This study is the first to compare the clinical effectiveness of second-generation EGFR-TKIs (dacomitinib or afatinib) and osimertinib in Taiwanese patients with NSCLC with common EGFR mutations. Our findings indicate that, in real-world scenarios, both second-generation EGFR-TKIs and osimertinib confer comparable median PFS and TTF. Notably, median PFS did not differ significantly between these two treatment strategies in patients with initial brain metastasis. The initial disease stage independently predicts PFS. Moreover, second-line treatment patterns differed significantly between second-generation EGFR-TKIs (dacomitinib or afatinib) and osimertinib.
In treating advanced EGFR-mutated NSCLC, the FLAURA trial and its subsequent studies10,20,21 have demonstrated the survival benefit of osimertinib as first-line therapy compared to first-generation EGFR-TKIs. Its safety profile and efficacy have led to its designation as a first-line treatment. However, inconsistent results have been reported in the Asian population and among EGFR mutation subtypes (the L858R mutation in exon 21).21 There is also limited research on whether osimertinib is superior to second-generation EGFR-TKIs as first-line treatment for EGFR-mutated NSCLC. Few real-world studies have investigated using osimertinib and afatinib as first-line treatment for EGFR-mutant NSCLC (Table 3).14–17
The retrospective, multicenter CJLSG1903 study15 in Japan compared afatinib (n = 224) and osimertinib (n = 326) as first-line treatments, showing that osimertinib did not significantly extend the time to discontinuation of EGFR-TKIs (20.5 vs. 18.6 months, p = 0.204), time to treatment failure (20.5 vs. 16.0 months, p = 0.443), or PFS (20.5 vs. 16.5 months, p = 0.864) compared to afatinib. Propensity-score-adjusted OS favored afatinib over osimertinib (25.1 vs. 36.2 months, p = 0.018). However, a considerable disparity in median follow-up periods between afatinib (26.2 months) and osimertinib (9.4 months) raises concerns about potential bias, indicating that the results should be interpreted cautiously. Another real-world study conducted in Japan by Mitsuya et al. 16 reported no significant difference in median OS between osimertinib and afatinib in patients with advanced EGFR-mutated NSCLC (36 vs. 33 months, p = 0.112). However, their results should also be interpreted cautiously due to their limited sample size of 49 patients. Similarly, a real-world retrospective study conducted in the USA by Gilardone et al.17 reported no differences in PFS or OS between patients treated with afatinib or osimertinib as first-line therapy. However, the median follow-up periods differed significantly between the afatinib (56 months) and osimertinib (22 months) groups. A Taiwanese study by Huang et al.14 demonstrated no significant difference between osimertinib and afatinib in median PFS (18.8 vs. 13.1 months, p = 0.208) and OS (not reached vs. 41.7 months, p = 0.553).
In our observational study conducted in Taiwan, the median follow-up time was 17.6 months for patients given second-generation EGFR-TKIs and 21.9 months for patients given osimertinib. In addition, the median PFS was not significantly longer with osimertinib (28.3 months) than with second-generation EGFR-TKIs (17.6 months for NSCLC with del19 mutations and 20.0 months for NSCLC with the L858R mutation in exon 21). Notably, the second-generation EGFR-TKIs conferred comparable PFS for patients with del19 and L858R mutations. Kohsaka et al. found that 15.9% of 390 specimens from EGFR-mutated NSCLC had compound EGFR mutations. Notably, the L858R mutation (19.5%) was more common than the del19 mutation (4.7%).22
A recent next-generation sequencing study indicated that around 10% of patients with NSCLC have compound EGFR mutations involving multiple distinct genetic changes in the EGFR gene at initial diagnosis.23 Patients with compound EGFR mutations typically show reduced responsiveness to EGFR-TKI therapies than those with a single EGFR mutation.24,25 Yang et al.validated the effectiveness of afatinib in treating NSCLC with very rare mutations (G719X, S768I, and L861Q).26 Li et al. demonstrated the effectiveness of dacomitinib in patients with NSCLC and rare EGFR mutations, both in first-line and subsequent treatments.27,28 Therefore, second-generation EGFR-TKIs appear to overcome reduced treatment responses with compound EGFR mutations. Wang et al. also reported that afatinib and osimertinib demonstrated efficacy against rare EGFR mutations, with afatinib conferring a longer PFS than osimertinib.29 However, in our study, the osimertinib group primarily comprised patients with a del19 mutation (n = 53, 96.4%) due to health insurance coverage constraints. When considering only patients with del19 mutations, osimertinib did not confer significantly longer PFS (28.3 vs. 17.6 months; p = 0.118) and TTF (30.2 vs. 22.7 months; p = 0.772) than second-generation EGFR-TKIs.
Several studies have suggested that osimertinib may reduce the risk of CNS progression compared to standard EGFR-TKIs.30,31 The CJLSG1903 study observed that osimertinib had a similar median PFS (HR = 0.60, p = 0.062) and time to EGFR-TKI discontinuation (HR = 0.66, p = 0.0103) to afatinib, indicating no clear advantage.15 However, our study does not definitively establish osimertinib as superior to second-generation EGFR-TKIs in the first-line treatment of patients with NSCLC, the del19 mutation, and CNS metastasis. The observed difference in median PFS between osimertinib (14.3 months) and second-generation EGFR-TKIs (17.6 months) was not statistically significant. Huang et al. reported that patients with NSCLC and brain metastasis treated with osimertinib had significantly improved median PFS compared to those treated with afatinib. Larger-scale studies are needed to provide further clarity in this area.
Numerous small-scale studies have examined the independent predictive factors for shorter PFS in first-line EGFR-TKI treatment of EGFR-mutated NSCLC. These factors include poor ECOG PS,32 carrying the T790M mutation before treatment,33 concomitant mutations (e.g., in axin 2 [AXIN2], phospholipase C gamma 2 [PLCG2], and RAD51 paralog C [RAD51C]) and/or high marker of proliferation Ki-67 (MKI67) expression,34 tumor protein p53 (TP53) co-mutations,35 and dynamic plasma EGFR mutation status.36 However, the results of these studies lack consistency and are not easily applied in clinical practice. Our multivariate regression analysis revealed that the NSCLC stage was the only independent negative predictor of PFS. There was no compelling evidence suggesting a significant impact on PFS between osimertinib and second-generation EGFR-TKIs, consistent with Huang et al.14
Our study observed significant differences in second-line treatment patterns after disease progression between osimertinib and second-generation EGFR-TKIs (p = 0.008). Upon failure of first-line afatinib treatment, chemotherapy (39%) and osimertinib (31%) are the most common second-line treatments. In contrast, upon failure of first-line osimertinib treatment, chemotherapy (57%) is the most common second-line treatments, followed by opting for no further treatment (33%).
In real-world clinical practice, such as in the GioTag,11 RESET,12 and UpSwinG13 studies, sequential administration of afatinib and osimertinib has shown encouraging outcomes in patients with EGFR-mutated NSCLC, particularly those with del19 mutations and Asian ancestry. Interestingly, the RESET study12 revealed that patients treated with pemetrexed-platinum doublet therapy in the second line had a comparable OS (50.0 months) to those treated with osimertinib in the second line (54.3 months) after afatinib failure (p = 0.6). In the FLAURA study,10 the OS with first-line osimertinib treatment was 38.6 months. These findings reemphasize the potential advantages of using second-generation EGFR-TKIs instead of osimertinib as the first-line treatment.
While contributing valuable insights, this study had several limitations. Firstly, its retrospective design introduces potential bias since there is an inherent risk of inaccuracies or incomplete documentation. Secondly, since it was conducted at a single center in Taiwan with a small sample size, the applicability of its findings to broader populations may be limited. Thirdly, given the relatively short follow-up period, the OS analysis is still in its early stages, limiting the comprehensive understanding of long-term outcomes. Fourthly, health insurance coverage constraints have impacted the data, with the osimertinib group predominantly composed of patients with del19 mutations, preventing a thorough examination of osimertinib’s effects on NSCLC with the L858R mutation in exon 21. Finally, it did not analyze adverse events associated with EGFR-TKIs, leaving an important aspect of treatment outcomes unexplored.