November 25, 2008 — A large phase 3 trial has shown that the oral drug gefitinib (Iressa, AstraZeneca) is just as effective as but has fewer adverse effects than intravenous docetaxel (Taxotere, Sanofi Aventis) when used in the second-line treatment of patients with non-small-cell lung cancer (NSCLC).
The oral drug presents an "alternative treatment option" and represents an "important shift in the treatment paradigm for this disease," say the authors of a study published in the November 22 issue of the Lancet.
"Based on our findings, I'm hopeful that gefitinib can return as a treatment for lung cancer is the United States," said lead author Edward Kim, MD, assistant professor of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center, in Houston, in a statement.
Gefitinib fell out of use in the United States in 2005 after a large study showed no significant improvement in survival, compared with placebo, in patients with NSCLC. The drug continues to be available for patients who were already taking it and were judged to be doing well on it, but the US Food and Drug Association (FDA) ruled that no new patients were to be given the drug.
However, gefitinib continued to be used elsewhere in the world, and the current study enrolled patients from 24 countries (Europe, Asia, and the Americas, but not the United States). Known as INTEREST (Iressa in NSCLC Trial Evaluating REsponse and Survival vs Taxotere), the study was mandated by the FDA and sponsored by AstraZeneca.
A total of 1466 patients were enrolled, and 1433 were evaluable. All had locally advanced or metastatic disease and had previously been treated with at least 1 platinum-containing regimen. Patients were randomized to receive either gefitinib 250 mg/day every day, or docetaxel 75 mg/m2 in a 1-hour infusion every 3 weeks.
The results were similar for the 2 groups, the researchers report. Median overall survival was 7.6 months in the gefitinib group and 8.0 months in the docetaxel group, and 1-year survival was 32% and 34%, respectively. Median progression-free survival was 2.2 months with gefitinib and 2.7 months with docetaxel, and progression-free survival at 6 months was 19% vs 18%, respectively. Objective response rates were also similar: 9.1% with gefitinib and 7.6% with docetaxel.
However, gefitinib was associated with lower rates of treatment-related adverse events than docetaxel, and the 2 drugs showed a different pattern of adverse effects. The most common adverse effects were rash or acne and diarrhea with gefitinib, and hematological toxicity, asthenic disorders, and alopecia with docetaxel.
Treatment-Related Adverse Events| Adverse Events | Gefitinib | Docetaxel |
| Overall | 72% | 82% |
| Serious | 4% | 18% |
| Leading to discontinuation of therapy | 4% | 11% |
| Grade 3 or 4 | 9% | 41% |
| Leading to death | 1% | 2% |
In addition, significantly more patients on gefitinib had a sustained and clinically relevant improvement in quality of life, as assessed by Functional Assessment of Cancer Therapy-Lung questionnaires.
"The clinical management of advanced NSCLC remains challenging, but an oral agent that has similar efficacy, has a more favorable tolerability profile, and results in a better quality of life than intravenous chemotherapy is an important shift in the treatment paradigm of this disease and presents an alternative option for patients," Dr. Kim and colleagues conclude.
Previous Trial Involved Predominantly Refractory Patients
In their paper, Dr. Kim and colleagues refer back to the study that prompted the FDA to restrict the use of gefitinib. That study, known as ISEL (Iressa Survival Evaluation in Lung Cancer), involved 1692 patients randomized to gefitinib or placebo (Lancet 2005;366:1527-1537). It showed no significant improvement in survival from the drug (median overall survival, 5.6 months with gefitinib vs 5.1 months with placebo).
However, Dr. Kim and colleagues point out that most of the participants (90%) in that study were refractory patients unsuitable for further chemotherapy, and these patients are known to have a poor prognosis. This may partly explain the lack of a significant effect on survival, they suggest. In contrast, the current study had only 58% of participants in this category.
Previous Findings Overturns
The current study overturns several previous findings related to biomarkers and patient characteristics influencing outcomes.
Gefitinib acts as an inhibitor of epidermal growth-factor receptor (EGFR), and previous studies with other agents in this class have suggested that a better response to these drugs is seen in patients whose tumors have high EGFR gene-copy numbers. However, the current study did not find this to be the case.
An unexpected finding from the INTEREST study is that patients with high EBFR gene-copy numbers showed no difference in survival between gefitinib and docetaxel, Dr. Kim and colleagues report.
In addition, clinical factors, such as never having smoked, being female, being of Asian origin, and having adenocarcinoma histology, have also been reported to predict a better response to EGFR inhibitors, and also to predict a better overall patient outcome. Another unexpected finding from the INTEREST trial is that patients with these characteristics had longer survival in both the gefitinib and the docetaxel groups, the researchers note. This contrasts with previous findings suggesting that docetaxel produces similar survival in all patients.
"The implication is that these groupings are prognostic factors unrelated to treatment or nonspecific factors that predict increased sensitivity to quite different interventions," comment the authors of an accompanying editorial, Michael Cullen, MD, and Nicholas Thatcher, FRCP, from the Birmingham University Hospital Cancer Centre in the United Kingdom. But the finding that patients with high EGFR gene-copy numbers do not have a better response to gefitinib is "even more disconcerting," say the editorialists.
One of the important lessons to learn from this experience, they write, is "not to jump to conclusions about specific predictive factors only because they fit the scientific foundations that underpin the design and development of new targeted agents with the fashionable goal of tailoring treatment to the individual patient and the tumor's biology."
Dr. Kim and several coauthors report having served on the advisory board and receiving consultancy fees from AstraZeneca as well as several other companies; 4 of the coauthors are employees of AstraZeneca. Both of the editorialists report having received honoraria from AstraZeneca.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου