EGFR mutation status may not be known at the time treatment is started in patients with advanced non–small cell lung cancer (NSCLC). Further, some data suggest that the efficacy of concurrent treatment with an EGFR tyrosine kinase inhibitor and chemotherapy is reduced because the G1 cell-cycle arrest caused by the tyrosine kinase inhibitor reduces the cell-cycle phase–dependent activity of chemotherapy.
In a phase III trial (FASTACT-2) conducted in 28 centers in seven Asian countries, Yi-Long Wu, MD, of the Guangdong Academy of Medical Sciences and colleagues found that the intercalated combination of erlotinib (Tarceva) and chemotherapy improved progression-free survival vs chemotherapy alone as first-line treatment in a population of advanced NSCLC patients with known and unknown EGFR mutation status.
The trial, reported in Lancet Oncology,1 showed that benefit was primarily limited to patients known to have activating EGFR mutations, but suggests that a proportion of those with unknown mutation status also benefit. Activating EGFR mutations are more common in Asian patients and in never-smokers, the latter of whom were also highly represented in the trial.
Study Details
In the trial, patients with untreated stage IIIB/IV NSCLC were randomly assigned to six cycles of gemcitabine (1,250 mg/m2 on days 1 and 8) plus platinum (carboplatin 5 × AUC or cisplatin at 75 mg/m2 on day 1) with intercalated erlotinib (150 mg/d on days 15–28; n = 226) or placebo (n = 225) every 4 weeks. All patients in the placebo group were offered second-line erlotinib at the time of disease progression.
The erlotinib and chemotherapy groups were well-matched for age (median, 59 and 57 years), sex (58% and 62% male), smoking status (50% and 48% never-smokers), disease stage (IV in 91% and 89%), histology (adenocarcinoma in 77% and 75%), and ECOG performance status (0 or 1 in all patents). EGFR mutation status was wild-type in 31% and 30%, single resistance mutation in < 1% and 3%, activating EGFR mutation in 22%and 21%, and unknown in 47% and 46%.
Survival Prolonged
Progression-free survival was significantly prolonged with chemotherapy plus erlotinib (median, 7.6 vs 6.0 months, hazard ratio [HR] = 0.57, P < .0001). Analysis of progression-free survival by patient characteristics showed that hazard ratios favored erlotinib in all subgroups, with the greatest benefit observed in female patients, never-smokers, and adenocarcinoma cases.
Median overall survival was also prolonged in the erlotinib group (18.3 vs 15.2 months, HR = 0.79, P = .0420). On investigator assessment, objective response was observed in 43% of patients in the erlotinib group and in 18% of patients in the chemotherapy group (P < .0001).
On disease progression, 79% of the patients in the chemotherapy group received an EGFR tyrosine kinase inhibitor as second-line treatment and 6% as third-line treatment. Only 6% of patients in the erlotinib group received platinum-based chemotherapy as second-line treatment and 6% as third-line treatment.
Analysis by EGFR Mutation Status
On subgroup analysis by EGFR mutation status, erlotinib benefit was observed primarily in patients with an activating EGFR gene mutation, with both progression-free survival (16.8 vs 6.9 months, HR = 0.25, P < .0001) and overall survival (31.4 vs 20.6 months, HR 0.48, P = .0092) being significantly prolonged in this subgroup. In this subgroup, objective response was observed in 84% of erlotinib patients and in 15% of chemotherapy patients (P < .0001).
Among patients with wild-type EGFR, there were no significant differences between erlotinib patients and chemotherapy patients in progression-free survival (6.7 vs 5.9 months, HR = 0.97, P = .8467) or overall survival (14.9 vs 12.2 months, HR = 0.77, P = .1612). Objective response was observed in 26% vs 19% (P = .35).
Among patients with unknown EGFR status, progression-free survival was significantly prolonged in the erlotinib group (7.1 vs 6.0 months, HR = 0.61, P = .0009), suggesting that a proportion of these patients had activating EGFR mutations. No difference in overall survival (18.1 vs 16.2, HR = 0.93, P = .64) was observed in this subgroup.
More EGFR tyrosine kinase inhibitor–type toxicity, including skin rash (5% grade 3) and diarrhea, was observed in the erlotinib group. The most commonly reported adverse events of any grade included neutropenia, anemia, nausea, and rash. Serious adverse events occurred in 31% of patients in the erlotinib group and 34% of chemotherapy group patients. The most common grade 3 or higher adverse events were neutropenia (25% and 29%), thrombocytopenia (14% in both groups), and anemia (9% and 12%). Death occurred in 12 patients in the erlotinib group and in 7 in the chemotherapy group, and was considered treatment-related in 3 patients in each group.
The investigators noted that the good outcomes among patients with known EGFR mutation receiving intercalated erlotinib and chemotherapy suggest that such patients may benefit from this strategy in first-line treatment. They recommended that a randomized trial be conducted to compare intercalated therapy with an EGFR tyrosine kinase inhibitor plus pemetrexed (Alimta) or cisplatin vs EGFR tyrosine kinase inhibitor monotherapy as the control treatment.
Conclusions
The investigators concluded, “Intercalated chemotherapy and erlotinib is a viable first-line option for patients with NSCLC with EGFR mutation–positive disease or selected patients with unknown EGFR mutation status.” Noting that use of the intercalated combination might provide better outcomes in patients with unknown EGFR status than the standard chemotherapy that such patients might otherwise receive, they stated, “We would suggest that the regimen be considered for patients with an unknown mutation status in whom clinical parameters are suggestive of a high incidence of EGFR mutations.” ■
Disclosure: The trial was funded by F. Hoffman-La Roche. For full disclosures of the study authors, visit www.thelancet.com.
Reference
1. Wu Y-L, Lee JS, Thongprasert S, et al: Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): A randomised, double-blind trial. Lancet Oncol 14:777-786, 2013.
