Part 1. Gefitinib and Erlotinib for Non-Small Cell Lung Cancer (continued)

Discussion

The use of epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors in non-small cell lung cancer (NSCLC) is a rapidly evolving field; much of the data addressing the key questions of this report has become available since the key questions were formulated just over a year ago. In this section we summarize the findings of the review in terms of answering the key questions initially posed, and then discuss the clinical and research implications of these data.

1. In patients with locally advanced or metastatic non-small cell lung cancer, what are the effects of gefitinib and erlotinib compared to platinum-based chemotherapy regimens on survival, disease-free survival, and quality of life?

There is good evidence from four randomized controlled trials (RCTs) that addition of either gefitinib or erlotinib to combination chemotherapy does not improve survival or disease-free survival for patients with previously untreated, advanced non-small cell lung cancer. While quality of life results have not been published from any of the four randomized studies, it is unlikely that quality of life would be improved by the addition of an agent known to induce toxicity without concomitant improvement in the quantity of life. Based on an unpublished subgroup analysis, one study suggested that non-smokers may benefit from the addition of erlotinib to chemotherapy. However, this is not currently supported by completed prospective studies.

First-line treatment alone (i.e., not in combination with traditional cytotoxic chemotherapy) has been studied only in phase II (uncontrolled) trials; each of these studies has important limitations such as small number of patients or limited generalizability due to special populations (elderly, poor performance status, BAC histology). Few complete responses were observed in these studies, and the rates of partial responses observed are no higher than those observed in studies using traditional chemotherapy. These data, although limited in terms of quality and generalizability, do not suggest that first line treatment with EGFR-TK inhibitors in unselected patients is beneficial compared to traditional chemotherapy.

2. In patients with locally advanced or metastatic non-small cell lung cancer who have failed to respond to platinum-based chemotherapy, what are the effects of gefitinib and erlotinib compared to docetaxel plus supportive care or best supportive care alone on survival, disease-free survival, and quality of life?

A single RCT of gefitinib versus placebo in patients with previously treated (second- or third-line) advanced NSCLC was reported through a press release not to show a survival benefit for gefitinib.^25,26 While the hazard ratio of 0.89 favored gefitinib, this was not statistically significant (p = 0.11). The effect of gefitinib on progression-free survival or quality of life has not been reported. A single RCT of erlotinib versus placebo in a similar clinical setting did show a survival benefit that was statistically significant with a hazard ratio of 0.73 (p = 0.0001).^24,25 Median survival was 6.7 months in the erlotinib arm compared to 4.7 months in the placebo arm. Progression-free survival also improved significantly with erlotinib. The reported quality-of-life analysis was limited to determination of the effect of erlotinib on the time to deterioration of three symptoms (cough, dyspnea, and pain). For each measure, there was improvement in the erlotinib arm compared to placebo. In both studies, all patients received best supportive care.

There are no completed studies of gefitinib or erlotinib compared to docetaxel or other cytotoxic agents for this clinical setting for directly assessing the relative effect of EGFR-TK inhibitors with cytotoxic agents, such as docetaxel. As a point of reference for comparison, an RCT of two different doses of docetaxel versus best supportive care alone favored docetaxel over the control arm, especially at the lower dose (75 mg/m²).³³ Median survival time improved from 4.6 months in the control arm to 7.5 months with docetaxel 75 mg/m², while it was 5.9 months in the 100-mg/m² arm. The lower dose is widely adopted as the appropriate dose due to several deaths due to drug-related toxicity at the higher dose. A second RCT compared docetaxel 75 or 100 mg/m² with a control arm of either vinorelbine or ifosfamide, neither of which has been shown to improve outcomes in this clinical setting.³⁴ The median survival in the docetaxel arms were 5.8 and 6.6 for the 75 and 100 mg/m² doses, respectively, compared to 5.4 months in the control arm.

Comparing the median survival times between the erlotinib RCT and the two docetaxel trials does not demonstrate a clear advantage for one drug; however, such comparisons are of limited utility. One of the docetaxel RCTs included quality of life data that has been published, but the measures used were distinct from that used in the erlotinib trial, which severely limits the ability to compare between trials.

Several possible explanations have been proposed for the divergent results from the two similar studies in patients with previously treated NSCLC that used what was previously thought to be two similar drugs.

First, the trials differed with respect to the drug dosage relative to the maximal tolerated dose, which may have resulted in less inhibition of EGFR in the gefitinib study. The more potent erlotinib was administered at the maximal tolerated dose, whereas the gefitinib dose was selected to achieve an optimal biologic dose.

Second, there may have been important differences in the patients between the two studies, in particular with respect to smoking status. The fraction of never smokers in the ISEL study (gefitinib versus placebo) has not been reported, while that in BR21 (erlotinib versus placebo) was 20 percent, higher than is typical among patients with NSCLC in North America. Final reports of the ISEL study will need to be scrutinized for smoking status and method of ascertainment.

Other differences in study populations such as prior chemotherapy and presence of KRAS mutations may also be related to differences in the results of these two trials. Finally, the difference may simply be stochastic.

3. In patients with locally advanced or metastatic non-small cell lung cancer, what are the effects of gefitinib and erlotinib compared to platinum-based chemotherapy regimens on adverse effects, tolerability and compliance?

The toxicity of gefitinib and erlotinib alone has not been directly compared with platinum-based chemotherapy in previously untreated patients with advanced NSCLC. However, the addition of gefitinib to chemotherapy in this clinical setting in two RCTs resulted in additive toxicity, but did not significantly limit the ability to deliver the chemotherapy or compliance with gefitinib. Similar results were presented in preliminary format with erlotinib.

4. In patients with locally advanced or metastatic non-small cell lung cancer who have failed to respond to platinum-based chemotherapy, what are the effects of gefitinib and erlotinib compared to docetaxel plus supportive care or best supportive care alone on adverse effects, tolerability and compliance?

The toxicities of gefitinib and erlotinib are sufficiently distinct from those of docetaxel that it is possible to infer differences in the adverse effects of these two classes of agents based on indirect comparison between trials. The toxicity of gefitinib and erlotinib is primarily dermatologic and diarrhea, and is less than grade 3 toxicity in all but several percent of patients taking these agents. Drug-related mortality is less than 1 percent. In contrast, docetaxel is associated with grade 3 toxicity in more than 10 percent of subjects for hematologic toxicity (primarily neutropenia), neurosensory toxicity, asthenia, and pulmonary toxicity.

5. What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy?

There was the expected lack of uniformity of possible prognostic factors across studies with regard to grouping for analysis and variable inclusion of different factors within a particular study. We therefore first reviewed studies to identify the number of studies that included a particular prognostic factor and then further examined the factors that were most commonly found to be associated with response.

The strongest patient characteristics predicting response to gefitinib or erlotinib therapy appear to be smoking status and sex, each of which is supported by several studies showing statistically significant associations with response. The development of rash during treatment also was associated with response in some studies, but is, of course, not a characteristic available at baseline that could be used to select patients for treatment.

The magnitude of the association for predictors of response is, for the most part, relatively small; few exceed a relative risk of 2. Publication bias favoring studies reporting positive associations may tend to exaggerate the strength of association. For smoking status, one study³⁸ suggested a dose-response with smoking: never (63 percent response), moderate (23 percent response), and heavy (16 percent response). A similar trend was observed with rash: grade 0 (12 percent response), grade 1 (33 percent response), and grade 2 (46 percent response). East Asian ethnicity was also associated with increased likelihood of response in a few studies that reported this variable.

Among the tumor characteristics, EGFR mutations were most strongly and consistently associated with response, with a risk ratio of response varying between studies from 1.3 to 9.7. While most of the studies were small, the total number of patients studied for EGFR mutations (a total of 312 patients with mutation and 816 without mutation in 22 studies) has grown rapidly over that last 6 months. This relatively expensive assay is now clinically available.

Histologic subtype of adenocarcinoma and its various subtypes were also associated with response. Histology was classified differently among the studies examining this factor, with most comparing response in adenocarcinomas versus non-adenocarcinoma, while several considered specific subtypes of adenocarcinoma, particularly BAC, but also papillary adenocarcinoma in one study.

Current State of Clinical Use

Gefitinib use in clinical practice is currently declining given the disappointing results of the Iressa Survival Evaluation in Lung cancer (ISEL) study, which failed to show a survival benefit for gefitinib compared with best supportive care.²⁶ Patients currently receiving gefitinib are being continued on therapy, but new patients are not being started except when they have characteristics that predict increased likelihood of response (e.g., never smokers, women with adenocarcinoma, EGFR mutation).

Erlotinib is a treatment option for patients in second- or greater line of therapy and for selected patients (e.g., never smokers, women with adenocarcinoma) for first-line therapy. Combination of an EGFR-TK with chemotherapy or radiotherapy is not currently recommended outside a clinical trial.

Projections for Future Clinical Use

Erlotinib will continue to be used as a treatment for previously treated patients. Gefitinib's use will likely be limited to subgroups of previously treated patients or may ultimately be completely supplanted by erlotinib. AstraZeneca recently withdrew their Marketing Authorization Application (MAA) with the European Medicines Agency; while acknowledging that it may consider a new MAA after the full ISEL data set is evaluated.³⁹

Implications for Future Research

The identification of EGFR mutations in the NSCLC tumors of never smokers and their association with response to EGFR-TK inhibitors suggests that the differentiation of subgroups of NSCLC may now have important implications for therapeutic decision making. An important question to be addressed is the role of erlotinib in the treatment of smokers or those without EGFR mutation.

Studies are now being initiated to examine EGFR-TK inhibitors as first-line therapy in patients selected on the basis of clinical or tumor characteristics. Recent early findings extending the association of EGFR mutation with response include increased gene copy numbers associated with response.^40-42 KRAS mutations associated with lack of response^36,37 and secondary EGFR mutations associated with acquired resistance^43,44 will also likely be active areas of inquiry into the use of genetic testing not only for initial treatment selection, but ongoing treatment decision making.

Ongoing studies also will address the role of EGFR-TK inhibitors in treatment of patients with earlier stage disease. The combination of EGFR-TK inhibitors with other targeted agents is being studied. New EGFR-TK inhibitors are being investigated, which may have distinct roles either by targeting multiple members of the EGFR family, or by having different activity for the various EGFR mutations.

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