Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR

First-generation EGFR TKIs gefitinib and erlotinib have shown improved efficacy and tolerability compared with chemotherapy in phase III trials.

“have shown improved efficacy and tolerability compared with chemotherapy in numerous phase III trials”

Eight randomised controlled phase III trials have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and PFS.

“Eight randomised controlled phase III trials (table 1) have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and progression-free survival (PFS).4–11”

Patients with EGFR-mutant NSCLC usually respond to first-generation TKIs but most progress after about 9-14 months.

“Unfortunately, whilst patients with EGFRm+ tumors typically show good initial responses to first generation TKIs, most patients who respond to therapy ultimately develop disease progression after about 9-14 months of treatment (7-11).”

The sensitivity of uncommon EGFR mutations to first- and second-generation EGFR TKIs is less well known compared with classic mutations.

“the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation)”

Most pivotal first-line studies with EGFR TKIs, with few exceptions, excluded patients with rare and/or complex EGFR variants.

“since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants”

Most patients with exon 19 deletions or L858R have radiographic responses to gefitinib, erlotinib, and afatinib.

“Most patients whose tumors harbor exon 19 deletions or L858R EGFR activating mutations have radiographic responses to monotherapy with the reversible adenosine triphosphate (ATP)-competitive EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib 17–23 and the irreversible EGFR TKI afatinib 24.”

Response rates to EGFR TKIs in patients with NSCLC with sensitizing EGFR mutations (exon 19 deletions or L858R) are approximately 60% to 80%.

“Response rates to EGFR TKIs in patients with NSCLC with sensitizing EGFR mutations (exon 19 deletions or L858R) are approximately 60% to 80%, 3,5”

Randomized trials show that EGFR TKIs improve response rate and progression-free survival compared with chemotherapy as initial systemic therapy for advanced EGFR-mutant NSCLC.

“Several randomized clinical trials have demonstrated that EGFR TKIs are more effective, as measured by response rate (RR) and progression free survival (PFS), than chemotherapy when used as initial systemic treatment for advanced EGFR mutant NSCLC (1, 4–9).”

Retrospective analyses of large phase III trials reported inferior ORR than commonly observed in the front-line setting in EGFR-mutated patients treated with EGFR TKIs after chemotherapy.

“However, retrospective analyses of large phase III trials reported inferior ORR than commonly observed in the front-line setting in EGFR-mutated patients treated with EGFR TKIs after chemotherapy [41–44].”

Several other trials conducted in Asia confirmed the superiority of Gefitinib over chemotherapy in EGFR-mutated patients.

“Several other trials conducted in Asia confirmed the superiority of Gefitinib over chemotherapy in EGFR-mutated patients [16, 44, 64].”

Targeted therapies for EGFR-mutant lung cancers were established based on 7 phase III randomized trials.

“Targeted therapies for these lung cancers were established based on 7 phase III randomized trials.5, 6, 7, 8, 9, 10, 11”

Randomized phase III trials demonstrated superiority of gefitinib and erlotinib in progression-free survival to conventional chemotherapy in patients with EGFR-mutant lung cancers.

“Randomized phase III trials have demonstrated the superiority of these TKI, in terms of progression free survival (PFS), to conventional chemotherapy in patients with lung cancers harboring EGFR mutations.5, 6, 11”

In prospective trials of common EGFR mutations, gefitinib, erlotinib and afatinib showed objective response rates of approximately 60% and progression-free survival of 9-13 months.

“Evidence of these common mutations has been developed in prospective trials: gefitinib, erlotinib and afatinib showed ORR of approximately 60% and PFS of 9–13 months.5, 6, 7, 8, 9, 10, 11”

Disease progresses in most patients after 9 to 13 months of first-line EGFR-TKI therapy.

“Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment.5–12”

Several studies have consistently shown that EGFR TKIs (gefitinib, erlotinib, afatinib) produce higher response rates, longer PFS and improved quality of life compared with platinum-based doublet chemotherapy in PS 0-2 patients whose tumours have an activating EGFR mutation.

“Several studies have consistently demonstrated that the EGFR TKIs (gefitinib, erlotinib and afatinib) produce higher RRs, longer PFS and improve QoL compared with standard platinum-based doublet chemotherapy in patients with good PS (PS 0-2), whose tumour harbours an activating (sensitising) EGFR mutation [105-112].”

In the study by Maemondo et al, adverse events occurred at a higher frequency with carboplatin plus paclitaxel than with gefitinib.

“adverse events occurred at a higher frequency with carboplatin plus paclitaxel.”

In the study by Maemondo et al, carboplatin plus paclitaxel resulted in poorer outcomes in PFS and TTP compared with gefitinib.

“In the study by Maemondo et al,20 this regimen resulted in poorer outcomes in PFS and TTP and no statistically significant differences in OS with chemotherapy; adverse events occurred at a higher frequency with carboplatin plus paclitaxel.”

In the study by Maemondo et al, there were no statistically significant differences in OS between carboplatin plus paclitaxel and gefitinib.

“no statistically significant differences in OS with chemotherapy”

Neither the IPASS study nor the other phase III study reported survival of patients who did or did not experience an initial response to gefitinib.

“Neither study reported the survival of patients who did or did not experience an initial response to gefitinib.20,21”

Final results of OS have not been reported for most studies of first-line EGFR TKI versus cytotoxic chemotherapy in EGFR-mutant patients, so outcomes of patients who crossed over to chemotherapy have not been analyzed.

“However, final results of OS have not been reported for most studies; therefore, the outcomes of those patients who crossed over to chemotherapy have not been yet analyzed.11,13,20,29,94”

Other studies have randomly assigned patients with EGFR mutations to a first-line EGFR TKI or cytotoxic chemotherapy and found that PFS was improved in those who received the EGFR TKI.

“Other studies have randomly assigned patients with EGFR mutations to a first-line EGFR TKI or cytotoxic chemotherapy and found that PFS was improved in those who received the EGFR TKI.”

Another phase III study of gefitinib versus carboplatin plus paclitaxel in patients with EGFR-sensitizing mutations found an improvement in PFS but not OS, presumably due to crossover to chemotherapy in the gefitinib arm.

“Similarly, another phase III study of gefitinib versus carboplatin plus paclitaxel in patients with EGFR-sensitizing mutations also found an improvement in PFS but not OS, again presumably secondarily to crossover to chemotherapy in the gefitinib arm.”