First-Line Therapy in EGFR-Mutant Lung Cancer

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Molecular testing should guide the frontline treatment selection for patients with non-small cell lung cancer (NSCLC), Heather A. Wakelee, MD, stresses. This testing should go beyond simply EGFR status to include information on whether the EGFR mutation is on exon 19 or exon 21 (L858R), since this could lead to different treatment approaches.

In the United States, the TKIs erlotinib and afatinib are both approved as frontline therapies for patients with NSCLC, elsewhere gefitinib is also available. In the frontline setting, patients with an exon 19 deletions should receive erlotinib, with afatinib, often in combination with cetuximab, as a next step if needed, believes Wakelee. However, recent findings from a subgroup analysis from the combined LUX-Lung 3 and LUX-Lung 6 studies are challenging this treatment selection.

This subgroup analysis found that patients with an exon 19 deletions who received afatinib experienced an extension in overall survival. This survival benefit was not seen in tumors harboring the exon 21 mutation (L858R) and has not been seen in any other trials with TKIs. Based on these data, some practices always give first-line afatinib to treat tumors with exon 19 deletions, Wakelee adds.

Each patient responds differently to frontline therapy with a TKI, with some patients progressing slowly with only one site of metastatic disease that can be treated with localized therapy. Following progression on frontline therapy, a second biopsy should be performed to guide the next treatment decision.

Patients with slower progression should be rebiopsied to assess for resistance mutations, such as T790M, which is found in nearly 60% of patients who progress on a first-line TKI. Patients with rapid progression should be rebiopsied to determine whether there was a transition from NSCLC to small cell lung cancer.