Clinical Pearls & Morning Reports
Osimertinib is an oral, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR and T790M resistance mutations in patients with non–small-cell lung cancer. On the basis of results of phase 1 and phase 2 studies, the Food and Drug Administration approved osimertinib under the Breakthrough Therapy Designation Program. Mok et al. conducted a confirmatory, randomized, open-label, international, phase 3 trial (AURA 3) to show the superiority of osimertinib over platinum therapy plus pemetrexed (followed by optional pemetrexed maintenance) as standard of care for patients with centrally confirmed T790M-positive advanced non–small-cell lung cancer after first-line EGFR-TKI therapy. A new Original Article explains.
Q: What is the standard first-line therapy for patients with advanced non–small-cell lung cancer with a mutant epidermal growth factor receptor (EGFR)?
A: Among patients with advanced non–small-cell lung cancer with a mutant EGFR, EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy. Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment.
Q: What percentage of patients with advanced non–small-cell lung cancer and a mutant EGFR develop a T790M mutation?
A: At the time of progression, about 60% of patients (regardless of race or ethnic background) are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR. The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing EGFR-TKI–mediated inhibition of downstream signaling and potentially leading to disease progression.
A: In the trial by Mok et al., the authors found that patients with T790M-positive advanced non–small-cell lung cancer who received osimertinib had better response rates and a longer duration of progression-free survival than did those receiving platinum therapy plus pemetrexed after first-line EGFR-TKI therapy. The progression-free survival benefit with osimertinib was observed across all predefined subgroups, with hazard ratios of less than 0.50, including in patients with asymptomatic central nervous system metastases. In five prespecified measures of patient-reported symptoms, osimertinib had better results than platinum–pemetrexed.
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Table 2. (10.1056/NEJMoa1612674/T2) Response to Treatment (Intention-to-Treat Population).
A: In the trial by Mok et al., the safety profile for osimertinib was consistent with that reported previously and differed from that in the platinum–pemetrexed group. Overall, adverse events tended to be more severe in the platinum–pemetrexed group, despite the longer treatment duration with osimertinib. In the osimertinib group, the most commonly reported adverse events were diarrhea (in 113 patients [41%]), rash (in 94 [34%]), dry skin (in 65 [23%]), and paronychia (in 61 [22%]). Osimertinib was associated with a lower rate of adverse events leading to permanent discontinuation than was platinum–pemetrexed (in 19 patients [7%] and 14 patients [10%], respectively).