Abstract and Introduction
Abstract
Background: We investigated the clinical characteristics and treatment outcomes of Korean patients receiving first-line afatinib for advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) in a real-world setting.
Methods: Electronic case reports were retrospectively reviewed from patients across 15 sites in South Korea. Outcome measures included baseline characteristics, overall response rate (ORR), time-to-treatment discontinuation (TTD), and overall survival (OS). Subgroups were: presence/absence of brain metastases at baseline, dose reductions, and baseline EGFR mutation category.
Results: Among 422 patients, 39.8% had brain metastases and 59.0%/25.1%/10.0%/5.0% had Del19/L858R/compound/uncommon EGFR mutations at baseline. ORR was 62.6% overall; responses were observed across all EGFR mutation categories, including against compound mutations. Median TTD was 17.8 months; median OS was not reached (NR). Median TTD and OS were longer in patients without versus with brain metastases (TTD: 22.9 vs. 14.8 months, P=0.001; OS: NR vs. 40.3 months, P=0.0009) and patients with versus without dose reductions (TTD: 22.2 vs. 14.2 months, P=0.0004; OS: NR vs. 40.3 months, P=0.0117). Median OS was 30.5/37.7 months in patients receiving chemotherapy/osimertinib as subsequent therapy. The most common treatment-related adverse events (TRAEs; any grade/grade ≥3) were diarrhea (31.3%/8.5%) and rash (23.0%/8.1%). Overall, 34 patients (8.1%) discontinued afatinib due to AEs.
Conclusions: Afatinib was well tolerated with no new safety signals, and efficacy was encouraging in Korean patients with EGFRm+ NSCLC, including those with baseline brain metastases and/or uncommon EGFR mutations. AE management with dose reductions facilitated a long TTD, prolonging the chemotherapy-free period for many patients.
Introduction
Lung cancer is the most common cause of cancer-related mortality worldwide,[1] and in South Korea, where it is expected to account for approximately 18,796 deaths in 2020.[2] Activating mutations in the epidermal growth factor receptor (EGFR) gene, which lead to dysregulated EGFR signaling, are observed in up to 50% of Asian patients with non-small cell lung cancer (NSCLC).[3,4] EGFR-mutated tumors tend to be dependent on EGFR activity, rendering them highly sensitive to targeted inhibition with EGFR tyrosine kinase inhibitors (TKIs).[5] Accordingly, EGFR TKIs are now the first-line treatment of choice for patients with EGFR mutation-positive (EGFRm+) NSCLC, and five such agents are currently approved in this setting. These are: the first-generation reversible EGFR TKIs, gefitinib and erlotinib; the second-generation irreversible ErbB family blockers, afatinib and dacomitinib; and the third-generation irreversible, wild-type sparing EGFR TKI, osimertinib.[6]
Afatinib is an ErbB family blocker that irreversibly inhibits EGFR, human epidermal growth factor receptor (HER)2 and HER4, and blocks transphosphorylation of HER3, thereby blocking signaling via all ErbB family homo- and hetero-dimers.[7,8] In randomized clinical trials, afatinib demonstrated superior efficacy as first-line treatment versus chemotherapy (LUX-Lung 3 and 6) and gefitinib (LUX-Lung 7) in patients with EGFRm+ NSCLC.[9–11] Across these trials, afatinib was well tolerated, with few treatment discontinuations due to adverse events (AEs). Treatment-related AEs (TRAEs) with afatinib were predominantly class-related gastrointestinal and skin-related toxicities, and these were managed effectively with tolerability-guided dose reductions.[9–11]
As well as being highly active against common (Del19 and L858R) EGFR mutations, afatinib shows a broad preclinical and clinical inhibitory profile against many uncommon EGFR mutations, including those occurring in combination with an independent common or uncommon mutation (known as 'compound mutations').[12,13] Afatinib is clinically active against the most prevalent uncommon mutations, G719X, S768I, and L861Q, in exons 18, 20, and 21, respectively,[14] and is approved in many countries for the treatment of NSCLC harboring these activating mutations, as well as for Del19-/L858R-positive NSCLC. In South Korea, afatinib has been approved and reimbursed in this indication since 2014. Evidence also suggests that afatinib can also effectively penetrate the blood-brain barrier, and that it may be effective both in treating existing central nervous system (CNS) metastases and in mitigating the risk of CNS progression.[15]
Randomized controlled trials such as the LUX-Lung studies demonstrate the efficacy and safety of study drugs under highly controlled settings, often with strict inclusion criteria. Therefore, it is important to evaluate the efficacy and tolerability of afatinib in real-world studies in broader patient populations, which may better reflect daily clinical practice.[16] Real-world data can be used to assess treatment effectiveness in patient populations that are generally under-represented in clinical trials, such as elderly patients, patients with brain metastases, patients with uncommon EGFR mutations, and those with comorbidities. Furthermore, clinical trials often have strict discontinuation and stopping criteria, whereas in the real-world setting, treatment may continue beyond radiological progression. So far, available real-world evidence suggests that afatinib is tolerable and effective in diverse patient populations in everyday clinical practice. Several real-world comparative studies also indicate that afatinib is associated with improved efficacy compared with first-generation EGFR TKIs, consistent with the results of LUX-Lung 7.[17] For example, in a recent single-center analysis of 467 patients treated with first-line EGFR TKIs in South Korea, median progression-free survival (PFS) was significantly longer with afatinib versus gefitinib or erlotinib, and the PFS benefit with afatinib was particularly pronounced in subgroups with Del19 or uncommon EGFR mutations.[18]
In this study, we investigate the clinical characteristics and treatment courses of patients who received afatinib as first-line therapy for advanced EGFRm+ NSCLC in the real-world setting in South Korea. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-501).
Transl Lung Cancer Res. 2021;10(12):4353-4367. © 2021 AME Publishing Company
