Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?

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.

Keywords: epidermal growth factor receptor; lung cancer; osimertinib; personalized medicine; resistance; tyrosine kinase inhibitors.

Figure 1

Theoretical comparison of the overall duration of response with two different sequencing paradigms. Pictured above is the sequencing strategy in which an earlier-generation EGFR TKI, erlotinib, is used in the first line, followed by the later-generation EGFR TKI osimertinib after progression in the setting of acquired T790M mutation. Progression-free survival (PFS) for first-line erlotinib is drawn from the phase 3 EURTAC trial, which compared erlotinib to conventional chemotherapy in the first-line setting [15]. The median PFS for osimertinib after progression on early-generation EGFR TKIs in T790M-positive patients was derived from the AURA3 trial [55]. The median PFS for osimertinib after progression on EGFR TKIs in T790M-negative patients was derived from the AURA trial [60]. Pictured below is the sequencing strategy in which the later-generation TKI was used in as a first-line treatment based on the PFS demonstrated in the FLAURA trial [29]. In this comparison, sequential therapy with the earlier-generation EGFR TKI followed by the later-generation TKI after progression with T790M-positivity yielded a greater overall duration of response than the use of later-generation EGFR TKI as the first-line treatment. Fully acknowledging the limitations of the cross-trial comparison, this nonetheless illustrates that the superior efficacy of later-generation therapies in the front line may not lead to superior overall survival despite a clearly superior PFS when comparing front-line therapies in isolation.

Figure 2

Comparison of cumulative months of progression free survival in theoretical cohorts of 10 patients treated with two sequencing strategies. (a) A theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with osimertinib in the first line using the median PFS observed in the FLAURA trial. The estimated cumulative duration of the response for the entire cohort is calculated below. (b) The paradigm of sequential therapy in which a theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with erlotinib in the first line followed by osimertinib if T790M-positive mutational status was present after disease progression. The median progression-free survival (PFS) for erlotinib in the first line was derived from the EURTAC trial [15]. The median PFS for osimertinib after progression on early-generation EGFR TKIs in T790M-positive patients was derived from the AURA3 trial. The median PFS for osimertinib after progression on EGFR TKIs in T790M-negative patients was derived from the AURA trial [60]. The estimated cumulative duration of response for the cohort of patients was calculated for each therapeutic step and for the entire treatment course. (c) A theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with erlotinib in the first line followed by osimertinib regardless of their T790M mutational status after disease progression as part of the paradigm of sequential therapy. The estimated cumulative duration of response for the cohort of patients was calculated for each therapeutic step and for the entire treatment course. Acknowledging the limitation of the cross-trial comparison, this thought experiment demonstrates that the use of later-generation osimertinib may yield an overall superior duration of response in a cohort of patients even if the overall duration of response with erlotinib followed by osimertinib (9.7 months + 10.1 months = 19.8 months) in an individual patient was longer than that seen in osimertinib in the first line (18.9 months).

Figure 2

Comparison of cumulative months of progression free survival in theoretical cohorts of 10 patients treated with two sequencing strategies. (a) A theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with osimertinib in the first line using the median PFS observed in the FLAURA trial. The estimated cumulative duration of the response for the entire cohort is calculated below. (b) The paradigm of sequential therapy in which a theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with erlotinib in the first line followed by osimertinib if T790M-positive mutational status was present after disease progression. The median progression-free survival (PFS) for erlotinib in the first line was derived from the EURTAC trial [15]. The median PFS for osimertinib after progression on early-generation EGFR TKIs in T790M-positive patients was derived from the AURA3 trial. The median PFS for osimertinib after progression on EGFR TKIs in T790M-negative patients was derived from the AURA trial [60]. The estimated cumulative duration of response for the cohort of patients was calculated for each therapeutic step and for the entire treatment course. (c) A theoretical cohort of 10 patients with advanced EGFR mutant NSCLC treated with erlotinib in the first line followed by osimertinib regardless of their T790M mutational status after disease progression as part of the paradigm of sequential therapy. The estimated cumulative duration of response for the cohort of patients was calculated for each therapeutic step and for the entire treatment course. Acknowledging the limitation of the cross-trial comparison, this thought experiment demonstrates that the use of later-generation osimertinib may yield an overall superior duration of response in a cohort of patients even if the overall duration of response with erlotinib followed by osimertinib (9.7 months + 10.1 months = 19.8 months) in an individual patient was longer than that seen in osimertinib in the first line (18.9 months).