Erlotinib Bests Gefitinib in Phase III NSCLC Study

David Spigel, MD

Treatment with gefitinib (Iressa) failed to show noninferiority compared with erlotinib (Tarceva) for patients with pretreated non—small cell lung cancer (NSCLC), according to findings from a phase III study that were published in the Journal of Clinical Oncology.

In patients with EGFR-mutant advanced lung adenocarcinoma (n = 401), the median progression-free survival (PFS) with gefitinib was 8.3 versus 10.0 months with erlotinib (HR, 1.093; 95% CI, 0.879-1.358; P = .424). Grade 3 rash was more common with erlotinib versus gefitinib (18.1% vs 2.2%) and liver enzymes were more frequently elevated with gefitinib versus erlotinib.

“This was the first phase III study to compare erlotinib with gefitinib in NSCLC,” said David Spigel, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute, who was not involved in the trial. “The aim of the study, PFS, was not met; however, there were issues with the methods of the study. The PFS plots were similar.”

In the study, which was conducted exclusively in Japan, 553 patients received treatment with gefitinib (n = 277) or erlotinib (n = 276). Gefitinib was administered at 250 mg per day and erlotinib was given at 150 mg per day. The median age of patients was 67 years and the majority had stage IV disease (69.2%).

Predefined testing for EGFR revealed a mutation in 66.4% of participants. However, a secondary post-hoc assessment of EGFR revealed that 71.7% of tumors were positive for L858R mutations, exon 19 deletions, double mutations, or uncommon EGFR alterations.

Baseline characteristics were well balanced between the two arms, except for performance status (PS). Overall, the PS was higher in the gefitinib arm compared with erlotinib (P = .028). In the erlotinib and gefitinib arms, respectively, the PS was 0 (50% vs 40.1%), 1 (42.5% vs 53.8%), and 2 (7.5% vs 6.1%).

The primary endpoint of the study was noninferiority in PFS by investigator assessment. The secondary endpoints focused on overall survival (OS), overall response rate (ORR), disease control rate (DCR), safety, and time to treatment failure (TTF).

In those with EGFR alterations, median OS was 26.5 months with gefitinib versus 31.4 months with erlotinib (HR, 1.189; 95% CI, 0.900-1.570; P = .221). The ORR was 58.9% versus 55% and the DCR was 81.7% versus 84.4% for gefitinib and erlotinib, respectively.

In patients with exon 19 deletions, the median PFS was 11.1 versus 11.5 months for gefitinib and erlotinib, respectively (HR, 1.120; 95% CI, 0.813-1.544; P = .487). In the L858R mutation group, the median PFS with gefitinib was 8.1 versus 8.5 months with erlotinib (HR, 0.938; 95% CI, 0.675-1.304; P = .704). In those with uncommon EGFR mutations, median PFS was 6.4 months with gefitinib versus 5.3 months with erlotinib (HR, 1.109; 95% CI, 0.464-2.653; P = .815).

Across the full study, including those without EGFR mutations, the median PFS was 6.5 months with gefitinib versus 7.5 months with erlotinib (adjusted HR, 1.125; 95% CI, 0.940-1.347). Median OS was 22.8 months with gefitinib versus 24.5 months with erlotinib (HR, 1.038; 95% CI, 0.833-1.294). The TTF was 5.6 versus 5.3 months, in the gefitinib and erlotinib arms, respectively (HR, 1.032; 95% CI, 0.866-1.231). The ORRs were 45.9% versus 44.1% and the DCRs were 70.9% versus 75.3%, for gefitinib and erlotinib, respectively.

Overall, toxicity was lower in the gefitinib arm compared with erlotinib (P <.001). Grade 3/4 aspartate aminotransferase increases occurred in 6.1% of patients treated with gefitinib versus 2.2% of those in the erlotinib arm. Grade 3/4 alanine aminotransferase increases were seen in 13% of those in the gefitinib arm versus 3.3% in the erlotinib group.

These data add to a phase IIb analysis that compared afatinib (Gilotrif) with gefitinib for patients with untreated EGFR-mutant NSCLC, according to Gregory J. Riely, MD, PhD. In this study, which was labeled LUX-Lung 7, 319 patients were randomized to receive afatinib at 40 mg per day (n = 160) or gefitinib at 250 mg per day (n = 159).

Median PFS was 11.0 versus 10.9 months, for afatinib and gefitinib, respectively (HR, 0.73; 95% CI, 0.57-0.95; P = .0165). The 18-month PFS rates were 27% versus 15%, for afatinib and gefitinib, respectively. At 24 months, 18% of those in the afatinib arm remained alive and progression-free compared with 8% in the gefitinib group. After a median follow-up of 27.3 months, median overall survival data were not yet mature.

TTF was 13.7 months with afatinib versus 11.5 months with gefitinib (HR, 0.73; 95% CI, 0.58-0.92; P = .0073). The ORR was 70% compared with 56% for afatinib and gefitinib, respectively (P = .0083).

“The results of recent randomized studies comparing EGFR tyrosine kinase inhibitors helps inform a decision that we have largely had to make without data,” said Riely, vice chair, Clinical Trials Office, Department of Medicine, Memorial Sloan Kettering Cancer Center, who was not involved in the trial. “Unfortunately, these studies have been imperfect, sometimes enrolling patients without EGFR mutations or being too small. They are provocative, but I don't think they are really going to change many people's practice.”

Urata Y, Katakami N, Morita S, at al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L [published online March 28, 2016]. J Clin Oncol. doi: 10.1200/JCO.2015.63.4154