented in the Oral Abstract Presentation Session, Lung Cancer II.
Frances A. Shepherd, MD, of Princess Margaret Hospital, presented positive results of a phase III randomized placebo-controlled trial of erlotinib when used alone to treat patients with stage IIIB/IV non-small cell lung cancer (abstract #7022). After her presentation, two other phase III studies in which erlotinib was combined with chemotherapy regimens were reported to have shown no benefit to adding the EGF receptor inhibitor to two standard treatment protocols for non-small cell lung cancer (abstracts #7010 and #7011).
Dr. Shepherd?s study is the first randomized trial to confirm that erlotinib can prolong survival for patients with non-small cell lung cancer for whom first or second-line treatment has failed. ?Treatment with erlotinib was associated with longer overall survival, longer progression-free survival, improved lung cancer-related symptoms, and improved quality of life,? she said.
A total of 731 patients were entered into the study; half had received two prior regimens of chemotherapy. The overall survival of patients who received erlotinib was 6.7 months, compared with 4.7 months for patients who received placebo (p = 0.001). The progression-free survival associated with erlotinib was 2.23 months, compared with 1.84 months for placebo (p < 0.001). Mutational analysis of biopsies of tissue from patients is currently underway. Dr. Shepherd also noted that during the first two to three months of the study, the results of the two arms began to diverge and that more study is needed to better understand these results.
Audience members posed many questions for Dr. Shepherd about the study?s design and the specifics of patient selection based on EGFR mutation or overexpression, and she agreed there is a need to begin more randomized studies to better understand and enhance the clinical use of erlotinib.
?Obviously, the last two or three years have represented a steep learning curve. I think we need to look at moving this treatment into earlier stages of disease, looking at it as a single maintenance agent after failure, selecting subgroups of patients who will most benefit from this, and examining its role as a first-line treatment for previously untreated patients,? she said. ?I expect a very rich next five years in terms of answering these questions. Right now, we clearly don?t have all the final answers.?
The two other studies that evaluated the use of erlotinib with chemotherapy were presented by Ulrich Gatzemeier, MD, of Hospital Grosshansdorf, and Roy S. Herbst, MD, PhD, of M.D. Anderson Cancer Center. These two studies shared a protocol design strategy and produced similar results. Both studies enrolled patients with stage IIB/IV non-small cell lung cancer. Dr. Gatzemeier, lead investigator of the TALENT study, concluded that the addition of erlotinib to a regimen of gemcitabine and cisplatin did not result in increased survival or delay in symptomatic deterioration when compared with the same chemotherapy regimen and placebo.
?These results are in marked contrast to the significant survival benefit seen in second and third-line erlotinib monotherapy,? said Dr. Gatzemeier. He speculated that ?untargeted targeted therapy? (patient selection), or an antagonistic effect between erlotinib and the cytotoxic agents could be potential reasons for failure to see positive results from adding erlotinib to chemotherapy regimens.
Dr. Herbst, lead investigator of the TRIBUTE study, presented results of a similarly designed study, in which a regimen of carboplatin and paclitaxel plus erlotinib was compared with the same chemotherapy regimen and a placebo. The results of that study similar to those presented by Dr. Gatzemeier, with a twist?non-smokers appeared to have better results with erlotinib compared with current or former smokers. Like Dr. Gatzemeier, he recommended that more studies be done to tease out the subtle differences among all the studies, and better delineate the critical task of appropriately selecting patients for erlotinib therapy.
Also noted in the study presented by Dr. Herbst was an early increase in survival rates at one point that led study investigators to drop a continuous therapy option for patients; patients receiving erlotinib appeared to do worse during the first six months of therapy, then show improvement.
?The lesson here may be the same that we had to learn with tamoxifen,? Dr. Herbst said. He commented that it took investigators time to determine the appropriate stage at which to administer tamoxifen to see its best potential effect, and he added that use of erlotinib may present future study investigators with the same type of challenge.
All three presenters agreed with discussant Fred R. Hirsch, MD, PhD, of the University of Colorado, who said that patient selection for erlotinib therapy is a critical component of clinical successful patient outcome.
?These studies raise questions we need to answer,? said Dr. Hirsch. ?Is erlotinib better than second-line chemotherapy? Will this survival advantage persist in early stage disease? When should erlotinib be given vis-à-vis chemotherapy?before, immediately after, or at relapse? Will this survival benefit extend to other EGF receptor inhibitors??
Probing to determine why there is no survival benefit when erlotinib is combined with chemotherapy, Dr. Hirsch noted that only a small minority of patients may benefit from the agent and that patient selection is critical. ?It may be that there is a possible synergy in some patients and antagonism in others,? he said. ?And we don?t know whether we?re giving this agent in the wrong sequence or whether chemotherapy affects the sensitivity of the tyrosine kinase inhibitors.?
Dr. Hirsch outlined a series of proposed steps that would help clinicians select patients who would most benefit from agents like erlotinib, including careful examination of clinical features and histopathologic characteristics, use of fluorescent in situ hybridization analysis to specify gene amplification, reviewing DNA mutations, and using gene arrays for genetic profiles and proteomics for protein profiles.
?We?ve all seen the data from The New England Journal of Medicine and the Science issues on selecting for EGFR mutations and sensitivity,? said Dr. Hirsch. ?But there?s more to the story of developing biomarkers for resistant and sensitive cell lines.? While important work is being done in this area, predicting clinical responses to EGF receptor therapy is still very much underway. |
