preface
Epidermal growth factor receptor (EGFR) mutation is the most common driver gene variant in non-small cell lung cancer (NSCLC), and the advent of molecularly targeted drugs represented by EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has brought great changes to the diagnosis and treatment of NSCLC and opened the era of targeted therapy for lung cancer. At present, EGFR-TKI has been widely used in clinical practice, and the combination regimen based on EGFR-TKI has become an important direction for EGFR-mutant NSCLC to seek a breakthrough in efficacy. Among them, the EGFR-TKI combined with chemotherapy model has taken the lead in confirming the clinical benefits of the targeted combination regimen, and the treatment of EGFR-mutant advanced NSCLC is steadily entering a new era of "EGFR-TKI+".
Focusing on clinical practice, the wave of EGFR-TKI combination therapy has begun
The successful development and clinical application of EGFR-TKI have fundamentally changed the treatment model of EGFR-sensitive mutations in advanced NSCLC, and the prognosis of patients has been significantly improved, and it has become the standard treatment for this part of patients. With the continuous development and continuous advancement of targeted drug research and development, EGFR-TKI has been iterated to three generations, and the overall efficacy of patients with EGFR-mutant NSCLC is continuously improving. However, considering the strong tumor heterogeneity of EGFR-mutant NSCLC, a single treatment modality may not cover all tumor cell types, so the exploration of EGFR-TKI combination therapy regimen is the only way to further improve the efficacy.
As one of the traditional treatments for lung cancer, chemotherapy still plays an important role in the treatment of advanced NSCLC. Previous studies have suggested that EGFR-TKI combined with chemotherapy has a synergistic mechanism that can up-regulate EGFR protein expression and modulate signal transduction in tumor cells, thereby improving the targeting and sensitivity of EGFR-TKI[1]. Other studies suggest that tumor cells with high expression of EGFR protein are relatively sensitive to chemotherapy, and tumor resistance to chemotherapy is mainly related to the downregulation of growth signaling, and EGFR-TKI can effectively inhibit chemotherapy-mediated DNA damage repair and maintain the concentration of chemotherapy drugs in cells, ultimately promoting and maintaining chemotherapy-induced apoptosis of tumor cells [2]. The above basic studies suggest that EGFR-TKI combined with chemotherapy may be an effective treatment strategy that can improve prognosis.
Based on evidence, EGFR-TKI combined with chemotherapy breaks through existing standards
A randomized controlled study explored the efficacy of icotinib plus chemotherapy versus icotinib monotherapy in patients with previously untreated EGFR-sensitive mutations (Ex19del/L858R) in advanced NSCLC, with the primary endpoint being progression-free survival (PFS). The results showed that PFS was significantly longer in the combination group than in the single-agent group (16.0 months vs. 16.0 months). 10.0 months; HR=0.59 [95% CI 0.42-0.84]，P = 0.003）。 Unfortunately, there was no significant difference in overall survival (OS) between the two groups (36.0 months vs. 36.0 months). 34.0 months; HR=0.81 [95%CI 0.54-1.22]，P = 0.309）[3]。 Icotinib combined with chemotherapy did not prolong the survival time of patients. In addition, the exploration of second-generation EGFR-TKI combined with chemotherapy is limited, and there is no reference evidence.
Under the wave of EGFR-TKI combination therapy, the world's first international multicenter, open-label, randomized phase III clinical study to explore the first-line treatment of EGFR-sensitive mutation (Ex19del/L858R) in the first-line treatment of advanced NSCLC with EGFR-sensitive mutation (Ex19del/L858R), FLAURA2 was born, evaluating the efficacy and safety of osimertinib in combination with platinum-containing chemotherapy compared with osimertinib alone as the first-line treatment for EGFR-sensitive mutations in advanced NSCLC[4]. The results of the study showed that both investigator-assessed (25.5 months vs. 16.7 months; HR = 0.62 [95% CI 0.49-0.79], P<0.0001) or blinded independent central review (BICR) assessment (29.4 months vs. 19.9 months; HR=0.62 [95% CI 0.48-0.80], P=0.0002), osimertinib plus chemotherapy was associated with a significant improvement in PFS benefit and a 38% reduction in the risk of disease progression or death compared with osimertinib alone[4]. OS in the study was not mature (maturity 41%), and the latest reported OS data showed an encouraging trend in OS benefit observed with osimertinib plus chemotherapy compared with osimertinib alone in the first-line line (NR vs. 36.7 months; HR=0.75 [95% CI 0.57-0.97]）[5]。
Figure 1. Population-wide PFS analysis in FLAURA2 study (A. Investigator assessment; B. BICR Assessment)
In addition, FLAURA2 study analyzed the benefits of different subgroups, especially patients with L858R mutations and central nervous system (CNS) metastases that are clinically challenging. The results showed that osimertinib plus chemotherapy was significantly more effective than osimertinib monotherapy in the L858R mutant subgroup (24.7 months vs. 13.9 months; HR = 0.63 [95% CI 0.44-0.90]) and the baseline with CNS metastases subgroup (24.9 months vs. 13.8 months; HR = 0.47 [95% CI 0.33-0.66]) [4]. In the CNS metastasis subgroup, the median CNS PFS was 30.2 months vs. 27.6 months (HR=0.58 [95% CI 0.33-1.01], P=0.0548), respectively, and the CR (complete response) rate was as high as 59% in the combination therapy group, which provides a new treatment idea for the breakthrough of current clinical difficulties [6]. Notably, Chinese cohort data from the FLAURA2 study showed that osimertinib plus chemotherapy was also effective in improving PFS compared with osimertinib monotherapy in the first-line line (investigator assessment: 27.4 months vs. 22.3 months, HR = 0.56 [95% CI 0.34-0.92]; BICR assessment: 33.2 versus 22.0 months, HR=0.58 [95% CI 0.34-1.01]), which is more practical for domestic clinical guidance [7].
Figure 2. PFS analysis of the L858R mutation subgroup and the CNS metastasis subgroup was investigated FLAURA2
Figure 3. PFS analysis of the Chinese cohort was studied FLAURA2
In addition to osimertinib, the domestic third-generation EGFR-TKI combined chemotherapy regimen has also achieved preliminary results in the first-line treatment of advanced NSCLC with EGFR-sensitive mutations. A single-arm, single-center, phase II study explored the efficacy of ametinib in combination with chemotherapy in the first-line treatment of EGFR-sensitive mutant NSCLC, with the primary endpoint of PFS. In a preliminary analysis, median PFS was not reached in the overall population, with an objective response rate (ORR) of 88.2 percent and an ORR of 89.4 percent in the subgroup with CNS metastases at baseline [8]. At present, only a small sample of phase II clinical study data has been published for the third-generation EGFR-TKI in China, and there is no phase III clinical study to verify it. Overall, however, this evidence suggests that third-generation EGFR-TKIs combined with chemotherapy may be the preferred first-line treatment for patients with EGFR-mutated advanced NSCLC with a poor prognosis.
In practice, EGFR-TKI combined with chemotherapy meets clinical needs
The first-line foundation of EGFR-TKI was established, and the efficacy of EGFR-TKI combined with chemotherapy was further upgraded. At present, EGFR-TKI combined chemotherapy regimen has been written into authoritative guidelines at home and abroad, and has become an important choice for the first-line treatment of advanced NSCLC with EGFR-sensitive mutations. Especially for certain subsets of patients, such as brain metastases and L858R mutation populations, the combination chemotherapy may bring greater clinical benefit, and this result deserves special attention. In addition, in terms of safety, even though combination therapy will increase the occurrence of adverse reactions to a certain extent, it does not significantly increase the difficulty in management and treatment, and there are relatively mature clinical treatment strategies for chemotherapy-related reactions. The key is to develop the most suitable and individualized treatment plan for the specific situation of the patient. EGFR-TKI combination chemotherapy regimens may be considered for patients who are medically well, have a need for treatment, and can tolerate combination chemotherapy, especially those with brain metastases or L858R mutations.
The first-line treatment of EGFR-TKI combined with chemotherapy has achieved a phased victory, EGFR-mutated advanced NSCLC has ushered in a more effective treatment regimen, and the exploration of other third-generation EGFR-TKI combined chemotherapy and different combination modes has also begun. In the future, EGFR-TKI combination therapy will further develop to be precise and individualized, so as to meet the treatment needs of different types of patients to a greater extent and continue to improve the clinical benefits of patients. We look forward to more evidence of combination therapy in the field of EGFR-mutant NSCLC, helping patients achieve longer survival and fully enter the new era of "EGFR-TKI+"!
Bibliography:
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2.Zhou J, Qin H, Miao J, et al. Efficacy observation and prognosis analysis of EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy in advanced lung adenocarcinoma with EGFR Exon 19 Deletion, Exon 21 L858R mutation: A historical cohort study. Medicine (Baltimore). 2023 Jun 30; 102(26):e34110.
3.Xu L, Qi Q, Zhang Y, et al. Combination of icotinib and chemotherapy as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A randomized controlled study. Lung Cancer. 2019 Jul;133:23-31.
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5.Natalia Isabel Valdiviezo Lama, et al. First-line (1L) osimertinib (osi) ± platinum-pemetrexed in EGFR-mutated (EGFRm) advanced NSCLC: FLAURA2 post-progression outcomes. 2024 ELCC. Abstract 4O.
6.Jänne PA, Planchard D, Kobayashi K, et al. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2024 Mar 1; 42(7):808-820.
7.Planchard D, Jänne PA, Cheng Y, et al. First-line (1L) osimertinib (osi) ± platinum-pemetrexed in patients (pts) with EGFRm advanced NSCLC: FLAURA2 China cohort. 2023 ESMO Asia. Abstract 562P.
8.Y Li, ZY Pan,Y Zhang, et al. Aumolertinib Plus Chemotherapy as 1st Line Treatment in Advanced Lung Cancer EGFR Mutation and ctDNA Cleared Analysis. 2022 WCLC. EP08.02-003.
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Expiration Date: 2024-09-30
Edited by Ari
Reviewer: Ari
Typesetting: KIKI
Executive: Babel
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