Adjuvant Targeted Therapy--Epidermal Growth Factor TKIs and More
Adjuvant Targeted Therapy--Epidermal Growth Factor TKIs and More
Over 10 years ago, two large randomized trials were designed to test EGFR TKIs in early stage NSCLC (not molecularly-selected patients)—one involving chemoradiation followed by gefitinib in stage III NSCLC (SWOG S0023), and the other with adjuvant gefitinib in stage I-III NSCLC. Unfortunately, in 2005, the large ISEL trial of second line gefitinib in unselected stage IV NSCLC failed to meet its overall survival endpoint, which prematurely disrupted enrollment in both early stage trials.
The phase III S0023 study enrolled a total of 243 patients with stage III NSCLC expected to receive concurrent chemotherapy and radiation and randomized them to outback gefitinib for up to 5 years or placebo. An unplanned interim analysis in 2005 at the time of the ISEL read-out demonstrated a signal of harm for gefitinib, with a median survival time of 23 months for patients receiving gefitinib, and 35 months for patients who received placebo (P=0.013). A subset analysis to look for potential benefit, or at least lack of harm, in patients with EGFR mutation-positive disease could not be retrospectively performed. Based on this study, EGFR-TKI therapy after combined chemoradiation is not recommended outside of a clinical trial.
In the phase III BR.19 study, patients with stage IB-IIIA NSCLC were randomized, following surgical resection and optional adjuvant chemotherapy, to 2 years of adjuvant gefitinib or equivalent placebo. Of a planned 1,160 patients, enrollment stopped at 503 in 2005 based on the negative ISEL trial and S0023 interim report. All patients were taken off of their assigned therapy. The analysis reported in 2010 demonstrated no difference between the groups, but a trend toward harm with gefitinib was observed for both disease free and overall survival. In the subgroup analysis of patients with EGFR mutant NSCLC, 40 patients treated with placebo had a numerically, but not significantly, improved overall survival compared with 36 patients who received adjuvant gefitinib. However, given the small numbers of patients and the shorter-than-planned 5 months median duration of adjuvant TKI, firm conclusions regarding the efficacy of adjuvant TKIs for EGFR mutant NSCLC should not be based on this trial.
At ASCO 2013, a relatively small Chinese trial was presented in which 60 patients with primarily resected stage IIIA-N2 NSCLC were treated with either 4 cycles of adjuvant carboplatin and pemetrexed, or the same chemotherapy followed by 6 months of gefitinib. Unlike the S0023 and BR.19 trials, no patients received radiation, and all patients had tumors with sensitizing EGFR mutations. An improvement was observed for the gefitinib arm versus the control arm for median DFS (39.8 vs. 27.0 mo, P=0.014, HR 0.37) and a trend toward improved median overall survival was noted (41.6 vs. 32.6 mo, P=0.066, HR 0.37). While this study is small, it does suggest benefit for an EGFR mutant population with adjuvant gefitinib treatment.
Adjuvant Gefitinib
Over 10 years ago, two large randomized trials were designed to test EGFR TKIs in early stage NSCLC (not molecularly-selected patients)—one involving chemoradiation followed by gefitinib in stage III NSCLC (SWOG S0023), and the other with adjuvant gefitinib in stage I-III NSCLC. Unfortunately, in 2005, the large ISEL trial of second line gefitinib in unselected stage IV NSCLC failed to meet its overall survival endpoint, which prematurely disrupted enrollment in both early stage trials.
The phase III S0023 study enrolled a total of 243 patients with stage III NSCLC expected to receive concurrent chemotherapy and radiation and randomized them to outback gefitinib for up to 5 years or placebo. An unplanned interim analysis in 2005 at the time of the ISEL read-out demonstrated a signal of harm for gefitinib, with a median survival time of 23 months for patients receiving gefitinib, and 35 months for patients who received placebo (P=0.013). A subset analysis to look for potential benefit, or at least lack of harm, in patients with EGFR mutation-positive disease could not be retrospectively performed. Based on this study, EGFR-TKI therapy after combined chemoradiation is not recommended outside of a clinical trial.
In the phase III BR.19 study, patients with stage IB-IIIA NSCLC were randomized, following surgical resection and optional adjuvant chemotherapy, to 2 years of adjuvant gefitinib or equivalent placebo. Of a planned 1,160 patients, enrollment stopped at 503 in 2005 based on the negative ISEL trial and S0023 interim report. All patients were taken off of their assigned therapy. The analysis reported in 2010 demonstrated no difference between the groups, but a trend toward harm with gefitinib was observed for both disease free and overall survival. In the subgroup analysis of patients with EGFR mutant NSCLC, 40 patients treated with placebo had a numerically, but not significantly, improved overall survival compared with 36 patients who received adjuvant gefitinib. However, given the small numbers of patients and the shorter-than-planned 5 months median duration of adjuvant TKI, firm conclusions regarding the efficacy of adjuvant TKIs for EGFR mutant NSCLC should not be based on this trial.
At ASCO 2013, a relatively small Chinese trial was presented in which 60 patients with primarily resected stage IIIA-N2 NSCLC were treated with either 4 cycles of adjuvant carboplatin and pemetrexed, or the same chemotherapy followed by 6 months of gefitinib. Unlike the S0023 and BR.19 trials, no patients received radiation, and all patients had tumors with sensitizing EGFR mutations. An improvement was observed for the gefitinib arm versus the control arm for median DFS (39.8 vs. 27.0 mo, P=0.014, HR 0.37) and a trend toward improved median overall survival was noted (41.6 vs. 32.6 mo, P=0.066, HR 0.37). While this study is small, it does suggest benefit for an EGFR mutant population with adjuvant gefitinib treatment.
