Abstract
The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies.
Highlights
The development of molecularly targeted cancer therapies has followed a characteristic progression in which newer agents have been developed to overcome resistance mechanisms in order to prolong disease control
The study demonstrated the superiority of osimertinib, with a median progression-free survival (PFS) of 18.9 months versus 10.2 months for the earlier-generation epidermal growth factor receptor (EGFR) inhibitors (HR 0.46, 95% CI, 0.37–0.57; p < 0.001)
While dacomitinib resulted in an improved overall survival compared to gefitinib in advanced EGFR mutant non-small cell lung cancer (NSCLC) (HR 0.76; 95% CI, 0.58–0.99; p = 0.04), afatinib did not achieve a significant improvement in overall survival compared to gefitinib (HR 0.86; 95% CI, 0.66–1.12; p = 0.26) [47,48]
Summary
The development of molecularly targeted cancer therapies has followed a characteristic progression in which newer agents have been developed to overcome resistance mechanisms in order to prolong disease control. The BCR-ABL tyrosine kinase inhibitor imatinib is a first-generation drug that has provided astounding initial response rates, good progression-free survival (PFS), and has improved long-term survival outcomes in patients [1,2,3]. Later-generation molecularly targeted therapies are able to overcome resistance through the use of multiple mechanisms, including improved potency, superior penetration into sanctuary sites such as the central nervous system, and increased binding to resistance mutations. The ENESTnd investigators observed that in the first-line treatment of chronic myelogenous leukemia, nilotinib had higher and earlier response rates with a lower risk of progression when compared to imatinib [12,13]. The ALEX Trial Investigators demonstrated that alectinib had superior PFS when compared to crizotinib as a first-line treatment [14]. Overall survival still remains the most important outcome for researchers, clinicians, and patients alike
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