The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs; gefitinib and erlotinib) in advanced non-small cell lung cancer has only been around for a few years, but like a dark horse, it has shown great vitality and vigor since its introduction, and it has been running neck and neck with conventional chemotherapy for more than half a century, representing two very different but inextricably linked treatment modalities for advanced lung cancer. They represent two distinct but inextricably linked treatment modalities for advanced lung cancer.
Throughout the clinical research trajectory of EGFR-TKIs, it reflects the development of targeted drugs from clinical non-selective (e.g. BR21, ISEAL, INTEREST, etc.) to selective (IPASS, First-SIGNAL, etc.) and finally to molecular marker-based selection (NEJ002, WJTOG3405, OPTIMAL, etc.). The inevitable development of individualized therapy. EGFR mutations play an important role in individualized targeted therapy throughout the first-line, second-line or maintenance treatment of EGFR-TKIs.
First-line TKIs treatment.
The Pivotal Role of EGFR Mutation Screening
The IPASS study was the first multicenter, randomized, large-sample trial to show that first-line gefitinib treatment in patients with advanced non-small cell lung cancer with EGFR mutations has better efficacy and progression-free survival than standard chemotherapy, initially establishing the place of EGFR mutations in individualized targeted therapy. However, the analysis of molecular markers in the IPASS study was retrospective, thus weakening the evidence for evidence-based medicine. Recently, three multicenter phase III randomized clinical trials (NEJGSG 002, WJOG3405, and OPTIMAL studies) from Japan and mainland China, which prospectively studied EGFR mutation status, have remedied the shortcomings of the IPASS study. By comparing with the standard chemotherapy paclitaxel/carboplatin and the more potent docetaxel/cisplatin or gemcitabine/cisplatin, it is indisputable that EGFR mutations play a pivotal role in determining first-line TKI therapy.
While the dust has settled on the role of EGFR mutations in predicting the efficacy of first-line EGFR-TKI, two major issues plague clinicians. One is that in almost all phase III randomized clinical studies comparing head-to-head first-line EGFR-TKI with standard chemotherapy (including IPASS, NEJ002, and WJTOG3405), PFS was significantly prolonged in the EGFR-TKI treatment group, but the prolongation of OS was not statistically significant, so what is the reason? The sample sizes of the above studies were calculated based on the primary endpoint of disease-free survival rather than the secondary endpoint of median survival time, and the sample sizes may not reach the level of certainty to test the difference in median survival time; secondly, follow-up treatment greatly affects OS, and the imbalance in follow-up treatment between the trial and control groups may affect the outcome of OS. Therefore, future challenging studies should be limited to all follow-up treatments in both groups to make them balanced, so that they can be comparable and obtain real OS, but such a rigorous clinical study is difficult to conduct in practice.
Second, what is the ideal treatment sequence of EGFR-TKI and chemotherapy for patients with EGFR mutations? In the NEJ002 study, 94.6% of those who failed first-line chemotherapy received gefitinib, while 67.5% of those who failed first-line gefitinib alternated to the chemotherapy arm, with a much greater chance of alternating than in other studies (only 39% in the IPASS arm), but the median OS between the two treatment arms still did not reach a significant difference. The SLCG study by Rosell et al. showed similar PFS and median OS between first-line and second-line treatment for EGFR-mutated patients, which seems to support this hypothesis. However, this has yet to be confirmed by rigorous prospective clinical studies designed for both first-line and subsequent alternate therapy.
Pending the results of new studies on the optimal sequence of TKI versus chemotherapy in patients with EGFR mutations, the author believes that first-line treatment with TKI in patients with mutations has a greater benefit than chemotherapy for three reasons: (1) The efficacy of first-line treatment greatly affects the efficacy of subsequent treatment and overall survival of patients, with effective patients surviving longer than those who are not effective, and the efficiency of EGFR-TKI in patients with EGFR mutations is The efficiency of EGFR-TKI in patients with EGFR mutation is 70%~80%, which is much higher than that of chemotherapy patients (about 30%~40%); (2) about 10%~20% of patients enter the end stage rapidly after first-line treatment once the disease progresses until death, and the PFS of first-line treatment is similar to the overall survival at this time. The PFS of TKI treatment in patients with mutations is prolonged by 3-8 months compared with chemotherapy patients, and such prolongation will translate into prolongation of overall survival in patients with disease progression; (3) Chinese people talk about “timing, location and harmony”, and the efficacy and quality of life of the best treatment given at the best time and in the best condition may be better than that of the same regimen when the body is in a declining condition (second-line or multi-line). treatment when the status is declining (after second or multiple lines).
TKIs maintenance.
EGFR mutations play an important role
Maintenance therapy has been a hot topic of research in recent years. Theoretically, for those who have reached disease control with first-line therapy, maintenance with a drug that is not cross-resistant to the previous treatment and that is highly effective and less toxic has the potential to delay disease progression, improve quality of life, and thus prolong overall survival, while also increasing the patient’s chances of receiving subsequent therapy.
Since the publication of the first article on paclitaxel maintenance therapy by Professor Beleni in J Clin Oncol in 2005, maintenance therapy has undergone a journey from the end of the road to the light of day. In particular, after the publication of the JMEN study, maintenance therapy has turned around and pemetrexed has entered the NCCN treatment guidelines as an option for those who have not progressed in first-line treatment.
The SATURN studies published in recent years have gained attention because of the potential of using small molecule tyrosine inhibitors with low side effects as maintenance therapy to better realize the concept and pursuit of highly effective and less toxic maintenance drugs.
Although these studies have some shortcomings in study design due to the use of placebo rather than delayed second-line therapy as a control, the benefits in survival time associated with the new treatment paradigm cannot be ignored. In the SATURN study, patients benefited from erlotinib maintenance therapy regardless of EGFR mutation. However, the benefit in PFS was about four times greater in mutant patients than in non-mutant patients, thus demonstrating the benefits of maintenance therapy in mutant patients. Possible reasons for the lack of positive results for overall survival in the mutation subgroup are the small sample size (only 49 patients) and the fact that approximately 65% of patients in the placebo group were treated with subsequent EGFR-TKIs.
Second-line TKIs treatment.
EGFR mutation screening increases the chances of winning
EGFR-TKI has become indisputable as the standard second- and third-line treatment for advanced non-small cell lung cancer after chemotherapy failure, but the need for EGFR mutation screening prior to TKI therapy has been a matter of debate among lung cancer scientists in recent years.
Unlike the strong predictive role of EGFR mutation testing in first-line TKI therapy, which has been confirmed by multiple prospective clinical studies, its role in second-line therapy has been variously reported, e.g., retrospective molecular markers from studies such as ISEL, BR21, and Trust did not show a correlation between EGFR mutations and TKI, but in the INTREST study, those with EGFR mutations treated with gefitinib had a better median PFS than the docetaxel chemotherapy group (7.0 months Vs 4.1 months, P=0.0012, HR=0.16), while the two treatments were similar in mutation-negative individuals (1.7 months Vs 2.6 months, P=0.125, HR=1.24).
Possible reasons for such inconsistency are that the molecular marker analyses in the above clinical studies of second-line EGFR-TKI treatment were retrospective, and EGFR mutation detection before second-line targeted therapy was mostly performed using biopsies or surgically resected specimens prior to first-line treatment. And does chemotherapy have any effect on EGFR mutation status? Are EGFR mutations in primary and metastatic sites consistent? This hot issue has received a lot of attention from lung cancer scientists in China and abroad.
Recently, more and more experts in China and abroad believe that the biological characteristics of tumors may have been changed after a series of treatments, and our study also shows that EGFR mutations tend to decrease after first-line chemotherapy. Therefore, only the tumor information obtained in real time before each treatment can reflect the tumor cell characteristics more accurately.
Conclusion
In conclusion, EGFR mutation is the most powerful predictor of first-line EGFR-TKI. Although the evidence for its predictive role in maintenance and second-line therapy has yet to be strengthened by evidence-based medicine, the results are beginning to emerge. The future direction will focus on prospective molecular selection-based maintenance and second-line therapy studies.