In this study, we evaluated the response to osimertinib among NSCLC patients with T790M EGFR-resistant mutations following treatment with first- or second-generation EGFR-TKIs. We found that the gefitinib group had better OS (Table 2), that osimertinib treatment after previous chemotherapy (Group A) had a better response rate (Table 3), that osimertinib as the third-line treatment had better PFS than osmertinib as the second-line treatment (Table 4), that brain metastasis noted during osimertinib treatment was a poor prognostic factor for PFS, that gefitinib as a first-line therapy and inclusion in Group A (osimertinib treatment after previous chemotherapy) were better prognostic factors for OS, and that COPD tended to be a poor prognostic factor for PFS and OS (Table 6).
As shown in Table 7. In group A, 12 (26.67%) patients were with brain metastasis before osimertinib; the PFS was 11.07 months in patients with brain metastasis before osimertinib versus 21.13 months in patients without brain metastasis before osimertinib, respectively. In group B, 20 (37.7%) patients were with brain metastasis before osimertinib; the PFS was 10.27 months in patients with brain metastasis before osimertinib versus 11.87 months in patients without brain metastasis before osimertinib, respectively. So, this could explain osimertinib as the third-line treatment had better PFS than osimertinib as the second-line treatment.
In the LUX-Lung 3 and LUX-Lung 6 trials, OS was significantly longer for patients with EGFR Del19-positive tumors in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median OS was 33.3 months (95% CI = 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR = 0.54, 95% CI = 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI = 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR = 0.64, 95% CI = 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR L858R-positive tumors in either trial. in LUX-Lung 3, median OS was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR = 1.30, 95% CI = 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI = 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). The absence of an effect in patients with L858R mutations suggests that EGFR Del19-positive disease might be distinct from EGFR L858R-positive disease[6, 20, 21]. This different EGFR-TKIs effect between Del19 and L858R could also explain why osimertinib as the third-line treatment had better PFS than osimertinib as the second-line treatment in our study. Furthermore, LUX-Lung 3 results suggested cisplatin plus pemetrexed promoted longer PFS in L858R patients (8.1 months) than in Del19 patients (5.6 months); another Japan study results also suggested cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients in second line or later settings[22]. These suggested that chemotherapy has better survival benefit in L858R-positive than Del19-positive. Table 8 showed the survival difference between L858R and Del19 in our study. In L858R-positive patients, group A and group B have a trend of significant difference in PFS (12.5 months versus 9.0 months, p=0.319); by contrast, in Del19-positive patients, group A and group B have no significant difference in PFS (15.70 months versus 11.93 months, p=0.950). The survival difference between L858R and Del19 could explain osimertinib as the third-line treatment (chemotherapy treated before osimertinib) had better PFS than osimertinib as the second-line treatment.
Following pretreatment with gefitinib, osimertinib tended to have a better PFS in this study (Table 2). This data was similar to that of another study from Taiwan[23] in which the PFS for patients treated with first-generation and second-generation EGFR-TKIs was 20.3 and 11.6 months, respectively (hazard ratio HR=0.40, 95% CI= 0.18-0.82, P=0.031)[23]. Kuo et al.[23] digital PCR was used in the re-biopsy of the tissues to determine the differences between the alleles frequencies of mEGFR (19del or L858R) (AFmEGFR) and T790M (AFT790M) after acquiring resistance between the first and second generation EGFR-treated. In Kuo’s study, the AFT790M/AFmEGFR ratio of the first-generation EGFR-TKIs treatment group was significantly higher than that of the second-generation EGFR-TKIs treatment group. In addition, there was a highly significant correlation between AFT790M and AFmEGFR. This could explain why osimertinib tended to have a better PFS following pretreatment with gefitinib than with afatinib in this study. In our study, these data regarding AFT790M/AFmEGFR ratio was not available due to its retrospective study. So Kuo’s data cannot explain a better PFS following pretreatment with gefitinib than with erlotinib.
In Taiwan, gefitinib (since November 2007) was covered by national reimbursement earlier than erlotinib (since June 2008) and afatinib (since May 2014). Furthermore, osimertinib was approved with second-line use since 2016 and first-line use since 2019, but covered by national reimbursement since April 2020 in Taiwan. The timing difference of approval and national reimbursement time difference could affect outcome between these three first-line EGFR-TKIs.
Compared with the first-generation EGFR-TKIs, the second-generation EGFR-TKI exhibits a broader inhibition spectrum and has an irreversible effect on the tyrosine kinases of EGFR and other ErbB family members.[24] Previous investigations[25-27] have shown that tumors are resistant to second-generation EGFR-TKIs usually show undetectable levels of EGFR and HER2 amplification, which may indicate a greater advantage of activating EGFR mutant clones in tumors. In contrast, in tumors that acquired resistance to the first-generation EGFR-TKI, EGFR and HER2 amplification were found at a consistent frequency,[13, 28] suggesting a less dominant place of EGFR-activating mutations in this scenario.
Previous studies Oxnard and Remon yielded controversial results that investigated the predictive role of the T790M allele in liquid biopsies examined the ratio of T790M to activating EGFR-mutation alleles.[29, 30] Oxnard et al.[29] showed that he ratio of T790M to activating EGFR mutations is related to the depth of response to osimertinib treatment, while this association was not noted by Remon et al.[30] in a similar study setting. Instead of liquid biopsy samples, our study showed that using tissue re-biopsies (liquid biopsy: tissue re-biopsy= 31.6%: 68.4%, Table 1) is feasible for determining the predictive role of the T790M allele.
In our study, there was a trend toward a significant difference in median PFS between the use of osimertinib as a second-line, third-line, or ≧ fourth-line therapy, and there was a significant difference in median PFS between the use of osimertinib as a second-line therapy or third-line therapy (Table 4). This PFS data was different from the data of another study from Taiwan[23] in which the hazard ratio was 1.03 (95% CI=0.44-2.20, P=0.941). Also, the PFS data in our study is different from the PFS data from the AURA II study[31]; in that study, the PFS for osimertinib as the second-line or third-line therapy was 11.0 (6.7-NR) and 12.4 (9.5-15.5) months, respectively. Furthermore, there was no significant difference in OS in both of these studies. Many related studies also describe the effects of using the second EGFR-TKI after the initial exposure [32-36]; furthermore, these previous studies described different results. During chemotherapy, the original EGFR-dependent cells may re-grow, and a second remission may be obtained by introducing EGFR-TKIs after chemotherapy. In addition to sensitivity to acquired T790M mutations, osimertinib is also sensitive to original EGFR mutations (Del 19 and L8585R)[16]. This hypothesis may explain the higher RR and DCR seen in this study (Table 3) as compared with other study results for second-round EGFR-TKIs of different designs[32-35].
To detect T790M resistance mutations, in most studies, re-biopsy was performed when the disease progressed[13, 37], and the results showed that T790M accounted for 50-60% of the resistance mechanism. Since the cancer genome is heterogeneous, it can evolve over time, and it can also interact with different treatments[38], It is unclear whether the timing of a re-biopsy or liquid biopsy will affect the detection rate of T790M. However, in one previous study[39], The results provide evidence that there is no significant association between the timing of re-biopsy and the detection rate of T790M. In addition, this study also shows that T790M can exist for a long time after the progression of EGFR-TKI treatment, and it is also an important carcinogenic driving factor. In our study, the time interval between biopsies was 25.95±16.56 (1.33-99.10) months (Table 1); furthermore, the patients treated with gefitinib had a longer time interval between biopsies than those for the patients treated with erlotinib and afatinib. As previous description, gefitinib (since November 2007) was covered by national reimbursement earlier than erlotinib (since June 2008) and afatinib (since May 2014) in Taiwan. So, this could explain why the gefitinib group had a longer PFS than the erlotinib and afatinib groups. Furthermore, osimertinib was approved with second-line use since 2016 and first-line use since 2019, but covered by national reimbursement since April 2020. The timing difference of approval and national reimbursement time difference could affect outcome between these three first-line EGFR-TKIs.
Non-small cell lung cancer is the main cause of brain metastases.[40, 41] Amongst these with recurrent/advanced NSCLC, brain metastases are a common cause for cancer-related morbidity and mortality. As targeted therapy continues to improve the prognosis of NSCLC patients with target oncogene,[8] The deterrence of brain metastases has become an increasingly relevant treatment problem. The first and second generation EGFR-TKIs (ie gefitinib, erlotinib, and afatinib) cannot effectively cross the intact complete blood-brain barrier which the ratio of the patient's cerebrospinal fluid to plasma is as low as 0.01 to 0.003. In the AURA 3 and FLAURA studies[19, 42], the PFS benefit of osimertinib was observed in patients with or without known or treated brain metastases at trial entry. Patients with brain metastases tended to have a worse PFS benefit (PFS = 15.2, 95% CI = 12.1–21.4 months) than those without brain metastases (PFS =19.1, 95% CI = 15.2–23.5 months) in EGFR mutation NSCLC patients in the FLAURA study[42]. It seems that this could explain why initial brain metastasis did not influence the osimertinib PFS but brain metastasis during osimertinib treatment did influence the osimertinib PFS in our study.
This retrospective study has several limitations. First, this study was conducted at a single medical center, such that the patient population may be biased by patient selection and referral patterns. Second, this study was a retrospective survey, which not only resulted in incomplete data for some patients, but also did not control for laboratory examinations. Third, the multiple lines of treatment before administering osimertinib may have confounded the effects. Another limitation was that any genomic alterations beyond EGFR mutations were not measured in this study. Only first-generation EGFR-TKIs were enrolled for analysis in AURA 3 trial. Although both first- and second-generation EGFR-TKIs were enrolled for analysis, but it still is a retrospective analysis. In the future, further randomized controlled trial should be conducted to evaluate PFS and OS benefit between different sequences of EKFR-TKIs.