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  • Several EGFR TKIs provide marked efficacy

    2019-08-26

    Several EGFR TKIs provide marked efficacy benefits as first-line therapy in patients with EGFRm + NSCLC, with long-term responses occurring in some patients. These agents include the first-generation reversible TKIs, erlotinib and gefitinib; the irreversible second-generation ErbB family blockers, afatinib and dacomitinib; and the third-generation EGFR-wild-type sparing, irreversible EGFR/T790 M inhibitor, osimertinib [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]]. Recent data from the phase III LUX-Lung 3 and LUX-Lung 6 trials showed that treatment with afatinib resulted in significantly improved OS compared to platinum-based chemotherapy in patients with exon 19 deletion (Del19) mutations [19]. In addition, the LUX-Lung 7, ARCHER-1050 and FLAURA trials have demonstrated that second- and third-generation TKIs provide superior outcomes to first-generation TKIs [[16], [17], [18]]. Treatment with dacomitinib improved OS compared to gefitinib in the first-line setting in the ARCHER 1050 trial [20]. In contrast to the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 trials [[14], [15], [16]], the ARCHER 1050 trial excluded patients with Dorsomorphin metastases [17], limiting the generalizability of the OS data in a patient population where brain metastases are common [21].
    Methods
    Results
    Discussion In this post-hoc analysis, we identified a subgroup of patients who received prolonged treatment (≥ 3 years) with first-line afatinib. These LTRs benefited from long-term clinical activity with median PFS in excess of 3.5 years; over three quarters of these patients had an OR, the duration of which was impressive (19.4–34.5 months). Importantly, long-term treatment with afatinib was tolerable and manageable; most grade ≥ 3 AEs occurred during early treatment cycles and were managed on-treatment by utilizing a tolerability-guided dose reduction protocol. None of the LTRs had to discontinue treatment due to treatment-related AEs, and the frequency of dose reductions was consistent with the overall patient populations. Also, long-term treatment did not have any adverse effect on patients’ QoL. Finally, LTRs were generally sufficiently fit to be eligible for at least one further line of treatment following afatinib. Overall, these findings suggest that a substantial proportion of patients can achieve a favorable and sustained long-term benefit with afatinib. In the absence of head-to-head data comparing afatinib with third-generation EGFR TKIs, these data suggest that the sequential use of long-term afatinib followed by a third-generation TKI may be feasible in patients with EGFRm + NSCLC. There are limited data assessing long-term response to second-/third-generation EGFR TKIs in EGFRm + NSCLC. Moreover, differing definitions of long-term response have been used to generate the available data for first-generation TKIs. For example, some investigators defined LTRs as patients who achieved at least stable disease for > 6 months following treatment with gefitinib or erlotinib [5,6]. Conversely, in a recent expanded access program (EAP) study of 430 patients treated with gefitinib, 4% were considered LTRs because Enhancer received a minimum duration of 2 years of therapy [7]. Two other EAP studies found that 6.3% and 1.0% of patients were LTRs, respectively, when this group was defined in both studies as those treated with gefitinib for more than, or at least, 3 years [22,23]. In our analysis of LUX-Lung 7, 4% of gefitinib-treated patients received treatment for ≥ 3 years and were regarded as LTRs. Regardless of differences in the definition of LTRs, these studies indicate that LTRs to first-generation EGFR TKIs appear to be relatively rare. This may explain the perception that while targeted therapies are often associated with immediate responses, these are not considered durable. Nevertheless, a recent analysis of long-term (>10 years) safety and survival data from the IRESSA Clinical Access Program found that a subset of 75 patients continuing long-term gefitinib treatment (median duration 11.1 years) experienced excellent long-term safety, with 10- and 15-year survival rates of 86% and 59%, respectively [24]. This, together with the findings of the current analysis, suggests that outcomes can be favorable with both first- and second-generation EGFR TKIs for patients classed as LTRs. Of note, the immuno-oncology agents that have been introduced in the treatment of several cancers (including lung cancer, albeit they are not recommended for TKI-naïve EGFRm + NSCLC) are associated with long-term survival in less than 20% of NSCLC patients when used as monotherapy in unselected patients [[25], [26], [27], [28]]. Our analysis suggests that afatinib results in around 10% of patients achieving long-term clinical benefit (≥ 3 year PFS and OS), which is greater than that observed with first-generation EGFR-TKIs but slightly lower than the long-term survival rate observed with immuno-oncology agents for second/higher line treatment of patients without actionable mutations.