Afatinib Shows Benefit Beyond Progression in Metastatic NSCLC

Continuing EGFR inhibition beyond progression with afatinib (Gilotrif) plus paclitaxel significantly improved PFS and ORR compared with chemotherapy alone in patients with heavily pretreated metastatic NSCLC.

Martin H. Schuler, MD

Continuing EGFR inhibition beyond progression with afatinib (Gilotrif) plus paclitaxel significantly improved progression-free survival (PFS) and objective response rates (ORR) compared with chemotherapy alone in patients with heavily pretreated metastatic non-small-cell lung cancer (NSCLC).

The findings come from the phase III open-label LUX-Lung 5 trial, in which the efficacy of afatinib combined with paclitaxel was compared with investigator’s choice of chemotherapy in patients with NSCLC who experienced disease progression on erlotinib/gefitinib and afatinib. The data supports the notion that tumors progressing on EGFR inhibitors continue to depend on signaling through the ErbB receptor family, and that patients can benefit from continuous ErbB family blockade.

“This trial proves formally for the first time this new concept of maintaining EGFR inhibition beyond progression,” Martin H. Schuler, MD, said during a presentation at the 2014 ASCO Annual Meeting. “This is a concept that we have known for many years from HER2-positive breast cancer but it has never been shown in lung cancer, so this is the merit of this trial.”

Improved disease control with the continuation of EGFR inhibition beyond progression in lung cancer had been suggested in retrospective/non-randomized studies, but had not yet been evaluated prospectively in a randomized trial.

In part A of the LUX-Lung 5 trial, 1154 patients were treated with afatinib at 50 mg daily following progression on chemotherapy and erlotinib/gefitinib. In addition to at least one line of a TKI, “all of patients had a platinum doublet and most of them had had another line, so the majority of them had 3 lines before entering the trial,” said Schuler, the director of the Department of Medical Oncology, West German Cancer Center in Essen, Germany.

In part B of the trial, 202 patients who experienced disease stabilization or antitumor responses on afatinib in part A were randomized in a 2:1 ratio to continued afatinib plus paclitaxel (n = 134) or chemotherapy (n = 68). In general, the chemotherapy arm included paclitaxel (37%), pemetrexed (29%), and docetaxel (15%). Paclitaxel was chosen for combination with afatinib based on clinical evidence of synergism.

Tumor assessment in part B occurred at baseline and every 8 weeks thereafter. The primary endpoint was PFS according to RECIST v 1.1 by investigator review. In the combination arm, patients received daily afatinib at 40 mg and weekly paclitaxel at 80 mg/m2.

“The median time of disease control was doubled by the concept that you maintain afatinib treatment and add chemo as compared to just giving chemo [the current standard],” said Schuler.

In the analysis, the median PFS was 5.6 months in the afatinib arm compared with 2.8 months in the chemotherapy alone arm (HR = 0.60; 95% CI, 0.43—0.85;P= .0031). The overall response rate was 32.1% and 13.2% (P= .005), and the disease control rate was 74.6% and 45.6% in the afatinib and chemotherapy alone arms, respectively.

The median overall survival (OS) in was 12.2 months in both treatment groups (HR = 1.00; 95% CI, 0.70—1.43;P= .994). More than twice as many patients in the investigator’s choice arm than in the afatinib arm received 2 additional lines of therapy following progression on the trial (36% vs 15%). This may have confounded the possibility of detecting a difference in OS, according to Schuler.

Treatment-related adverse events (AEs) occurred in 88.6% of patients randomized to afatinib plus paclitaxel and in 70% of those assigned to investigator’s choice of chemotherapy. Rash/acne, nail disorders, and stomatitis occurred with greater frequency in the combination therapy arm. The most common AEs with the combination versus chemotherapy alone were diarrhea (53.8% vs 6.7%), alopecia (32.6% vs 15.0%) and asthenia (27.3% vs 28.3%). The incidence of peripheral neuropathy was similar at 9.1% and 8.3%, respectively.

Discontinuation rates due to treatment-related adverse events were 18.9% in the afatinib plus paclitaxel arm and 6.7% in the investigator’s choice arm. Global health status and quality of life were maintained throughout the treatment period.


Schuler MH, Yang CH, Park K, et al. Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatinib—LUX-Lung 5 (LL5).J Clin Oncol. 2014;32:5s (suppl; abstr 8019).


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