Selecting a First-Line EGFR Inhibitor in NSCLC

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On July 12, 2013, the FDA approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) who express EGFR exon 19 deletions or exon 21 substitutions. Along with this approval, the FDA also cleared a companion diagnostic for the detection of these specific mutations.

Following the approval, questions remain regarding the optimal utilization of afatinib, since other EGFR inhibitors are already approved and widely administered in the frontline setting, notes Karen Reckamp, MD. Moreover, results of clinical trials for EGFR inhibitors have shown that each of these agents is very active, notes Reckamp.

The approval for afatinib was based on results from the phase III LUX-Lung 3 trial that enrolled 345 patients with advanced lung adenocarcinoma. In the trial, patients were randomized to receive either afatinib or cisplatin and pemetrexed. For patients with EGFR alterations, progression-free survival (PFS) was 13.6 months with afatinib compared to 6.9 months with the chemotherapy combination.

In general, overall survival for patients treated with EGFR inhibitors is 2 to 3 years compared to 10 to 12 months for patients without the driver mutation, Reckamp states. As a result, treatment with these agents clearly changes a patient’s life.

At this point, a head-to-head comparison of erlotinib and afatinib is not available. Each agent possesses a unique toxicity profile, which could be utilized to select treatment, Reckamp suggests. However, outside of these criteria, current evidence does not indicate that one agent is superior to the other.

For the time being, moderator, Corey J. Langer, MD, suggests, most patients with EGFR mutations may have already received treatment with frontline erlotinib. As a result, the likely scenario for treatment with afatinib is in the second-line. However, at this point, afatinib is not approved to treat patients in this setting.

The LUX-Lung 1 trial specifically examined the efficacy of afatinib compared to placebo following a response to treatment with erlotinib, gefitinib, or both, for patients with NSCLC. In this trial, EGFR mutations were not part of the inclusion criteria. Patients treated with afatinib experienced a modest benefit in PFS, but overall survival was not significantly improved.

Based on these data, a second-line indication for afatinib was not sought. Despite this, Reckamp notes, there may still be a role for afatinib in this space, although it is not as impactful as the first-line setting.

Afatinib is unique compared to previous EGFR inhibitors, notes Roy S. Herbst, MD, PhD. It works as a pan-HER inhibitor, blocking not only EGFR (HER1) but also HER2 and HER3. As part of this mechanism, the agent has some activity against T790M resistance mutations, which develop in approximately 50% of patients, Herbst notes.

The greatest initial utility for afatinib is likely going to be the second-line setting, believes Herbst. Additionally, he adds, a great deal of activity has been seen with afatinib in combination with cetuximab in patients who are refractory to EGFR inhibitors. This combination strategy is currently being explored further in clinical trials in the refractory and eventually frontline setting, Herbst notes.

This combination is interesting, since cetuximab has never been formally approved to treat patients with NSCLC, notes Langer. Adding to this, Herbst suggests, given the greater understanding of biology, many agents that were overlooked before may now have utility in combinations.