In stage IB-IIIA NSCLC patients undergoing radical surgery, adjuvant therapy is required due to the presence of micro-metastases or residual tumor cells after surgery. Previous meta-analyses have demonstrated that adjuvant EGFR-TKIs could prolong DFS with fewer adverse reactions [32–36]. Nevertheless, those meta-analyses included fewer RCTs or retrospective studies. they were lower in quality and reliability. Our study included all RCTs to date, which is the largest meta-analysis of adjuvant EGFR-TKIs for stage IB-IIIA NSCLC patients undergoing radical surgery. The latest OS data and exploratory analysis of EVEN and ADJUVANT studies were included. Moreover, two recently published head-to-head research studies, EVIDENCE study and IMPACT study, were added, with an increase of 43% in the sample size of patients with EGFR mutations.
Our analysis revealed that adjuvant EGFR-TKIs significantly improved DFS and reduced the risk of recurrence by 62% compared with non-EGFR-TKIS treatment in NSCLC patients with EGFR-positive mutations after radical resection. Therefore, these studies strengthened the current evidence of a DFS benefit of EGFR-TKIs treatment, suggesting that they can provide an alternative to adjuvant chemotherapy for patients with EGFR-mutated NSCLC. However, DFS benefit did not transformed into an OS advantage in our study.
With respect to reasons why adjuvant EGFR-TKIs did not induce longer OS. The Br 19 study and Li’s study did not obtain significantly improved OS benefit, which may be due to the short treatment time and small sample size in EGFR mutations. In addition, the OS data of the RADIANT, ADAURA and EVIDENCE study were immature because of short follow-up times. Though the updated OS in EVAN was encouraging, it was challenging to determine whether adjuvant EGFR-TKIs has OS benefit since this was a statistically weak phase II trial. Treatment considerations after relapse will be of great importance. Another possible reason is that the control group may have received follow-up therapy after the disease relapsed, which would have improved OS the control group. But this makes it difficult to achieve statistically significant differences in OS between the experiment group and the control group. In ADJUVANT study, patients treated with follow-up EGFR-TKIs had longer OS compared with patients in the VP group who received other follow-up treatments. (Median OS, 62.8 months; 95% CI, 40.5 to NC and median OS, 49.5 months; 95% CI, 34.7 to NC, respectively). Therefore, the proposal of using DFS as an alternative for OS in the adjuvant setting should be also taken into consideration [37, 38]. The OS data of ongoing trial ADAURA regarding osimertinib is eagerly awaited.
We detected that adjuvant EGFR-TKIs did not improve DFS compared with placebo. In this subgroup, among three RCTs enrolled, the Br.19 and RADIANT trials included unselected NSCLC patients. The Br.19 trial terminated prematurely obtained negative results. And only 15 patients harboring EGFR-mutations were recruited. As for RADIANT study, the proportion of NSCLC patients with EGFR mutations after surgery was only 16.5%(161/973). Therefore, any conclusions drawn from the results including above two studies should be interpreted with caution. No improvement of OS was detected in the subgroup analysis of different therapeutic strategies. The results showed that adjuvant EGFR-TKIs following chemotherapy improved DFS significantly compared with chemotherapy alone in postoperative patients. But in this subgroup, only Feng’s study and Li’s study were included with a small sample size. Hence, whether the optimal treatment regimen for resected NSCLC patients with EGFR-mutations is adjuvant EGFR-TKIs alone or EGFR-TKIs after chemotherapy still needs better-designed researches are needed to confirm.
Over the last decade, status of EGFR mutation has been the most useful predictors of the response to EGFR-TKIs treatment in lung adenocarcinoma . Previous studies have shown that in advanced NSCLC, patients with exon 19 deletion mutations have longer progression-free survival and higher objective response rates than patients with exon 21 L858R point mutations . The reason may be that the tyrosine kinase domain of the exon 19 deletion has a more powerful binding force to EGFR-TKIs than that of the L858R mutant . How about the results when EGFR-TKIs administrated in EGFR-mutant NSCLC after surgery? In our exploratory study, DFS benefits were observed regardless of mutation subtypes. The pooled HR showed that adjuvant EGFR-TKIs treatment seems to be also more effective for exon 19 deletion subgroup. But the hypothesis needs additionally specific experimental designs to confirm.
Patients with different stages may have differential effects on survival outcomes. Br 19 study, Feng’s study, RADIANT study and ADAURA study enrolled stage IB–IIIA NSCLC patients while EVAN and Li’s studies only recruited stage IIIA patients. ADJUVANT, EVIDENCE and IMPACT trials mainly centered on stage II and IIIA disease. Included patients with different stages may be an important reason leading to significant heterogeneity among these trials. Previous literature reported that patients with stage II–IIIA disease could benefit from chemotherapy, but for those people with stage IB disease, chemotherapy is not recommended for standard treatment . Whether IB patients after radical operation can benefit from adjuvant EGFR-TKIs remained controversial. Our study detected that adjuvant EGFR-TKIs significantly improved DFS in patients with stage III NSCLC. DFS of stage I and II NSCLC patients were not statistically significant. We hypothesized that stage IIIA NSCLC patients might be related to higher levels of tumor residues or circulating tumor DNA (ctDNA) than stage I and II , which cannot be removed by surgery and may be sensitive to systemic treatment. The mechanism remains to be further studied.
Our study manifested that longer treatment duration may be related with better DFS benefits. But the optimal duration of adjuvant EGFR-TKIs treatment needs more specialized trials to confirm. The treatment duration of eight study that we included was 2 years, which was based on the previous studies such as the SELECT and that the highest peak for metastases post-surgery occurred within 1 year or 2 years with chemotherapy. Since many of the studies did not reach the required two-year treatment duration, our analysis observes a better DFS with median treatment duration more than 12 months. But no significant improvement of DFS was observed when median treatment duration less than 12 months. Our results manifested that treatment duration may be associated with difference DFS benefits. A RCT of three months or two years of adjuvant afatinib in resected stage I-III EGFR-mutant NSCLC by Joel W. Neal detected that the median Relapse Free Survival (RFS) was 42.8 months in the three-month group and 58.6 months in the two-year group. Relapses at 2 years were 11% less than with 3 months of adjuvant afatinib. Postoperative patients might obtain better DFS from adjuvant EGFR-TKIs with longer treatment duration. However, for patients considering long-term adjuvant EGFR-TKIs therapy, early drug withdrawal may also affect the study results. Therefore, taking tolerance of therapy into consideration will be essential. The ICOMPARE study is an ongoing trial comparing one year of adjuvant icotinib with two years of that in patients with resected stage II-IIIA NSCLC with EGFR mutations and may produce more important data regarding survival outcomes and toxic effects.
Osimertinib has been shown to cause longer DFS and OS than first generation EGFR-TKIs in advanced NSCLC . In addition, osimertinib has been proved to have higher blood concentrations in the brain than other generations EGFR-TKIs in advanced NSCLC . Osimertinib induced longer DFS than placebo dramatically according to ADAURA study and significantly decrease the risk of brain metastases. However, no direct comparisons between different generations of EGFR-TKIs were designed. And ADAURA study is not a head-to-head research study comparing EGFR-TKIs with chemotherapy. Hence more head-to-head RCTs of adjuvant osimertinib are needed. Only EVAN study provided an OS benefit with erlotinib to date. We are looking forward to the updated OS data of ADAURA.
Our previous published meta-analysis  showed that adjuvant EGFR-TKIs was associated with more grade 3 or higher AEs compared with the placebo but fewer grade 3 or higher AEs compared with adjuvant chemotherapy. In this meta-analysis, we specifically analyzed the respective adverse reactions of EGFR-TKIs and non-EGFR-TKIs group. It has been reported that adjuvant EGFR-TKIs increased the risk of rash, liver dysfunction, and diarrhea , and the most common adverse reactions of adjuvant chemotherapy were hematologic toxicity and inappetence , which were consistent with our results for toxicity of EGFR-TKIs. For the EGFR-TKIs group, all grade 3 or higher AEs were manageable, demonstrating that the tolerability of EGFR-TKIs is acceptable for postoperative patients.
The meta-analysis has several limitations. First, portion of the data used to synthesize the final results of our meta-analysis were extracted from subgroup analyses of published RCTs, rather than individual patient data. subgroup analyses could tend to overestimate treatment effects. Secondly, some pooled results of our meta-analysis had significant heterogeneity, although we took random-effects models, subgroup analyses and sensitivity analyses to reduce heterogeneity. Diversity and inadequacy of data, such as difference in characters of patients, Types of medicine, experimental designs and follow-up time, may lead to clinical heterogeneity. Moreover, Subsequent treatments and quality of life need to be taken into consideration.