Frontline Afatinib Outperforms Gefitinib in Phase II NSCLC Trial

Afatinib utilized as a frontline treatment reduced risk of progression or death by 27%, as compared to gefitinib in patients with EGFR-mutant non-small cell lung cancer. according to a recent phase IIb trial.

Keunchil Park, MD, PhD

Afatinib utilized as a frontline treatment (Gilotrif) reduced risk of progression or death by 27%, as compared to gefitinib (Iressa) in patients with EGFR-mutant non—small cell lung cancer (NSCLC), according to a recent phase IIb trial.

In the phase IIb trial, specifically LUX-Lung 7 presented at the 2015 ESMO Asia Congress, the 18-month progression-free survival (PFS) rates were 27% versus 15% for both afatinib and gefitinib, respectively. At 24 months, 18% of patients in the afatinib arm remained alive and progression-free, as compared with 8% in the gefitinib group.

The time to treatment failure was 13.7 versus 11.5 months and the objective response rates were 70% compared with 56% for afatinib and gefitinib, respectively (P = .0083).

“LUX-Lung 7 provides the first direct evidence that first-line afatinib significantly improves progression-free survival versus gefitinib in this patient population, also with consistent time to failure and objective response benefit without compromising tolerability,” lead investigator Keunchil Park, MD, from Sungkyunkwan University School of Medicine in Seoul, Korea, said in a statement.

In the study, 319 patients were randomized to receive afatinib at 40 mg per day (n = 160) or gefitinib at 250 mg per day (n = 159). Patients were stratified based on mutation type and the presence of brain metastases. The co-primary endpoints were PFS, time to treatment failure, and overall survival. Secondary outcome measures looked at response and safety.

Baseline characteristics were similar between each arm, with slightly more females in the gefitinib arm (56.9% vs 66.7%). Half of patients in the study were Asian (55.3% to 58.8%) and the most common EGFR mutation was a deletion in exon 19 (57.5% to 58.5%).

The median duration of response for afatinib was 10.1 months compared with 8.4 months with gefitinib. Improvement in response was seen regardless of mutation type, including in those with the exon 19 deletion and L858R mutation.

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). Time to treatment failure was improved by 27% with afatinib versus gefitinib (HR, 0.73; 95% CI, 0.58-0.92; P = .0073). After a median follow-up of 27.3 months, median overall survival data were not yet mature.

The most common grade ≥3 adverse events (AEs) with afatinib were diarrhea (11.9%) and rash/acne (9.4%). Alanine aminotransferase increase was the most common grade ≥3 AE with gefitinib (7.5%). Treatment-related interstitial lung disease occurred in 2.5% of patients treated with gefitinib versus 0% with afatinib.

Serious AEs-related to treatment were more frequent with afatinib (10.6%) versus gefitinib (4.4%). AEs resulting in dose reductions occurred in 41.9% of patients treated with afatinib versus 1.9% with gefitinib; however, treatment discontinuation due to AEs was the same in each arm, at 6.3%.

“The therapeutic landscape in this field is evolving," study discussant Pasi A. Jänne, MD, PhD, from Dana-Farber Cancer Institute, said in a statement. “Our opportunity and challenge is to develop the most effective and tolerable strategy to prevent or delay resistance for as long as possible.”

Afatinib was approved by the FDA in July 2013 as a first-line treatment for patients with metastatic NSCLC harboring an EGFR exon 19 deletion or L858R substitution. Altogether, there are three agents currently approved as frontline treatment for patients with EGFR-mutant NSCLC (gefitinib, afatinib, and erlotinib).

When determining treatment, the key is to balance efficacy and toxicity, according to Jänne. Regardless of frontline therapy utilized, subsequent treatments following progression remain the same, he noted.

In general, resistance is primarily due to T790M alterations with each treatment (50% to 60%). At this time, the only therapy specifically approved for patients with T790M-positive NSCLC is osimertinib (Tagrisso), which was approved in November 2015. The approval was based on an objective response rate with osimertinib of 57% to 61% for those with EGFR T790M-mutant NSCLC.


  1. Park K, Tan E, Zhang L, et al. Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 (LL7). Presented at: 2015 ESMO Asia Congress; Singapore; December 18-21, 2015.Abstract LBA2.