Post by Deanne Jenkyns on Aug 20, 2007 20:52:16 GMT 1
Targeted therapies
Targeted therapies directly target specific proteins and pathways involved in the growth and proliferation of cancer cells. Compared with chemotherapy, they tend to be less toxic to healthy tissue due to their specificity towards cancer cells.
The following are the main targeted agents that have been studied in non-small cell lung carcinoma (NSCLC). It should be noted that not all of these agents may be licensed for use in every country, and therefore local prescribing information reference sources should be consulted.
Gefitinib, a small molecule tyrosine kinase inhibitor (TKI) developed to specifically target the epidermal growth factor receptor (EGFR);
Erlotinib, another small molecule TKI that targets EGFR;
Vandetanib, a small molecule TKI that targets EGFR and VEGFR;
Cetuximab, a monoclonal antibody directed against EGFR;
Bevacizumab, a monoclonal antibody which is directed against the vascular endothelial growth factor receptor (VEGFR);
Panitumumab, another monoclonal antibody, which also targets EGFR.
These new drugs have been studied as monotherapy in patients with previously treated or advanced disease, and/or in combination with chemotherapy for treatment-naïve patients, and/or in combination with each other for advanced disease.
Monotherapy with targeted agents
Gefitinib was the first small molecule tyrosine kinase inhibitor to be licensed for the treatment of lung cancer, being conditionally approved by the US Food and Drug Administration (FDA) in 2003 for patients who had been previously treated with chemotherapy.
However, after the results of the phase III Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial were announced, the use of gefitinib was subsequently restricted in the US and Canada for patients that were already receiving and benefiting from gefitinib therapy. [1–3]
The primary endpoint of survival in the overall population in the ISEL trial did not achieve statistical significance, however preplanned subgroup analyses showed a significant overall survival benefit for gefitinib treatment in never-smokers and in patients of Asian origin, which may support the selective use of this agent in some patients.
In previously treated patients with advanced NSCLC, The National Cancer Institute of Canada's JBR.21 trial showed that erlotinib produced an overall survival benefit compared with placebo and best supportive care. As a result of these data, erlotinib is now approved for the treatment of patients with NSCLC who have progressed after treatment with chemotherapy. [4]
Combination with chemotherapy
Phase II trials of erlotinib or gefitinib in patients with advanced, refractory NSCLC showed very promising results. However, large-scale phase III trials of erlotinib and gefitinib in combination with standard chemotherapy regimens have shown variable results, failing to meet their primary endpoint of improvement in overall survival. [5]
The large-scale TRIBUTE [6] and TALENT [7] trials evaluated the addition of erlotinib to chemotherapy in treatment-naive patients with advanced NSCLC.
In the TRIBUTE trial, erlotinib (150 mg/day), or placebo was combined with carboplatin and paclitaxel. [6] Patients were randomized to receive placebo or erlotinib for six cycles, and then all patients received erlotinib maintenance monotherapy.
In over 1000 evaluable patients, no difference was observed for median overall survival (10.6 versus 10.5 months for erlotinib versus placebo, respectively) or time to progression; however, for non-smokers, the overall survival was superior in patients receiving erlotinib (22.5 versus 10.1 months for placebo). [8]
The similarly designed TALENT trial, [7] which evaluated gemcitabine and cisplatin with or without erlotinib also found that addition of erlotinib did not significantly improve overall survival (301 days for patients treated with erlotinib versus 309 days for patients in the placebo group). In addition, similar time to progression was reported for both groups (erlotinib 167 days; placebo 179 days).
The large-scale INTACT 1 [9] and INTACT 2 [10] trials evaluated gefitinib in combination with chemotherapy in treatment-naïve patients with advanced or metastatic NSCLC.
In the INTACT 1 trial gefitinib (500 mg/day or 250 mg/day), or placebo was combined with gemcitabine and cisplatin. The primary end point was overall survival. In the 1093 patients enrolled, no difference in efficacy endpoints was seen between the treatment groups, demonstrating that gefitinib in combination with chemotherapy did not appear to have improved efficacy over treatment with chemotherapy alone.
In the INTACT 2 trial gefitinib (500 mg/day or 250 mg/day), or placebo was combined with carboplatin and paclitaxel. Again the primary end point was overall survival. In the 1037 patients enrolled, no difference in overall survival, time to progression or response rate was seen between the treatment groups.
The anti-EGFR monoclonal antibody cetuximab has also been evaluated in combination with chemotherapy in the first-line setting. Rosell and colleagues conducted a randomized, phase II trial evaluating cisplatin and vinorelbine either alone or in combination with cetuximab. [11]
The overall response rate was higher in the cetuximab arm (31.7% versus 20% in the control arm), but this difference was not statistically significant. Time to progression (4.7 months versus 4.2 months) and median survival (8.3 versus 7.0 months) were also comparable between groups.
The SWOG 0342 randomized phase II trial also evaluated cetuximab, in combination with carboplatin plus paclitaxel. [12] The study included 225 previously untreated patients with advanced NSCLC randomized to receive carboplatin plus paclitaxel in combination with concurrent cetuximab, or carboplatin plus paclitaxel at the same doses followed by cetuximab.
Preliminary results indicated that efficacy and toxicity were comparable between the treatment groups, and both regimens were well tolerated. Median survival (10 months versus 9 months) and overall response rates were slightly better in patients receiving concurrent cetuximab with carboplatin plus paclitaxel versus those receiving carboplatin plus paclitaxel followed by cetuximab (37% and 25% in the concurrent and consecutive treatment arms, respectively). Median progression free survival at 4 months was the same in both treatment groups. A phase II trial evaluating carboplatin plus paclitaxel plus cetuximab plus bevacizumab is also in progress. [12]
Bevacizumab was found to improve survival when used in combination with paclitaxel plus carboplatin in patients with previously untreated stage IIIB or IV NSCLC. In the phase II/III ECOG 4599 trial, Sandler and colleagues randomized patients with previously untreated non-squamous NSCLC to receive standard chemotherapy with paclitaxel plus carboplatin with or without bevacizumab 15 mg/kg/day. [13]
A total of 878 patients were randomized to the two treatment arms. Patients receiving the bevacizumab/chemotherapy combination continued bevacizumab after six cycles of chemotherapy until progressive disease or unacceptable toxicity developed. Median overall survival was found to be statistically significantly higher in the bevacizumab/chemotherapy arm, being 12.3 months versus 10.3 months in the chemotherapy alone arm (hazard ratio 0.80 [repeated 95% CI 0.68, 0.94], p=0.013). Patients who received bevacizumab plus chemotherapy were reported to have a significantly higher response rate and longer progression-free survival than those receiving chemotherapy alone. [14]
The EGFR inhibitor panitumumab was approved by the FDA in September 2006 for the treatment of metastatic colorectal cancer. [15] It has been shown to be well tolerated in patients with advanced NSCLC in phase II trials, where it was used in combination with paclitaxel and carboplatin. [16]
Combining targeted agents
The tyrosine kinase inhibitor vandetanib inhibits EGFR, VEGF receptor (VEGFR), and RET signaling. It has been tested in trials on patients with advanced NSCLC, both as single-agent therapy, in comparison with gefitinib, and in a combination regimen with the chemotherapy agent docetaxel.
Vandetanib’s anti-EGFR activity inhibits invasion, cell proliferation, metastasis, and VEGF production, while promoting apoptosis. The anti-VEGFR activity of vandetanib inhibits angiogenesis by decreasing endothelial cell proliferation, migration and vascular permeability; its anti-RET activity decreases proliferation and increases cell death in RET-driven cancers. These effects have been demonstrated in a number of biological models, including: selective inhibition of VEGF signaling in a rat growth factor-induced hypertension model, antitumor activity in an immunocompetent mouse model, and inhibition of tumor-induced angiogenesis in mice. [17]
A recent phase II trial compared vandetanib (300 mg) as monotherapy with gefitinib (250 mg) in 168 patients with advanced NSCLC. [18] Vandetanib was found to significantly prolong progression free survival compared with gefitinib. Another phase II trial studied the combination of vandetanib with docetaxel, compared to docetaxel plus placebo) in 127 patients with refractory NSCLC. Patients were already receiving docetaxel therapy, to which vandetanib was added at dosages of 100 mg or 300 mg. The results demonstrated an increase in progression free survival of up to 19 weeks with docetaxel plus vandetanib, in comparison to 12 weeks with docetaxel plus placebo. Due to the promising results from this trial, phase III trials with vandetanib in second-line NSCLC have now begun
Targeted therapies directly target specific proteins and pathways involved in the growth and proliferation of cancer cells. Compared with chemotherapy, they tend to be less toxic to healthy tissue due to their specificity towards cancer cells.
The following are the main targeted agents that have been studied in non-small cell lung carcinoma (NSCLC). It should be noted that not all of these agents may be licensed for use in every country, and therefore local prescribing information reference sources should be consulted.
Gefitinib, a small molecule tyrosine kinase inhibitor (TKI) developed to specifically target the epidermal growth factor receptor (EGFR);
Erlotinib, another small molecule TKI that targets EGFR;
Vandetanib, a small molecule TKI that targets EGFR and VEGFR;
Cetuximab, a monoclonal antibody directed against EGFR;
Bevacizumab, a monoclonal antibody which is directed against the vascular endothelial growth factor receptor (VEGFR);
Panitumumab, another monoclonal antibody, which also targets EGFR.
These new drugs have been studied as monotherapy in patients with previously treated or advanced disease, and/or in combination with chemotherapy for treatment-naïve patients, and/or in combination with each other for advanced disease.
Monotherapy with targeted agents
Gefitinib was the first small molecule tyrosine kinase inhibitor to be licensed for the treatment of lung cancer, being conditionally approved by the US Food and Drug Administration (FDA) in 2003 for patients who had been previously treated with chemotherapy.
However, after the results of the phase III Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial were announced, the use of gefitinib was subsequently restricted in the US and Canada for patients that were already receiving and benefiting from gefitinib therapy. [1–3]
The primary endpoint of survival in the overall population in the ISEL trial did not achieve statistical significance, however preplanned subgroup analyses showed a significant overall survival benefit for gefitinib treatment in never-smokers and in patients of Asian origin, which may support the selective use of this agent in some patients.
In previously treated patients with advanced NSCLC, The National Cancer Institute of Canada's JBR.21 trial showed that erlotinib produced an overall survival benefit compared with placebo and best supportive care. As a result of these data, erlotinib is now approved for the treatment of patients with NSCLC who have progressed after treatment with chemotherapy. [4]
Combination with chemotherapy
Phase II trials of erlotinib or gefitinib in patients with advanced, refractory NSCLC showed very promising results. However, large-scale phase III trials of erlotinib and gefitinib in combination with standard chemotherapy regimens have shown variable results, failing to meet their primary endpoint of improvement in overall survival. [5]
The large-scale TRIBUTE [6] and TALENT [7] trials evaluated the addition of erlotinib to chemotherapy in treatment-naive patients with advanced NSCLC.
In the TRIBUTE trial, erlotinib (150 mg/day), or placebo was combined with carboplatin and paclitaxel. [6] Patients were randomized to receive placebo or erlotinib for six cycles, and then all patients received erlotinib maintenance monotherapy.
In over 1000 evaluable patients, no difference was observed for median overall survival (10.6 versus 10.5 months for erlotinib versus placebo, respectively) or time to progression; however, for non-smokers, the overall survival was superior in patients receiving erlotinib (22.5 versus 10.1 months for placebo). [8]
The similarly designed TALENT trial, [7] which evaluated gemcitabine and cisplatin with or without erlotinib also found that addition of erlotinib did not significantly improve overall survival (301 days for patients treated with erlotinib versus 309 days for patients in the placebo group). In addition, similar time to progression was reported for both groups (erlotinib 167 days; placebo 179 days).
The large-scale INTACT 1 [9] and INTACT 2 [10] trials evaluated gefitinib in combination with chemotherapy in treatment-naïve patients with advanced or metastatic NSCLC.
In the INTACT 1 trial gefitinib (500 mg/day or 250 mg/day), or placebo was combined with gemcitabine and cisplatin. The primary end point was overall survival. In the 1093 patients enrolled, no difference in efficacy endpoints was seen between the treatment groups, demonstrating that gefitinib in combination with chemotherapy did not appear to have improved efficacy over treatment with chemotherapy alone.
In the INTACT 2 trial gefitinib (500 mg/day or 250 mg/day), or placebo was combined with carboplatin and paclitaxel. Again the primary end point was overall survival. In the 1037 patients enrolled, no difference in overall survival, time to progression or response rate was seen between the treatment groups.
The anti-EGFR monoclonal antibody cetuximab has also been evaluated in combination with chemotherapy in the first-line setting. Rosell and colleagues conducted a randomized, phase II trial evaluating cisplatin and vinorelbine either alone or in combination with cetuximab. [11]
The overall response rate was higher in the cetuximab arm (31.7% versus 20% in the control arm), but this difference was not statistically significant. Time to progression (4.7 months versus 4.2 months) and median survival (8.3 versus 7.0 months) were also comparable between groups.
The SWOG 0342 randomized phase II trial also evaluated cetuximab, in combination with carboplatin plus paclitaxel. [12] The study included 225 previously untreated patients with advanced NSCLC randomized to receive carboplatin plus paclitaxel in combination with concurrent cetuximab, or carboplatin plus paclitaxel at the same doses followed by cetuximab.
Preliminary results indicated that efficacy and toxicity were comparable between the treatment groups, and both regimens were well tolerated. Median survival (10 months versus 9 months) and overall response rates were slightly better in patients receiving concurrent cetuximab with carboplatin plus paclitaxel versus those receiving carboplatin plus paclitaxel followed by cetuximab (37% and 25% in the concurrent and consecutive treatment arms, respectively). Median progression free survival at 4 months was the same in both treatment groups. A phase II trial evaluating carboplatin plus paclitaxel plus cetuximab plus bevacizumab is also in progress. [12]
Bevacizumab was found to improve survival when used in combination with paclitaxel plus carboplatin in patients with previously untreated stage IIIB or IV NSCLC. In the phase II/III ECOG 4599 trial, Sandler and colleagues randomized patients with previously untreated non-squamous NSCLC to receive standard chemotherapy with paclitaxel plus carboplatin with or without bevacizumab 15 mg/kg/day. [13]
A total of 878 patients were randomized to the two treatment arms. Patients receiving the bevacizumab/chemotherapy combination continued bevacizumab after six cycles of chemotherapy until progressive disease or unacceptable toxicity developed. Median overall survival was found to be statistically significantly higher in the bevacizumab/chemotherapy arm, being 12.3 months versus 10.3 months in the chemotherapy alone arm (hazard ratio 0.80 [repeated 95% CI 0.68, 0.94], p=0.013). Patients who received bevacizumab plus chemotherapy were reported to have a significantly higher response rate and longer progression-free survival than those receiving chemotherapy alone. [14]
The EGFR inhibitor panitumumab was approved by the FDA in September 2006 for the treatment of metastatic colorectal cancer. [15] It has been shown to be well tolerated in patients with advanced NSCLC in phase II trials, where it was used in combination with paclitaxel and carboplatin. [16]
Combining targeted agents
The tyrosine kinase inhibitor vandetanib inhibits EGFR, VEGF receptor (VEGFR), and RET signaling. It has been tested in trials on patients with advanced NSCLC, both as single-agent therapy, in comparison with gefitinib, and in a combination regimen with the chemotherapy agent docetaxel.
Vandetanib’s anti-EGFR activity inhibits invasion, cell proliferation, metastasis, and VEGF production, while promoting apoptosis. The anti-VEGFR activity of vandetanib inhibits angiogenesis by decreasing endothelial cell proliferation, migration and vascular permeability; its anti-RET activity decreases proliferation and increases cell death in RET-driven cancers. These effects have been demonstrated in a number of biological models, including: selective inhibition of VEGF signaling in a rat growth factor-induced hypertension model, antitumor activity in an immunocompetent mouse model, and inhibition of tumor-induced angiogenesis in mice. [17]
A recent phase II trial compared vandetanib (300 mg) as monotherapy with gefitinib (250 mg) in 168 patients with advanced NSCLC. [18] Vandetanib was found to significantly prolong progression free survival compared with gefitinib. Another phase II trial studied the combination of vandetanib with docetaxel, compared to docetaxel plus placebo) in 127 patients with refractory NSCLC. Patients were already receiving docetaxel therapy, to which vandetanib was added at dosages of 100 mg or 300 mg. The results demonstrated an increase in progression free survival of up to 19 weeks with docetaxel plus vandetanib, in comparison to 12 weeks with docetaxel plus placebo. Due to the promising results from this trial, phase III trials with vandetanib in second-line NSCLC have now begun