The present study compared the data of patients who received sequential treatment with afatinib and osimertinib to those of patients who received second-line treatments other than osimertinib. We comprehensively investigated clinical outcomes (i.e., TOT, OS, DCR, and ORR) and robustly evaluated the factors affecting TOT in afatinib and osimertinib treatments. Considering the controversies regarding the use of first-line osimertinib followed by other therapies or first-line first-/second-generation TKIs followed by osimertinib as appropriate options for treating EGFR-mutated NSCLC patients 15, the RWD from RESET might be of interest. RESET included a group of old-age patients with poor performance status and brain metastases, characteristics likely to exclude these patients from RCTs due to strict inclusion criteria. Thus, the results from RESET could be applicable across real-world clinical settings in the management of advanced-stage EGFR-mutated NSCLC patients.
RESET showed that clinical efficacy was better in group A patients than in group B patients. The estimated overall TOT in group A was 33.9 months, which was significantly longer than that in group B (21.3 months). Subgroup analyses also revealed that overall TOT was longer in group A than in group B for all subdivided clinical characteristics, such as smoking status or EGFR mutation type. If we separated first- and second-line treatments, the median TOTs in group A patients were superior to those in group B patients. In addition to TOT, group A was numerically superior to group B with respect to OS, DCR, and ORR for all subdivided clinical characteristics. The AURA-3 clinical trial demonstrated that second-line osimertinib had significantly greater efficacy than pemetrexed plus platinum-based therapy in advanced-stage T790M-mutated NSCLC during treatment with first-line EGFR TKIs such as gefitinib, erlotinib, and afatinib 7. AURA-3 reported 10.1 months of PFS on osimertinib and 4.4 months of PFS on platinum-based pemetrexed therapy, with results comparable to those of RESET, 11.2 months in group A and 5.1 months in group B.
RWD may differ from RCT data for several reasons. RCTs traditionally require strict criteria for study entry, but this would guarantee unbiased distribution of confounding factors, support causality, and provide strong internal validity; thus, evidence from the RCTs has been considered the gold standard. However, because patients with poor performance status, presence of brain metastasis, advanced age, and comorbidities are seldom included, RCTs may suffer from the loss of clinical diversity. Therefore, the importance of RWD in clinical practice has become apparent. RWD can provide supplemental data and additional understanding on top of that from RCTs 16. In particular, concordance between RWD and RCT data could establish the best approach for managing patients.
However, in terms of sequential therapy with afatinib and osimertinib, only a small number of studies have investigated the clinical characteristics and outcomes in patients with EGFR-mutated NSCLC. In the real-world GioTag study 8, when using sequential treatment of afatinib and osimertinib, encouraging TOT results were obtained, especially in Asian populations and Del19-positive NSCLC patients. The median TOT was 27.6 months in all patients, 30.3 months in Del19-positive NSCLC patients, and 46.7 months in Asian populations 8. Updated data on the GioTag study showed that the median OS was 41.3 months and the TTF was 28.1 months 17. In Del19-positive NSCLC patients, the OS was 45.7 months and the TTF was 30.6 months 17. Although an advantage of the GioTag study is its involvement of a variety of ethnic groups in several countries, it only included 50 Asian patients. During first- and second-line treatments, the overall TOT in all patients within RESET was 26.4 months. The median TOT in group A patients within RESET was estimated to be 33.9 months, which is slightly shorter than that of Asian patients within GioTag, 46.7 months 8. However, given that only a small number of Asian patients were included in GioTag, the proportion of elderly patients (≥ 65 years) was higher in RESET (43.9% vs. 34.8%), and RESET included a higher percentage of patients with baseline brain metastasis (43.9% vs. 10.3%) 8, the results of RESET are encouraging. The RWD from the RESET study is further supported by another multicenter retrospective study in Japanese patients 18. In this study, patients sequentially treated with afatinib and osimertinib showed better ORR and DCR than patients treated with other first-generation TKIs (i.e., gefitinib and erlotinib). The above observational studies using RWD highlight the efficacy of sequential treatment with afatinib and osimertinib.
Several RWD trials have estimated the efficacy of afatinib as a first-line treatment option in patients with EGFR-mutated NSCLC. The estimated TOT-1 in RESET (15.2 months) is similar to previously reported results from other real-world studies: TOT of 14.0 months for Asian populations in the GioTag study 8, TTF of 13.1 months in the Japanese population 10, and TTF of 13.6 months and PFS of 12.4 months in a Taiwanese group 13. On the contrary, in the Korean population, Kim et al. reported a longer PFS for first-line afatinib treatment (19.1 months) than in our study. This difference might be attributable to the different characteristics of the study subjects. Compared to the same ethnic group in the study by Kim et al., which analyzed 165 Koreans diagnosed with NSCLC, the subjects in our study were older (median age: 61.5 years vs. 57 years) and presented with a slightly higher percentage of brain metastasis (43.9% vs. 40.6%) 9.
RESET assessed several factors affecting TOT-1 using a multivariate Cox PH model. Poor performance status (ECOG PS ≥ 2 vs. 0–1), advanced tumor stage (AJCC 4B vs. 3), tissue type other than adenocarcinoma, liver metastasis, and no afatinib dose adjustment were shown to be related to decreased TOT-1. Interestingly, afatinib dose adjustment was associated with better outcomes for TOT. It is not clear whether TOT was better due to dose reductions, or whether TOT was worse due to dose maintenance, but a study that investigated the effect of dose adjustment on survival outcomes in patients with EGFR-mutated NSCLC reported that patients who received dose reductions experienced higher ORRs 19. Another RWD study showed that dose adjustment reduced the number and intensity of several side effects, emphasizing that tailored dose modification could help treatment optimization and improve survival outcomes 20. In addition, a post-hoc analysis of LUX-Lung 3 and 6 trials showed that dose reduction was more common in female, old-age, low-weight, and Asian-Japanese patients 21. Dose reduction led to fewer adverse events and less treatment discontinuation.
Notably, the TOT-1 in group A patients was greater than that in group B patients. Tanaka et al. reported that PFS was significantly longer in patients who developed the T790M mutation after the onset of first-line afatinib therapy than in those who did not develop the mutation 22. Indeed, in RESET, the percentage of T790M development after first-line afatinib was greater in group A than in group B patients: 126/131 (96.2%) in group A and 8/81 (9.9%) in group B. This result is consistent with another study showing that OS was significantly longer in patients with the T790M mutation than in those without it 23. Although the mechanism of resistance to EGFR-TKIs might be heterogeneous, the slow growth rate of T790M-harboring cells could partially explain this observation 24. These findings might account for the better survival outcomes in patients who developed the T790M mutation after first-line afatinib treatment, indicating potential association between a longer treatment period and development of the mutation.
Several EGFR-TKIs have been developed to address the problem of EGFR mutations following therapy. Currently, the standard treatment option for patients with EGFR-mutated advanced-stage NSCLC is an EGFR-TKI. Considering its superior efficacy in terms of PFS, OS, central nervous system activity, and adverse events, clinicians prefer osimertinib as first-line therapy 25. Despite these benefits, inevitably acquired mutations during osimertinib therapy, such as the C797S mutation 26, as well as the interpatient, intratumoral, and intertumoral heterogeneity of NSCLC 27, complicate the optimal therapeutic determination of EGFR-TKI sequence. The optimal sequence of treatment remains controversial 15. In particular, in the National Health Insurance of South Korea, osimertinib is only approved for second-line treatment after failure of other first-line EGFR-TKI treatments. Therefore, sequential treatment of first- or second-generation EGFR-TKIs with the third-generation EGFR-TKI, osimertinib, is a possible alternative.
The RESET study has limitations. First, the main limitation resulted from RESET's retrospective nature. Selection bias or misclassification existed. To mitigate this problem, subgroup analyses were performed to identify any potential factors significantly affecting survival outcomes. The results of multicenter hospital-based surveillance from RESET could provide insight into the universality of the efficacy of sequential treatment with afatinib and osimertinib. Second, TOT-2 was shorter than TOT-1, which is opposite to the finding in GioTag. TOT-1 in GioTag might have been rather short due to inclusion criteria and drug availability. And also, this may have originated from the short observation period of osimertinib treatment in RESET, in which survival data were not matured at the time of analysis; further data collection and analysis may be warranted. Third, five of the group A patients did not develop the T790M mutation and received osimertinib treatment, while seven of the group B patients developed T790M and did not receive the treatment. Fourth, because 377 patients were excluded, it was not feasible to obtain more detailed information, such as the percentage of patients who received second-line treatment or the frequency of T790M development. In the future, we are planning to also collect data in group A and B patients and in excluded patients who received first-line afatinib treatment. Despite these limitations, to the best of our knowledge, RESET is the first multicenter study in South Korea based on real-world experience, and its applicability to real clinical practice, especially for Asian populations, could allow better patient management and improved survival outcomes in patients with EGFR-mutated advanced NSCLC.