Editor's note: At present, EGFR-TKIs have significantly improved the treatment landscape of patients with EGFR-sensitive mutations in advanced NSCLC, and EGFR-TKIs monotherapy has become the first-line standard of choice for patients with EGFR-mutated advanced NSCLC. However, with the improvement of genetic testing technologies such as next-generation sequencing (NGS), more and more patients with mutations in other genes than EGFR are being detected. At present, there is some controversy about the treatment of patients with EGFR co-mutation NSCLC, and the guidelines do not make standardized recommendations for the treatment of patients with EGFR-positive co-mutations. Studies have shown that some EGFR co-mutations have an important impact on the biological behavior of lung cancer, and have a significant impact on the efficacy of EGFR-TKI monotherapy, and the treatment selection of EGFR-positive patients with co-mutated NSCLC is still a difficult problem in clinical practice.
Professor Li Gaofeng from Yunnan Hospital, Peking University Cancer Hospital, is the executive editor-in-chief of this issue of "Expert Group Draft", and Dr. Luo Xiangchong, Department of Cardiothoracic Surgery, Qujing Second People's Hospital, shared the "Most Complete Summary of First-line Treatment Strategies for Patients with Advanced NSCLC with EGFR Gene Co-mutations", providing more references for doctors and patients.
About the Speaker
Li Gaofeng
Vice President of Yunnan Hospital, Peking University Cancer Hospital (Yunnan Provincial Cancer Hospital, Third Affiliated Hospital of Kunming Medical University).
Doctoral supervisor, postdoctoral cooperative supervisor, second-level professor, chief physician
Yunnan Health Guard, Provincial Association for Science and Technology Outstanding Society Worker
President of Yunnan Translational Medicine Society
Vice Chairman of Yunnan Anti-Cancer Association
Chairman of the Thoracic and Cardiovascular Surgery Branch of Yunnan Medical Association
Chairman of the Minimally Invasive Treatment Committee of Thoracic Tumors of Yunnan Anti-Cancer Association
Executive Director of Yunnan Preventive Medicine Association and Chairman of Lung Cancer Professional Committee
Member of the International Association for the Study of Lung Cancer
He is a member of the Standing Committee of the Mediastinal Tumor Professional Committee of the Chinese Anti-Cancer Association
Member of the Thoracoscopic Surgery Group of the Thoracic and Cardiovascular Surgery Branch of the Chinese Medical Association
Member of the Working Committee of the Medical Consortium of the Chinese Hospital Association
Member of the National Lung Cancer MDT Expert Committee
National outstanding scientific and technological worker, expert enjoying special allowance of the State Council
Winner of the National May Day Labor Medal, Yunnan Provincial Medical Leading Talent, Yunling Famous Doctor
Yunnan Province has outstanding professional and technical personnel with outstanding contributions and experts contacted by the provincial party committee
Luo Xiangchong
Department of Cardiothoracic Surgery, Qujing Second People's Hospital, Master's Degree Candidate, Attending Physician
Member of the Thoracic Tumor Branch of Yunnan Translational Medical Association
Member of Yunnan Provincial Lung Cancer Precision Treatment Committee
Member of the Lung Cancer Professional Committee of Yunnan Preventive Medicine Association
As the first author, he has published 24 papers, including 2 SCIs, 8 core papers of Chinese Peking University, 10 core articles of science and technology, participated in the compilation of 1 book, and presided over 3 scientific research projects.
Title: The most complete summary of first-line treatment strategies for patients with advanced NSCLC with EGFR gene co-mutations
◾ Author: Luo Xiangchong
◾ Executive Editor-in-Chief: Li Gaofeng
1. EGFR and TP53 co-mutations
The TP53 gene is a tumor suppressor gene located on the short arm of chromosome 17, 17p13.1, which is involved in regulating DNA damage and repair, inducing apoptosis and senescence, and inhibiting the occurrence and development of tumors and tumor vascularization[1]. In NSCLC patients, TP53 mutation is the most common type of EGFR co-mutation, and TP53 co-mutation can be detected in about 50%~65% of EGFR mutation-positive patients. Mutations in TP53 include missense, silencing, frame switching (insertion and deletion), and nonsense, among which missense mutations are the most common type of TP53 mutations, which occur mostly in exons 5-8 [2] (Figure 1). TP53 mutations differ among different types of EGFR mutations, with TP53 exon 5 mutations commonly occurring in patients with EGFR exon 21 L861Q and TP53 exon 7 mutations occurring in patients with EGFR exon 19del [3].
Figure 1[2] :( ATP53 mutation plot and (B) distribution of EGFR mutation sites in patients with co-mutations
Studies have shown [4] that patients with EGFR-positive NSCLC with TP53 mutations show shorter PFS and OS compared with TP53 wild-type, and reduce the efficacy and poor prognosis of patients with NSCLC treated with EGFR-TKIs (Figure 2). The reasons for the poor response of EGFR and TP53 co-mutation targeted therapy are the susceptibility to small cell lung cancer (SCLC) transformation and the occurrence of acquired resistance to EGFR-TKIs [5].
Figure 2[4]: PFS and OS treated with EGFR-TKIs in patients with EGFR/TP53 co-mutations
The study found that the preferred treatment strategy for NSCLC patients with EGFR and TP53 co-mutations is combination therapy rather than single-agent EGFR-TKI therapy. Combination therapy strategies can be selected as follows:
(1) Targeted combination chemotherapy: The amazing data based on FLAURA2 studies confirm that osimertinib combined with chemotherapy is significantly better than single-agent osimertinib in the treatment of patients with EGFR-sensitive mutations in advanced NSCLC, which brings enlightenment for the exploration of targeted therapy with co-mutation and poor prognosis. In a retrospective study of 95 patients with EGFR/TP53 co-mutations [6], EGFR-TKIs combined with chemotherapy significantly improved ORR and TTP in patients with advanced NSCLC with EGFR/TP53 co-mutations compared with EGFR-TKIs alone, with ORR and TTP of 55.9% and 34.4% in the combination therapy group and EGFR-TKIs alone group (P<0.05) and 16.1 and 11.1 months, respectively (P). <0.05）。 At the same time, a number of similar clinical studies have verified that EGFR-TKIs combined with chemotherapy can significantly improve the clinical benefits of patients with EGFR and TP53 co-mutations, and targeted combination chemotherapy can be used as a potential treatment option for patients with EGFR and TP53 co-mutations [7-8].
(2) Targeted combination anti-angiogenic drugs: The ACTIVE study confirmed that apatinib + gefitinib can improve PFS in patients with EGFR and TP53 co-mutations[9]; In the RELAY study, ramucirumab + erlotinib was shown to improve PFS and DOR in patients with EGFR and TP53 comutations [10]; In the ALTER-L004 study, icotinib + anlotinib was demonstrated to improve ORR and DCR in patients with EGFR and TP53 comutations[11]. It can be seen that targeted combination anti-angiogenic drugs are expected to become a new choice for the treatment of patients with EGFR and TP53 co-mutations, and it is also a direction that needs to be explored in the future.
(3) Immunotherapy: Studies have shown that tumors with TP53 mutations significantly overexpress PD-L1, and tumor mutational burden (TMB) and copy number variant burden (CNA) are both increased, and overexpression of PD-L1 and EGFR is significantly associated with TP53 co-mutations, while EGFR mutations alone are not associated with high PD-L1 expression, which explains why patients with advanced NSCLC with EGFR mutations alone respond poorly to immunotherapy, while EGFR/ Patients with TP53 co-mutations may benefit from anti-PD-1/PD-L1 therapy. Several clinical studies have also shown that patients with NSCLC with EGFR/TP53 co-mutations can benefit from immunotherapy [12].
二、EGFR与PIK3CA共突变
The PIK3CA gene is located on chromosome 3q26.3 and contains 20 exons, and its mutations can activate the downstream PI3K/AKT/mTOR signaling pathway and mediate the occurrence and development of lung cancer. Studies have shown [13-14] that the mutation probability of PIK3CA in NSCLC is about 2-5%, and the mutation probability of lung squamous cell carcinoma is greater than that of lung adenocarcinoma. PIK3CA mutations occur primarily in exon 9 (E545K, E545Q, E545G, E545A, Q546R, E542K, and T536I) and exon 20 (H1047R, H1047L, M1043L, G1007R, and Y1021C) (Figure 3), with E545K and H1047R being the most common mutation sites. It has been demonstrated that PIK3CA mutations often coexist with mutations in other oncogenic drivers, particularly EGFR and KRAS, in NSCLC, with a co-mutation probability of approximately 3.5 percent [13].
Figure 3 [14] :(A) distribution of PIK3CA mutation and (B) EGFR mutation sites in patients with co-mutations
Notably, PIK3CA mutations have been shown to be one of the mechanisms leading to resistance to EGFR-TKIs in lung cancer patients. Multiple retrospective studies [14-15] have shown that NSCLC patients with EGFR and PIK3CA co-mutations are treated with EGFR-TKIs with shorter PFS and OS and a worse prognosis compared with EGFR single mutations (Fig. 4), but there is still a lack of prospective clinical confirmation in large samples.
Figure 4 [14]: TTP and OS in patients with EGFR/PIK3CA co-mutations treated with EGFR-TKIs
Based on the available evidence, the treatment strategy for patients with NSCLC with EGFR/PIK3CA comutations is as follows:
(1) Targeted combination chemotherapy: The combination of EGFR-TKIs and chemotherapy may produce synergistic effects through different pathways to delay drug resistance, which has been confirmed in retrospective studies [16] that osimertinib in combination with chemotherapy can significantly improve PFS in patients with EGFR/PIK3CA co-mutated advanced NSCLC compared with osimertinib alone.
(2) Targeted combination PI3K/AKT/mTOR signaling pathway inhibitors: Theoretically, EGFR inhibitors hinder EGFR activity, while PI3K/AKT/mTOR pathway inhibitors act on the PI3K/AKT/mTOR pathway, and these pathways may collaborate in inhibiting tumor cell proliferation, overcoming drug resistance faced by a single target, and prolonging OS. At present, EGFR-TKIs are combined with PI3K inhibitors such as erlotinib + LY294002, erlotinib + BKM120, erlotinib + pilaralisib; EGFR-TKIs in combination with AKT inhibitors such as erlotinib + MK-2206; EGFR-TKIs in combination with mTOR inhibitors such as EGFR-TKIs + Everolimus; Clinical studies of EGFR-TKIs combined with PI3K/mTOR dual inhibitors, such as erlotinib + XL765, are still in the exploratory stage, and follow-up results are expected.
(3) Targeted combination anti-angiogenic drugs: The RELAY study confirmed that ramucirumab + erlotinib can improve the PFS of patients with EGFR/PIK3CA co-mutations, but EGFR-TKIs combined with anlotinib or apatinib in the treatment of EGFR/PIK3CA co-synthetical NSCLC are only individual cases, and the cases are limited and need to be further explored.
3. Co-mutation of EGFR and ALK
Studies have shown that the total number of ALK-rearranged NSCLC is about 3%~5%, and mediates the proliferation, migration, and metastasis of lung cancer by activating downstream signals such as Ras/MAPK, PI3K/AKT, and JAK/STAT pathways. Early studies have found that the occurrence of EGFR mutations and ALK rearrangements are mutually exclusive, but with the improvement of detection technology, the incidence of NSCLC patients with EGFR/ALK rearrangement co-mutations is about 0.45%~1.6%, accounting for 3.9%~13.6% of EGFR mutations, and 15.4%~18.8% of ALK rearrangements [3], among which the incidence of EML4-ALK/EGFR co-mutations in patients is lower than that in patients with non-EML4-ALK/EGFR co-mutations[17]。
At present, the molecular mechanism of EGFR/ALK co-mutation has not been clearly studied, and it is believed that the tumor tissue of patients with EGFR/ALK co-mutation is highly heterogeneous, that is, the two mutations can occur in different tumor cells or in the same tumor cell. Given the available evidence, the treatment strategies for patients with NSCLC with EGFR/ALK co-mutations are as follows:
(1) Sequential treatment with single-agent targeted agents: Some studies have shown that EGFR-TKIs are superior to ALK-TKIs in the first-line treatment of NSCLC patients with EGFR/ALK comutations [18-20] (Fig. 5); Other studies have shown that ALK-TKIs are superior to EGFR-TKIs in the first-line treatment of patients with EGFR/ALK co-mutated NSCLC [21] (Fig. 6), so there is a lack of consensus on how to choose a first-line regimen. Based on the existence of tumor heterogeneity, the treatment regimen can be selected according to the detection of the abundance of EGFR and ALK gene mutations and the level of EGFR and ALK phosphorylation, that is, ALK-TKIs are preferred for patients with low abundance of EGFR, and EGFR-TKIs are preferred for patients with high abundance of EGFR; The level of EGFR phosphorylation was higher than that of EGFR-TKIs preferred in ALK phosphorylated patients, and the level of EGFR phosphorylation was lower than that preferred ALK-TKIs in ALK phosphorylated patients. Sequential treatment with two targeted agents is optimal, with EGFR-TKIs/ALK-TKIs being selected for first-line resistance before another targeted agent is selected [22].
(2) Simultaneous treatment of dual-targeted drugs: Theoretically, EGFR-TKIs and ALK-TKIs can be used at the same time for the first-line treatment of NSCLC patients with EGFR/ALK co-mutations, but considering the superposition of adverse drug reactions and drug economy, the simultaneous use of the two targeted drugs should be carefully considered.
Figure 5 [20]: EGFR-TKIs are superior to ALK-TKIs in the first-line treatment of NSCLC patients with EGFR/ALK co-mutations
Figure 6 [21]: ALK-TKIs are superior to EGFR-TKIs in the first-line treatment of NSCLC patients with EGFR/ALK co-mutations
4. EGFR and KRAS co-mutations
KRAS is the most common oncogene in RAS genotype, and when the KRAS gene is mutated, it can continuously activate the downstream PI3K-AKT-mTOR and Ras-Raf-MEK-ERK signaling pathways to mediate the proliferation, invasion and metastasis of tumor cells, and promote the occurrence and development of tumors. KRAS mutations are present in 32 percent of lung adenocarcinomas and 4 percent of squamous cell lung cancers, with the most common KRAS mutation site being KRASG12C, accounting for 40 percent of all KRAS mutations, along with G12D, G12V, G12A, G12R, and G12S [23]. It is generally believed that KRAS and EGFR mutations are mutually exclusive, but 5.8%~35.8% of NSCLC patients have EGFR/KRAS co-mutations [24].
EGFR-TKIs can undoubtedly be selected for EGFR mutations, and the targeted therapy of KRAS mutations is still the bottleneck of current treatment, whether it is ASCO, ESMO or CSCO, the research of KRAS inhibitors is still the star of KRAS targets. Previous studies have shown that KRAS mutations reduce the sensitivity of EGFR-TKIs, thereby reducing PFS and OS [25], and it is foreseeable that combination therapy will be the best strategy in the future.
Based on current drug availability and evidence, the treatment strategies for patients with NSCLC with EGFR/KRAS co-mutations are as follows:
(1) Single-agent targeted therapy: In view of the availability of drugs, single-agent EGFR-TKIs can be selected first, and some patients can still benefit from EGFR-TKIs, and if there is progression, then consider late-line therapy such as KRAS inhibitors or immune checkpoint inhibitors combined with anti-angiogenic drugs + chemotherapy.
(2) Dual-target therapy: If the target of the KRAS mutation is G12C, the corresponding inhibitors such as Sotorasib (AM510) and Adagrasib (MRTX849) have achieved good efficacy. At the 2024 ASCO Annual Meeting, the phase II clinical study of the KRASG12C inhibitor fulzerasib (GFH925) combined with the EGFR inhibitor cetuximab in the first-line treatment of NSCLC obtained 80% ORR and 100% DCR [26], suggesting that KRAS inhibitor combined with EGFR inhibitor for EGFR/ Feasibility in patients with KRAS co-mutated NSCLC.
5. EGFR and MET amplification co-mutations
Abnormalities in the MET gene can activate the downstream signaling pathways RAS/RAF/MAP and PI3K/AKT/mTOR to lead to the proliferation, migration and invasion of tumor cells, and the abnormalities of the MET gene mainly include: MET14 exon skipping protrusion, MET amplification and MET fusion. MET amplification refers to the increase in copy number of MET genes, including polysomy and local amplification, which can be used as both primary and secondary driver genes, and secondary MET amplification has been recognized as one of the common mechanisms of acquired resistance to EGFR-TKIs. Data show that primary MET gene amplification accounts for 1%~5% of NSCLC, while the probability of EGFR/MET amplification co-mutation is about 3% [27].
EGFR/MET amplification co-mutations have been shown to reduce the sensitivity of EGFR-TKIs treatment, and MET amplification can mediate the development of resistance to EGFR-TKIs by activating the bypass pathway, and an effective strategy to overcome this resistance is EGFR-TKIs in combination with MET-TKIs.
Current evidence suggests that the treatment strategy for patients with EGFR/MET-amplified co-mutations in NSCLC is EGFR-TKIs in combination with MET-TKIs. In a retrospective study [28], EGFR-TKIs in combination with crizotinib showed promising efficacy in patients with EGFR/MET-amplified coherent NSCLC. Osimertinib in combination with savolitinib has also shown amazing efficacy in the treatment of patients with EGFR/MET-amplified sympathetic NSCLC, and the FLOWERS study and SANOVO study are also underway to explore the efficacy of osimertinib in combination with savolitinib in patients with EGFR and primary MET-amplified NSCLC, and look forward to follow-up results.
6. Co-mutation of EGFR and PTEN
When the protein level is down-regulated, heterozygosity loss and epigenetic silencing lead to the inactivation of PTEN protein and activate the PI3K/AKT signaling pathway to promote the proliferation of tumor cells. The probability of PTEN deletion occurring in NSCLC accounts for more than 40%, and co-mutations of EGFR gene and PTEN deletion are rare, and there are still countless statistics.
PTEN deficiency has been shown to be associated with poor clinical prognosis and to reduce the sensitivity of EGFR-TKIs [29]. It has been found that patients with EGFR mutations and PTEN deletion have shorter PFS and OS than patients with EGFR mutations alone, and PTEN deletion and low PTEN protein expression are independent factors influencing the poor prognosis of EGFR-TKIs [30] (Fig. 7). However, high PTEN expression levels are associated with prolonged OS [31].
Figure 7 [30]: PFS and OS in patients with EGFR/PTEN deletion co-mutations treated with EGFR-TKIs
At present, due to the lack of case reports, retrospective analysis and evidence support from prospective clinical studies, it is difficult to make a better choice of regimen for patients with EGFR/PTEN co-mutations.
summary
In summary, when exploring the optimal regimen for EGFR co-mutation populations, different EGFR co-mutation populations should understand that the use of different treatment strategies such as single-target therapy, targeted combination chemotherapy, targeted combination anti-angiogenic drugs, dual-target sequential therapy, and dual-target simultaneous therapy should not be limited to EGFR-TKIs and shorten the PFS and OS of patients. On this basis, the mechanism of combination therapy and how to screen the dominant population should be further explored, and the treatment of different methods should not be superimposed indiscriminately, which will affect the efficacy and increase the side effects and reduce the clinical benefit of patients.
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